Azathioprine is a prodrug that is metabolized to the active compound 6-mercaptopurine. It inhibits purine synthesis and impairs DNA synthesis.

It has been listed in the WHO's list of essential medicine

It is used for the treatment of the following conditions:

• As adjunctive therapy for the prevention of kidney transplant rejection. (It is not recommended as a first-line of therapy. The KDIGO guidelines recommend a calcineurin inhibitor and anti-proliferative drugs like mycophenolate mofetil).

• For the treatment of active Rheumatoid arthritis

• Off Label Uses Of Azathioprine in Adults include:

  • Management of Crohn disease (after surgical resection);

  • For the maintenance of Crohn disease

  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

  • Autoimmune hepatitis

  • Chronic immune thrombocytopenic purpura

  • For the maintenance therapy of lupus nephritis

  • Multiple sclerosis

  • Myasthenia gravis

  • Recurrent Pericarditis

  • Psoriasis

  • Uveitis

  • As adjunctive treatment in the prevention of rejection of solid organ nonrenal transplants

  • Ulcerative colitis

  • Dermatomyositis and polymyositis

  • Erythema multiforme

  • Pemphigus Vulgaris

Azathioprine Dose in Adults

Off Label use in the treatment of Crohn disease (after surgical resection):

• Monotherapy:
  • 2 - 2.5 mg/kg/day orally
  • Treatment should begin within 2 - 4 weeks after surgery and continued for 12 - 24 months.
• Combination therapy ( with metronidazole):
  • 100 mg orally daily in patients weighing less than 60 kgs or
  • 150 mg orally daily in patients weighing more than 60 kg for up to 52 weeks or
  • 2 mg/kg/day orally for 18 months after surgery.

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Off Label Use for maintenance therapy in patients with Crohn disease:

• 0.5 - 2.5 mg/kg/day orally in combination with an anti-TNF agent like adalimumab or infliximab.

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Off label use as adjunctive therapy in the treatment of Dermatomyositis and polymyositis:

• 50 mg/day orally with prednisone.
• The dose may be increased by 50 mg/week to a total dose of 2 - 3 mg/kg/day.
• The maximum effects may take 3 - 6 months.

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Off label use in the treatment of Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome):

• 2 mg/kg/day orally for 6 months.

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Off label use in the treatment of autoimmune Hepatitis:

• 1 mg/kg/day oral or intravenous in combination with corticosteroids.
• The dose may be increased to 2 mg/kg/day in patients who do not respond to therapy or relapse.
• Patients who achieve complete remission for at least one year may be continued on azathioprine without corticosteroids at a dose of 2 mg/kg/day.

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Off label use in the treatment of chronic immune thrombocytopenic purpura (in patients who are refractory or relapse):

• 1 - 2 mg/kg/day orally to a maximum dose of 150 mg/day.
• The initial response is usually observed at 30 - 90 days.
• It may take up to 6 months for the peak response.

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Dose in the maintenance therapy of Lupus nephritis (as off-label use):

• 2 mg/kg/day orally.
• The dose may be reduced to 1.5 mg/kg/day after one month (if the creatinine is stable and 24-hour urinary proteins estimation drops to less than 1 gms)
• The target dose is 2 mg/kg/day
• The dose should be reduced in pregnant patients to less than 2 mg/kg/day.

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Dose in the treatment of multiple sclerosis (Off label use):

• 2 - 3 mg/kg/day orally.

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Dose in the treatment of Myasthenia gravis (off-label):

• Symptomatic patients despite pyridostigmine therapy:
  • 50 mg/day orally.
  • The dose may be increased by 50 mg increments every 1 - 2 weeks to a target dose of 2.5 - 3 mg/kg/day.
  • It may be added to glucocorticoids or pyridostigmine or may be used as monotherapy.
  • The clinical response may take up to one year.
  • The maximum effect may take up to 1 - 2 years.

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Dose in the treatment of recurrent Pericarditis (off-label use):

• 150 mg orally once a day for 2 - 3 months.
• The dose may be increased to 100 mg once a day to suppress the clinical symptoms.

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Dose in the treatment of Psoriasis (off-label):

• 0.5 mg/kg/day orally
• The dose may be increased by 0.5 mg/kg/day every four weeks (if no cytopenias are observed after 6 - 8 weeks of therapy) until clinical response.
• The usual dose is 75 - 150 mg/ day.

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Dose of Azathioprine in Renal transplantation:

• 3 - 5 mg/kg once a day orally or intravenous as initial therapy following transplant, then 1 - 3 mg/kg once a day to the usual dose of 50 - 150 mg/day.
• Pregnant patients should be advised less than 2 mg/kg/day.

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Dose in the treatment of Rheumatoid arthritis:

• 1 mg/kg/day orally once a day or in two divided doses initially.
• The dose is increased (after 6 - 8 weeks) by 0.5 mg/kg every four weeks up to 2.5 mg/kg/day or clinical response for a minimum of 12 weeks.
• Maintenance dose:
  • The dose is reduced by 0.5 mg/kg (25 mg per day) every four weeks until the lowest effective dose is reached.
  • The optimum duration has not been specified. Furthermore, therapy may be discontinued abruptly.
• Pregnant patients should be advised a lower dose i.e. less than 2 mg/kg/day.

Intravenous azathioprine:

Note: Intravenous formulation is only indicated in patients who can not tolerate oral medications. Oral therapy should be resumed as soon as the patient can tolerate.

• 1 mg/kg/day (50 - 100 mg) given once a day or in two divided doses initially.
• The dose may be increased after 6 - 8 weeks by 0.5 mg/kg every four weeks until clinical response or up to a maximum dose of 2.5 mg/kg/day for a minimum of 12 weeks.
• The dose should be reduced by 0.5 mg/kg (25 mg per day) every four weeks until the lowest effective dose is reached.
• The optimum duration is not specified. Therapy may be abruptly discontinued.

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For the maintenance therapy of ulcerative colitis (Off label use as steroid-sparing agent):

• 0.5 - 2.5 mg/kg/day orally.

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Dose in the treatment of Uveitis (Off-label use):

• 2 - 3 mg/kg/day orally given either as monotherapy or in conjunction with other immunosuppressants or corticosteroids.

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Dosage adjustment for TPMT or NUDT15 deficiency:

• Heterozygous deficiency (intermediate activity):
  • Individuals with a known heterozygous deficiency of TPMT or NUDT15 should be advised a lower initial dose (30% - 70% of the target dose based on tolerance)
• Homozygous deficiency:
  • Patients with a homozygous deficiency of TMPT or NUDT15 should not be advised azathioprine.
  • If treatment can not be avoided, the daily dose should be reduced by 10 times and administered three times a week.

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Dosage adjustment for concomitant use with allopurinol:

• The dose should be reduced to 1/3 or 1/4 in patients with concomitant allopurinol use.

Azathioprine Dose in Children

Dose in the treatment of autoimmune Hepatitis: 

• Children and Adolescents:
  • 0.5 mg/kg/dose orally once a day initially.
  • titrate the dose as needed up to 2 mg/kg/dose once a day.
  • Some patients may respond to a low-dose of 1 - 1.5 mg/kg/day as maintenance therapy.

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Dose in the treatment of Inflammatory bowel disease: 

• Infants, Children, and Adolescents:
  • 2 - 2.5 mg/kg/dose orally once a day.
  • The usual reported dosage range is 1 - 3 mg/kg/dose ( the maximum dose is 4 mg/kg/day or 200 mg/day).

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Dose in the treatment of chronic refractory Immune thrombocytopenia (ITP):

• Children older than 2 years and Adolescents:
  • 2 - 2.5 mg/kg/day orally for maintenance therapy.

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Dose in Juvenile-idiopathic arthritis (rheumatoid arthritis):

• Children and Adolescents:
  • 2 - 2.5 mg/kg/dose orally once a day.
  • A minimum of 12 weeks is required for a full therapeutic response.

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Dose in the treatment of mild Lupus nephritis: 

• Children and Adolescents:
  • 2 - 2.5 mg/kg/dose orally once a day.

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Dose in the treatment of juvenile Myasthenia gravis:

• Children and Adolescents:
  • 1 - 3 mg/kg/dose orally once a day.

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Dose in Solid Organ Transplantation:

• Infants, Children, and Adolescents:
  • 3 - 5 mg/kg/dose orally once a day initiated at the time of transplant.
  • The maintenance dose is 1 - 3 mg/kg/dose once a day.

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Dose in the treatment JIA-associated Uveitis: 

• Children and Adolescents:
  • 2.4 mg/kg/dose orally once a day as an initial dose.
  • The reported dosage range is 1.4 - 3.2 mg/kg/dose once a day.

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Dosage adjustment for concomitant use with allopurinol:

• Reduce azathioprine dose to 1/3 rd or 1/4 th the usual dose when used with allopurinol.

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Dosage adjustment for toxicity:

• Azathioprine should be withheld or the dose reduced if the patient develops a rapid decrease in the WBC count, have persistently low WBC count, or develop a serious infection:
• Patients who develop severe drug-related toxicity ( in renal transplant patients) like hepatic sinusoidal obstruction syndrome may require discontinuation of therapy.

Pregnancy Risk Factor D

• Azathioprine crosses over to the placenta.
• Pregnant women have experienced adverse fetal and maternal outcomes.
• Negative fetal effects include:
  • Congenital anomalies
  • Immunosuppression
  • Hematologic toxicities such as lymphopenia or pancytopenia can occur.
  • Intrauterine growth retardation
• After kidney transplant, preterm delivery and intrauterine retardation were also reported.
• It is compatible with pregnant patients who have had a kidney transplant at low doses (less that 2 mg/kg/day).
• Most experts consider it compatible for pregnant patients with rheumatoid-arthritis. However, the manufacturer suggests avoiding it.
• It is compatible in pregnant patients with Lupus Nephritis.
• Patients with inflammatory bowel diseases who are pregnant and on maintenance therapy can continue their treatment during pregnancy.
• Patients suffering from immune thrombocytopenic purpura need to be offered other therapies.
• Manufacturer recommends that pregnant women avoid azathioprine treatment and use effective contraception.

Azathioprine use during breastfeeding:​​​​​​​

• 6-mercaptopurine (6–MP), a metabolite from azathioprine, is excreted in breastmilk.
• It is not advised to breastfeed during azathioprine therapy due to the potential for immunosuppression, growth restriction and carcinogenesis in a breastfed baby.
• WHO also disapproves of breastfeeding during azathioprine treatment.
• Experts do not recommend stopping breastfeeding. They do recommend monitoring infants' blood count after two weeks.

Azathioprine Dose in Renal Disease:

• Adjustment in the dose has not been provided in the manufacturer's labeling.
• Patients with oliguria, particularly in post-transplant patients, should receive lower doses.

Alternative recommendations include:

• CrCl of more than 50 mL/minute:
  • Adjustment in the dose is not recommended.
• CrCl 10 - 50 mL/minute:
  • Administer 75% of normal dose.
• CrCl less than 10 mL/minute:
  • Administer half the usual dose.
• Hemodialysis:
  • Administer half the usual dose.
  • Supplemental dose of 0.25 mg/kg may be given post hemodialysis
• CRRT:
  • Administer 75% of the ususal dose.

Azathioprine Dose in Liver Disease:

 Adjustment in the dose has not been recommended by the manufacturer in patients with liver disease.

Side Effects of Azathioprine 

Frequency not defined:

• Central Nervous System:
  • Malaise
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Diarrhea
• Hematologic & Oncologic:
  • Leukopenia
  • Neoplasia
  • Thrombocytopenia
• Hepatic:
  • Hepatotoxicity
  • Increased serum alkaline phosphatase
  • Increased serum bilirubin
  • Increased serum transaminases
• Infection:
  • Increased susceptibility to infection
• Neuromuscular & skeletal:
  • Myalgia
• Miscellaneous:
  • Fever

Contraindication to Azathioprine Include:

• Allergy reactions to azathioprine and any component of the formulation
• Patients with RA may become pregnant

Warnings and Precautions

• GI toxicity:
  • Nausea and vomiting are common side effects of azathioprine in the gastro-intestinal tract.
  • It is possible to reduce these symptoms by diluting the dose and giving it after eating.
  • Patients can also experience diarrhea, rash and fever.
  • The majority of adverse side effects can be seen within the first few weeks of starting therapy. They are usually reversible once treatment is stopped.
• Hematologic toxicities:
  • Cytopenias can manifest as anemias, thrombocytopenias, or leukopenia.
  • Patients at higher risk for developing hematological toxicity need to be tested for Thiopurine methyltransferase genotyping or phenotyping, and nudix Hydrolase 15 (nucleotide dimphosphate [NUDT15]).
  • Monitor Blood CBC with differential count and platelets once a weeks during the first month.
  • Then, twice a monthly for two months. Finally, monthly or as indicated.
  • Hematological toxicities can lead to patients needing to be reduced in therapy, stopped or discontinued.
  • Leukopenia does not indicate therapeutic efficacy. The dose should not be increased to decrease the white cell count.
• Hepatotoxicity:
  • Hepatic impairment (high transaminase, high bilirubin and/or elevated alkaline phosphatase levels) can occur in patients undergoing renal transplant.
  • It usually occurs within six months of transplantation and can be reversed with discontinuation.
  • Regularly monitor liver function.
  • Rarely, hepatic Sinoidal Obstruction Syndrome (SOS; previously called Veno-occlusive Disease [VOD]), has been reported. If hepatic SOS is suspected, discontinue treatment.
• Infections
  • Chronic immunosuppression with azathioprine can increase the risk of serious, bacterial and fungal infections, including reactivation or reactivation, as well as opportunistic infections.
• Malignancy [US Boxed Warning]
  • Certain malignancies are more likely to occur when there is chronic immunosuppression.
  • These include post-transplant lymphoma, and hepatosplenic-splenic T cell lymphoma (HSTCL), in patients with inflammatory-bowel disease.
  • HSTCL is rare and often fatal hematological malignancy.
  • It affects young adults and teens who have been treated for inflammatory intestinal disease with azathioprine or mercaptopurine.
  • Patients who have received strong immunosuppressants after a renal transplant are at greater risk for skin cancer and lymphoma. 
  • Patients should be advised to avoid sun exposure and to use sunscreens.
• Progressive multifocal Leukoencephalopathy
  • Patients treated with azathioprine have reported progressive multifocal leukoencephalopathy (caused JC virus ).
  • Patients taking immunosuppressants for new-onset neurological manifestations need to be suspected of PML. A neurologist should provide an opinion.
• Hepatic impairment
  • Patients suffering from liver disease should be cautious about taking the drug.
• Genetic variation NUDT15:
  • Patients who have a germline mutation in nudixhydralase are at greater risk for hematologic toxicities.
  • Patients with severe or repeated episodes of myelosuppression or cytopenia should be genotyped for NUDT15 deficiencies.
  • Patients with homozygous NUDT15 deficiencies should not take azathioprine. However, heterozygotes may be advised to take the drug in lower doses.
• Renal impairment
  • Patients with impaired renal function should not take it. 
  • These patients should have the dose reduced.
• TPMT deficiency:
  • Patients with a genetic deficiency in thiopurine Smethyltransferase may experience life-threatening hematological toxicities even at conventional doses.
  • To identify patients at high risk for developing hematological toxicities, TPMT genotyping is recommended.
  • Recent blood transfusions can cause patients to not be able to accurately estimate red blood cell TPMT activity.
  • Patients with homozygous TPMT deficiencies should be offered an alternative treatment. Patients with heterozygous deficiencies may be given the drug in a lower dose.

Azathioprine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
5-Aminosalicylic Acid Derivatives	May reduce the metabolism of Thiopurine Analogs.
Angiotensin-Converting Enzyme Inhibitors	May increase the myelosuppressive effects of AzaTHIOprine.
Anti-TNF Agents	Thiopurine Analogs may have an adverse/toxic effect. In particular, there may be an increase in the risk of T-cell nonHodgkin’s lymphoma (including Hepatosplenic T cell lymphoma). Exceptions: Lenalidomide; Pomalidomide; Thalidomide.
Coccidioides immitis Skin Test	Coccidioides immitis Skin Test may be affected by immunosuppressants.
Cyclophosphamide	AzaTHIOprine could increase the hepatotoxic effects of Cyclophosphamide.
Denosumab	Might increase the toxic/adverse effects of Immunosuppressants. In particular, there may be an increase in the risk of serious infections.
InFLIXimab	AzaTHIOprine may have an adverse/toxic effect. Tcell non-Hodgkin’s lymphoma, including hepatosplenic T cell lymphoma, may increase. InFLIXimab can increase serum levels of active metabolites of AzaTHIOprine.
Ocrelizumab	May increase the immunosuppressive effects of Immunosuppressants.
Pidotimod	Pidotimod's therapeutic effects may be diminished by immunosuppressants.
Siponimod	Siponimod's immunosuppressive effects may be enhanced by taking immunosuppressants.
Sipuleucel-T	Sipuleucel T's therapeutic effects may be diminished by immunosuppressants
Sulfamethoxazole	May increase the myelosuppressive effects of AzaTHIOprine.
Tertomotide	Tertomotide's therapeutic effects may be diminished by immunosuppressants.
Trastuzumab	May increase the neutropenic effects of Immunosuppressants.
Trimethoprim	May increase the myelosuppressive effects of AzaTHIOprine.
Vitamin K antagonists (eg warfarin)	AzaTHIOprine could decrease the anticoagulant effects of Vitamin K Antagonists.
Risk Factor D (Regard therapy modification)
Allopurinol	May increase serum levels of active metabolites of AzaTHIOprine. Allopurinol can increase serum mercaptopurine concentrations and promote the formation of active thioguanine ncleotides. Management: Reduce the azathioprine dose to one third to one quarter of the usual dose if used concomitantly with allopurinol, and monitor closely for systemic toxicity (particularly hematologic toxicity, nausea, and vomiting).
Baricitinib	Baricitinib's immunosuppressive effects may be enhanced by immunosuppressants. Baricitinib should not be used in combination with immunosuppressants like azathioprine and cyclosporine. It is permissible to use methotrexate antirheumatically or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently.
Echinacea	Might decrease the therapeutic effects of Immunosuppressants.
Fingolimod	Fingolimod may be immunosuppressed by immunosuppressants. When possible, avoid the use of fingolimod with other immunosuppressants. Patients should be closely monitored for any additive immunosuppressant effects, such as infections, if they are used together.
Leflunomide	Leflunomide's toxic/adverse effects may be exacerbated by immunosuppressants. The risk of hematologic toxicities such as pancytopenia and agranulocytosis may increase. Patients on immunosuppressants should not be given a leflunomide loading dosage. Patients who are receiving leflunomide or another immunosuppressant must be checked for bone marrow suppression at minimum monthly.
Nivolumab	Nivolumab's therapeutic effects may be diminished by immunosuppressants.
Ribavirin (Oral Inhalation)	Increased serum levels of active metabolites of AzaTHIOprine. Particularly, the serum concentrations may increase in potentially myelotoxic, methylated metabolites, while they may decrease in active 6-thioguanine nucleotides. When possible, consider using an alternative agent. If these drugs are combined, be sure to monitor your patients for any signs/symptoms that may indicate myelosuppression.
Ribavirin (Systemic)	Increased serum levels of active metabolites of AzaTHIOprine. Particularly, the serum concentrations may increase in potentially myelotoxic, methylated metabolites, while they may decrease in active 6-thioguanine nucleotides. When possible, consider using an alternative agent. If these drugs are combined, be sure to monitor for myelosuppression signs and symptoms.
Roflumilast	May increase the immunosuppressive effects of Immunosuppressants.
Tofacitinib	Tofacitinib's immunosuppressive effects may be enhanced by immunosuppressants. Management: It is permissible to use methotrexate (or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently with antirheumatic doses. This warning appears to be particularly targeted at more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants can reduce the therapeutic effects of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. All age-appropriate vaccines must be completed at least two weeks before you start an immunosuppressant. Re-vaccinate anyone who was vaccinated while on immunosuppressant therapy.
Vaccines (Live)	AzaTHIOprine could increase the toxic/adverse effects of Vaccines (Live). AzaTHIOprine can decrease the therapeutic effects of Vaccines. Management: A low-dose azathioprine dose (3 mg/kg/day) is considered not sufficiently immunosuppressive for vaccine safety concerns. It is not contraindicated for the administration of zoster vaccination. Avoid higher doses of Azathioprine.
Risk Factor X (Avoid Combination)
BCG (Intravesical).	The therapeutic effects of BCG (Intravesical) may be diminished by immunosuppressants
Cladribine	May increase the immunosuppressive effects of Immunosuppressants.
Febuxostat	May increase serum AzaTHIOprine concentrations.
Mercaptopurine	AzaTHIOprine could increase the myelosuppressive effects of Mercaptopurine.
Natalizumab	Natalizumab's toxic/adverse effects may be exacerbated by immunosuppressants. Particularly, concurrent infections may increase.
Pimecrolimus	May increase the toxic/adverse effects of Immunosuppressants
Tacrolimus (Topical).	May increase the toxic/adverse effects of Immunosuppressants

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How to administer Azathioprine?

• Oral administration:
  • It is administered orally as a once-daily dose. It may be administered in divided doses to reduce the gastrointestinal side effects.
• Intravenous administration:
  • It is usually administered as an intravenous infusion over 30 - 60 minutes depending on the total volume of infusate.
  • It may be administered as rapidly as over 5 minutes to as slowly over 8 hours.

Mechanism of action of Azathioprine:

• It is a derivative of mercaptopurine. It also blocks purine synthesis. 
• Most of the immunosuppressive or toxic effects of Azathioprine are caused by 6-thioguanine nucleotide metabolisms

Onset of action: After oral administration, the duration of immunothrombocytopenia is between 30 and 90 days. A peak response can be seen within 30 to 120 days.

After oral administration, it is easily absorbed and 30% protein-bound.

It is metabolized in the liver to 6-mercaptopurine via glutathione S-transferase (GST) reduction. 

It is further metabolized into three metabolites 6-thioguanine-nucleotides ( 6-TGNs), 6-thiouric acid, and 6-methylmercaptopurine. 6-thioguanine-nucleotides is the active metabolite while 6-thiouric acid, and 6-methylmercaptopurine are the inactive metabolites.

Azathioprine takes about 2 hours toreach the peak plasma concentration.

Oral administration can take between 1 and 2 hours.

It is excreted ​​​​​​​primarily in the urine  

International Brands of Azathioprine:

• APO-AzaTHIOprine
• AzaTHIOprine-50
• Imuran
• MYLAN-AzaTHIOprine
• NU-AzaTHIOprine
• TEVA-AzaTHIOprineAza-Q
• Azadus
• Azafalk
• Azafrine
• Azamun
• Azamune
• Azapin
• Azapress
• Azaprin
• Azaprine
• Azarekhexal
• Azarin
• Azathiodura
• Azatioprina
• Azatioprina Wellcome
• Azatrilem
• Azoran
• Azostal
• Colinsan
• Imazan
• Immuthera
• Imuger
• Imunen
• Imuprin
• Imuprine
• Imuran
• Imurek
• Imurel
• Renzat
• Thioprine
• Transimune
• Zaprine
• Zytrim

Azathioprine in Pakistan:

Azathioprine [Inj 50 mg/vial]
Azathioprine	Turner Grahams Of Pakistan (Pvt) Ltd.

Azathioprine [Tabs 50 mg]
Amorin	Mass Pharma (Private) Limited
Amorin	Mass Pharma (Private) Limited
Azafrine	Al-Habib Pharmaceuticals.
Azathioprine	Turner Grahams Of Pakistan (Pvt) Ltd.
Azoprine	Global Pharmaceuticals
Imuran	Glaxosmithkline
Pharmazorine	Pharmedic (Pvt) Ltd.