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.

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.

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.

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

• 2 mg/kg/day orally for 6 months.

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.

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.

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.

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

• 2 - 3 mg/kg/day orally.

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.

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.

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.

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.

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.

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

• 0.5 - 2.5 mg/kg/day orally.

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.

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.

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.

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).

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.

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.

Dose in the treatment of mild Lupus nephritis: 

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

Dose in the treatment of juvenile Myasthenia gravis:

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

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.

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.

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.

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

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: