Azathioprine is used as an immunosuppressive antimetabolite, either alone or more commonly in combination with other agents such as corticosteroids and therapeutic procedures that modify immune response. Its clinical benefits may take several weeks or months to become evident and may include a steroid-sparing effect, thereby reducing the toxicity associated with long-term or high-dose corticosteroid use.

In combination with corticosteroids and/or other immunosuppressive therapies, azathioprine is indicated to improve survival following organ transplantation, including kidney, heart, and liver transplants. It also helps reduce corticosteroid requirements in renal transplant patients.

Azathioprine is indicated for moderate to severe inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, particularly in patients who require corticosteroids, cannot tolerate them, or do not respond adequately to first-line treatments. It has also shown clinical benefit, either alone or in combination with corticosteroids and other therapies, in certain autoimmune conditions, including:

• Severe active rheumatoid arthritis
• Systemic lupus erythematosus
• Dermatomyositis and polymyositis
• Autoimmune chronic active hepatitis
• Pemphigus vulgaris
• Polyarteritis nodosa
• Autoimmune haemolytic anaemia
• Chronic refractory idiopathic thrombocytopenic purpura

Azathioprine is an immunosuppressive antimetabolite and a derivative of 6-mercaptopurine (6-MP). It is rapidly converted in the body to 6-MP and a methyl-nitroimidazole compound. The active metabolite, 6-MP, enters cells and is transformed into purine thioanalogues, including thioinosinic acid, which plays a key role in its immunosuppressive action.

These metabolites interfere with nucleic acid synthesis and inhibit proliferation of rapidly dividing immune cells. The drug is metabolized primarily into inactive thiouric acid through the action of xanthine oxidase. The activity of the methyl-nitroimidazole component is not fully understood but may influence the drug’s overall effect.

Therapeutic effects may take weeks to months to appear. Azathioprine is well absorbed from the gastrointestinal tract, although plasma levels do not reliably correlate with clinical efficacy or toxicity.

Absorption: Azathioprine is well absorbed after oral administration. Food may reduce the bioavailability of its active metabolite (6-MP), especially when taken with milk due to enzymatic degradation. Therefore, patients should take it consistently either with or without food but should avoid taking it with milk or dairy products.

After administration, peak plasma levels are typically reached within 1–2 hours, and elimination occurs over several hours. The drug is mainly excreted in urine as inactive metabolites.

Biotransformation: Thiopurine S-methyltransferase (TPMT) plays a significant role in metabolism. Reduced TPMT activity leads to higher levels of active metabolites, increasing the risk of bone marrow suppression, including decreased white blood cells and neutrophils.

Transplants:

• Depending on the immunosuppressive regimen employed, a dosage of up to 5mg/kg body weight/day may be given orally or intravenously on the first day of therapy.
• Maintenance dosage should range from 1 to 4mg/kg body weight/day and must be adjusted according to clinical requirements and haematological tolerance.
• Evidence indicates that azathioprine therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.

Dosage in Other indications:

• In general, the starting dosage is 1 to 3mg/kg body weight/day, and should be adjusted, within these limits, depending on the clinical response (which may not be evident for weeks or months) and haematological tolerance.
• When the therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with the maintenance of that response. If no improvement occurs in the patient's condition within three months, consideration should be given to withdrawing azathioprine. However, for patients with IBD, a treatment duration of at least twelve months should be considered and a response to treatment may not be clinically apparent until after three to four months of treatment.
• The maintenance dosage required may range from less than 1mg/kg body weight/day to 3mg/kg body weight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Overweight children: Children considered to be overweight may require doses at the higher end of the dose range and therefore close monitoring of response to treatment is recommended.

Elderly: There is limited experience of the administration of azathioprine to elderly patients. Although the available data do not provide evidence that the incidence of side effects among elderly patients is higher than that among other patients treated with azathioprine, it is recommended that the dosages used should be at the lower end of the range.

Renal impairment: In patients with renal insufficiency, consideration should be given to reducing the dosage.

Hepatic impairment: In patients with hepatic insufficiency, consideration should be given to reducing the dosage.

Administration

For oral use. Azathioprine should be taken at least 1 hour before or 2 hours after milk or dairy products

Allopurinol / Oxipurinol / Thiopurinol: When allopurinol, oxipurinol, or thiopurinol are used together with azathioprine or 6-mercaptopurine, the dose of azathioprine should be reduced to approximately 25% of the original dose.

Neuromuscular Blocking Agents: Azathioprine may alter the effects of neuromuscular blockers such as succinylcholine and tubocurarine, with variability in interaction strength.

Anticoagulants: Azathioprine has been reported to reduce the anticoagulant effect of warfarin when used concurrently.

Cytostatic / Myelosuppressive Agents: Concurrent use with cytotoxic or bone marrow–suppressing drugs (e.g., penicillamine) should be avoided whenever possible due to increased risk of bone marrow suppression.

Methotrexate: When used with high-dose methotrexate, azathioprine dosage may need adjustment to maintain an appropriate white blood cell count.

Vaccines: Due to its immunosuppressive effect, azathioprine may cause abnormal or harmful responses to live vaccines, which should generally be avoided. Response to inactivated vaccines may be reduced; diminished response to hepatitis B vaccine has been observed.

Ribavirin: Severe bone marrow suppression has been reported with concomitant use of azathioprine and ribavirin; therefore, this combination is not recommended.

Other Interactions: Aminosalicylates (such as olsalazine, mesalazine, and sulphasalazine) may inhibit TPMT enzyme activity, potentially increasing toxicity. Dose adjustment of azathioprine may be required.

Azathioprine is contraindicated in patients with known hypersensitivity to azathioprine, 6-mercaptopurine, or any component of the formulation.

Modern clinical data are limited for determining the exact frequency of adverse effects.

• Infections: Very common — viral, bacterial, and fungal infections in transplant patients receiving combination immunosuppressive therapy
• Neoplasms: Rare — lymphoproliferative disorders, skin cancers (melanoma and non-melanoma), sarcomas, cervical cancer in situ, acute myeloid leukemia, myelodysplasia
• Blood Disorders: Very common — bone marrow suppression, leukopenia; Common — thrombocytopenia
• Immune Disorders: Uncommon — hypersensitivity reactions
• Respiratory Disorders: Very rare
• Gastrointestinal Disorders: Common — nausea

Teratogenicity: Evidence regarding teratogenic effects in humans is inconclusive. As with all cytotoxic drugs, effective contraception is recommended during treatment.

Mutagenicity: Chromosomal abnormalities have been observed in offspring lymphocytes but may resolve over time. Physical abnormalities are rare. Combined exposure with ultraviolet light may increase genetic damage risk.

Fertility: The impact on human fertility remains uncertain.

Pregnancy: Azathioprine crosses the placenta. It is classified as Pregnancy Category D and should only be used if benefits outweigh risks. Careful evaluation is required before use in pregnant or potentially pregnant patients.

Contraception: Women should use effective contraception during treatment and for 1 month after stopping therapy. Men should avoid fathering a child during treatment and for 3 months after discontinuation.

Lactation: Breastfeeding is not recommended during azathioprine therapy, as 6-mercaptopurine has been detected in breast milk.