Azathioprine

Azathioprine is an Immunosuppressant belonging to Anti-inflammatory agent.

Azathioprine is an immunosuppressant used to prevent renal transplant rejection, treat rheumatoid arthritis, Crohn's disease, and ulcerative colitis.

Azathioprine well absorbed from the GI tract. Time to peak plasma concentration is about 1-2 hours (oral). Azathioprine enters breast milk (low concentration). The plasma protein binding is approximately 30%. Azathioprine hepatically metabolized to 6-mercaptopurine via glutathione S-transferase (GST) reduction; further metabolized in the liver and GI tract via 3 main pathways: Hypoxanthine guanine phosphoribosyl transferase (to active metabolite: 6thioguaninenucleotides), xanthine oxidase (to inactive metabolite: 6thiouric acid), and thiopurine methyltransferase (to inactive metabolite: 6methylmercaptopurine). Azathioprine excreted via urine (mainly as metabolites). The elimination half-life is approximately 2 hours.

Azathioprine shows side effects like Nausea, vomiting, diarrhea.

Azathioprine is available in the form of Oral Tablet, and Powder for Injection.

Azathioprine is available in India, US, Singapore, Canada, Italy, Malaysia, China, and Australia.

Azathioprine belongs to the Anti-inflammatory agent acts as an Immunosuppressant.

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.

The onset and duration of action of Azathioprine is not clinically established.

The Tmax of Azathioprine is approximately 1-2 hours (oral route).

Azathioprine is an immuno-suppressant medicine (medicine that suppresses the activity of the immune system). It is used after organ transplantation to prevent your body from rejecting the transplanted organ due to the body's immune activity. It is also used in severe cases of rheumatoid arthritis (pain and swelling in the small joints due to abnormal immune activity).

Azathioprine is approved for use in the following clinical indications

Adult Indication

• Behçet syndrome
• Bullous pemphigoid
• Crohn disease
• Dermatomyositis/polymyositis
• Eosinophilic granulomatosis with polyangiitis
• Granulomatosis with polyangiitis and microscopic polyangiitis
• Hepatitis, autoimmune
• Immune thrombocytopenia, chronic
• Interstitial pneumonia/interstitial lung disease
• Lupus nephritis
• Myasthenia gravis, chronic immunosuppressive therapy
• Pemphigus vulgaris and pemphigus foliaceus
• Polyarteritis nodosa
• Rheumatoid arthritis
• Sarcoidosis, pulmonary, steroid-refractory disease
• Solid organ transplantation
• Takayasu arteritis
• Ulcerative colitis
• Uveitis, noninfectious

Pediatric indication

• Hepatitis, autoimmune
• Inflammatory bowel disease
• Immune thrombocytopenia, chronic refractory
• Lupus nephritis
• Myasthenia gravis, juvenile
• Transplantation, solid organ
• Uveitis, juvenile idiopathic arthritis-associated; acute

Adult Dose

• Behçet syndrome

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.

• Bullous pemphigoid (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.

• Crohn disease (off-label use)

Oral: Initial: 50 mg once daily; titrate up to 2.5 mg/kg once daily over ≥12 weeks as indicated and tolerated. Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using lean body weight given the toxicities of azathioprine. For induction, give in combination with a tumor necrosis factor-alpha inhibitor. Duration is generally ≥1 to 2 years.

• Dermatomyositis/polymyositis (off-label use)

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; some experts do not exceed 250 mg/day. Once remission is achieved and glucocorticoids have been tapered, may consider slow taper at monthly intervals with planned cessation of therapy over ~6 months.

• Eosinophilic granulomatosis with polyangiitis (off-label use)

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); usual duration: 12 to 18 months; however, longer maintenance therapy may be needed in patients with multiple relapses.

• Granulomatosis with polyangiitis and microscopic polyangiitis (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.

• Hepatitis, autoimmune (off-label use)

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; some experts do not exceed 200 mg/day. 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).

• Immune thrombocytopenia, chronic (off-label use)

Oral: 1 to 2 mg/kg/day; maximum dose: 150 mg/day. Initial response is observed at 30 to 90 days; may take up to 6 months for peak response.

• Interstitial pneumonia/interstitial lung disease (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; some experts do not exceed 200 mg/day; generally given in combination with a glucocorticoid.

• Lupus nephritis (off-label use)

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; some experts do not exceed 200 mg/day; generally given in combination with a glucocorticoid. Duration is typically ≥2 years.

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

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; more rapid titration has also been described. Onset of clinical response to azathioprine may take up to 1 year; maximum efficacy may not be apparent until 1 to 2 years.

• Pemphigus vulgaris and pemphigus foliaceus (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. Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using ideal body weight given the toxicities of azathioprine. Administer in combination with a glucocorticoid.

• Polyarteritis nodosa (off-label use)

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).

• Rheumatoid arthritis (off-label use)

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; some experts do not exceed 200 mg/day.

• Sarcoidosis, pulmonary, steroid-refractory disease (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; some experts do not exceed 200 mg/day; generally given in combination with a glucocorticoid.

• Solid organ transplantation

Heart transplantation (off-label use): Oral, IV: 1 to 3 mg/kg once daily as part of an appropriate combination regimen; some experts do not exceed 200 mg/day.

Kidney transplantation: Oral, IV: 1 to 2 mg/kg once daily as part of an appropriate combination regimen; recommends up to 3 mg/kg once daily; some experts do not exceed 150 mg/day.

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

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

• Takayasu arteritis

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; some experts do not exceed 200 mg/day; give in combination with a glucocorticoid.

• Ulcerative colitis

Oral: Initial: 50 mg once daily; titrate up to 2.5 mg/kg once daily over ≥12 weeks as indicated and tolerated. Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using lean body weight given the toxicities of azathioprine.

• Uveitis, noninfectious

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

Pediatric Dose

• Hepatitis, autoimmune

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.

• Inflammatory bowel disease

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. Some data suggest that pediatric patients with early-onset disease (≤6 years) may require higher doses to achieve remission. 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).

• Immune thrombocytopenia, chronic refractory

Children ≥2 years and Adolescents: Oral: Maintenance: 2 to 2.5 mg/kg/day, rounded to the nearest 50 mg.

• Lupus nephritis

Children and Adolescents: Oral: 2 to 2.5 mg/kg/dose once daily.

• Myasthenia gravis, juvenile

Children and Adolescents: Oral: 1 to 3 mg/kg/dose once daily; most experience in pediatric patients extrapolated from adult trials; most used in combination with corticosteroids as a steroid-sparing agent; however, azathioprine may be a first choice in patients where corticosteroids are contraindicated.

• Transplantation, solid organ

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.

• Uveitis, juvenile idiopathic arthritis-associated; acute

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.

Azathioprine is available in the form of Oral Tablet, and Powder for injection.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: Initial: No dosage adjustment necessary.

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).

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).

Azathioprine is contraindicated in patients with

• Azathioprine should not be given to patients who have shown hypersensitivity to the drug. Azathioprine should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with Azathioprine.

• Malignancy

Patients receiving immunosuppressants, including Azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with Azathioprine. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

• Post-transplant

Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including Azathioprine. Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.

• Rheumatoid Arthritis

Information is available on the risk of malignancy with the use of Azathioprine in rheumatoid arthritis. It has not been possible to define the precise risk of malignancy due to Azathioprine. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received Azathioprine.

• Inflammatory Bowel Disease

Post marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with Azathioprine. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with Azathioprine as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis. The safety and efficacy of Azathioprine for the treatment of Crohn's disease and ulcerative colitis have not been established.

• Cytopenias

Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with Azathioprine. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of Azathioprine. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of Azathioprine. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing Azathioprine toxicity. Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on Azathioprine have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore, the dose should not be increased intentionally to lower the white blood cell count.

• Serious infections

Patients receiving immunosuppressants, including Azathioprine, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal outcomes.

• Progressive Multifocal Leukoencephalopathy

Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Azathioprine. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft.

The use of Azathioprine in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother.

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common

● Nausea and vomiting, Leukopenia, Infection, Neoplasm, Malignant lymphoma.

Rare

● Alopecia, skin rash, Sweet's syndrome, Negative nitrogen balance, Diarrhea, steatorrhea, Bone marrow depression, malignant neoplasm of skin, thrombocytopenia, Arthralgia, Interstitial pneumonitis, Fever.

• Use with Allopurinol

One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving Azathioprine and allopurinol concomitantly should have a dose reduction of Azathioprine, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving Azathioprine and allopurinol because both TPMT and XO inactivation pathways are affected.

• Use with Aminosalicylates

There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with Azathioprine should be done with caution.

• Use with Other Agents Affecting Myelopoesis

Drugs which may affect leukocyte production, including cotrimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

• Use with Angiotensin-Converting Enzyme Inhibitors

The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.

• Use with Warfarin

Azathioprine may inhibit the anticoagulant effect of warfarin.

• Use with ribavirin

The use of ribavirin for hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioionosine monophosphate (6MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary.

The common side effects of Azathioprine include the following

Common side effects

● Nausea, vomiting, diarrhea.

Rare side effects

● Fever, rash, weakness, muscle pain.

• Pregnancy

Pregnancy Category D

Azathioprine can cause fetal harm when administered to a pregnant woman. Azathioprine should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of Azathioprine in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12 Azathioprine is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies.

• Nursing Mothers

The use of Azathioprine in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother.

• Pediatric Use

As per FDA, the safety and efficacy of azathioprine in pediatric patients have not been established.

• Geriatric Use

Information is not available.

The oral LD50s for single doses of Azathioprine in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of Azathioprine is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis. A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg Azathioprine. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.

Pharmacodynamic

Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions. It has a long duration of action as it is given daily and has a narrow therapeutic index. Patients should be counselled regarding the risk of malignancies of the skin and lymphomas.

Pharmacokinetics

• Absorption

Azathioprine well absorbed from the GI tract. Time to peak plasma concentration is about 1-2 hours (oral).

• Distribution

Azathioprine enters breast milk (low concentration). The plasma protein binding is approximately 30%.

• Metabolism

Azathioprine hepatically metabolized to 6-mercaptopurine via glutathione S-transferase (GST) reduction; further metabolized in the liver and GI tract via 3 main pathways: Hypoxanthine guanine phosphoribosyl transferase (to active metabolite: 6thioguaninenucleotides), xanthine oxidase (to inactive metabolite: 6thiouric acid), and thiopurine methyltransferase (to inactive metabolite: 6methylmercaptopurine).

• Excretion

Azathioprine excreted via urine (mainly as metabolites). The elimination half-life is approximately 2 hours.

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