AZAMUN 50 mg

Indications

• Prophylaxis of organ rejection in kidney, liver, pancreas, heart, lung, and heart-lung transplantation
• Severe ulcerative colitis
• Severe Crohn’s disease
• Corticosteroid-resistant allograft rejection
• Systemic lupus erythematosus
• Vasculitis
• Autoimmune conditions

Dosage

Children: For children (1–17 years): 1–2.5 mg/kg daily for 3–5 days for organ transplantation, and 1.5 mg/kg daily for 7–14 days for autoimmune conditions, adjusted according to response.

Adults: For organ transplantation, 3–5 mg/kg daily given orally or intravenously, adjusted according to response.

Mechanism of action

Azathioprine is metabolized to 6-mercaptopurine, which inhibits purine synthesis, thus affecting the proliferation of lymphocytes and leading to immunosuppression.

Pharmacodynamics

The drug reduces the immune response by interfering with the synthesis of DNA and RNA in lymphocytes, leading to decreased lymphocyte proliferation and activity.

Pharmacokinetics

Azathioprine is well absorbed after oral administration and is widely distributed in body tissues. It is metabolized mainly in the liver, with a half-life of approximately 2 hours. The active metabolite, 6-mercaptopurine, has a longer half-life and is responsible for the drug's therapeutic effects.

Contra-indications

• Infection

Adverse effects

• Chills
• Diarrhoea
• Dysphagia
• Dyspnoea
• Fever
• Hypotension
• Infection
• Lymphopenia
• Myalgia
• Nausea
• Malignant neoplasms
• Neutropenia
• Reactivation of infection
• Secondary malignancy
• Sepsis
• Skin reactions
• Thrombocytopenia

Interactions

• Allopurinol: Increases risk of haematological toxicity
• Febuxostat: Increases exposure
• Filgotinib: Increases risk of immunosuppression
• ACE inhibitors: Increases risk of anaemia and/or leucopenia
• Coumarins: Decreases anticoagulant effect
• Live vaccines: Increases risk of generalised infection (possibly life-threatening)
• Trimethoprim (in renal transplant patients): Increases risk of haematological toxicity

Pregnancy

Use with caution; potential for harm to the fetus.

Breast-feeding

Use with caution; may cause immunosuppression in the infant.

Storage

Store below 25°C. Do not freeze.

Formulations

• Powder and solvent for solution for infusion
• Oral tablet

Mechanism of action

Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis. This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB. Following exposure to nucleophiles ... azathioprine is cleaved to 6-mercaptopurine which, in turn, is converted to additional metabolites that inhibit de novo purine synthesis. 6-Thio-IMP, a fraudulent nucleotide, is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA and gene translation is inhibited. Cell proliferation is prevented, inhibiting a variety of lymphocyte functions. Azathioprine (AZA), one of the antimetabolite drugs, is a purine analog that is more potent than the prototype 6-mercaptopurine, as an inhibitor of cell replication. Immunosuppression likely occurs because of the ability of the drug to inhibit purine biosynthesis. ... Although T-cell functions are the primary targets for this drug, inhibition of /(natural killer cells)/ NK function and macrophage activities has also been reported. Azathioprine inhibits DNA synthesis and, as a purine antimetabolite, exerts its effect on activated lymphocytes, which requires purines during their proliferative phase. It inhibits both cellular and humoral responses, but does not interfere with phagocytosis or interferon production. It is a nonspecific cytotoxic agent. Its immunosuppressive effect is believed to be due to mercaptopurine, to which it is metabolized. The exact mechanism of immunosuppressive action is unknown since the exact mechanism of the immune response itself is complex and not completely understood. The immunosuppressive effects of azathioprine involve a greater suppression of delayed hypersensitivity and cellular cytotoxicity tests than of antibody responses. Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins; it may also interfere with cellular metabolism and inhibit mitosis. For more Mechanism of Action (Complete) data for AZATHIOPRINE (6 total), please visit the HSDB record page.

Pharmacodynamics

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.