Azathioprine

Azathioprine is an immunosuppressive antimetabolite, chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. It is an imidazolyl derivative of 6-mercaptopurine. It inhibits DNA, RNA and protein synthesis and antagonises purine synthesis. It also inhibits mitosis and interferes with cellular metabolism of susceptible organisms.

Azathioprine is used to enhance the survival of organ transplants (renal, cardiac, hepatic transplants) and reduces corticosteroid requirements in transplant recipients. It is also indicated for 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, and moderate to severe inflammatory bowel disease (Crohn's disease or ulcerative colitis).

Common side effects include bone marrow suppression, leukopenia, nausea, increased infection risk, and bleeding tendency.

• Organ transplantation (kidney, heart, liver) - prevention of rejection
• Severe active rheumatoid arthritis
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
• 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 imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and a methylnitroimidazole moiety. 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid.

Thiopurine S-Methyl Transferase (TPMT) activity is inversely related to red blood cell 6-mercaptopurine derived thioguanine nucleotide concentration. Individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations.

The therapeutic effect of azathioprine may be evident only after several weeks or months of treatment. It is well absorbed from the upper gastrointestinal tract. Plasma levels of azathioprine and 6-mercaptopurine do not correlate well with therapeutic efficacy or toxicity.

Azathioprine is converted in vivo to 6-mercaptopurine (6-MP), which is taken up by cells and converted to active nucleotide metabolites (thioinosinic acid). These active metabolites inhibit de novo purine synthesis, preventing DNA, RNA, and protein synthesis. This inhibits proliferation of T-lymphocytes and B-lymphocytes, suppressing the immune system and reducing organ rejection and autoimmune disease activity.

Transplantation:

• Initial dose: up to 5 mg/kg/day (oral or IV)
• Maintenance: 1-4 mg/kg/day (adjusted according to hematological tolerance)

Other indications (Rheumatoid arthritis, IBD, SLE, etc.):

• Initial dose: 1-3 mg/kg/day
• Maintenance: less than 1 mg/kg/day to 3 mg/kg/day

Special populations:

• Elderly: Start at lower end of dose range
• Renal/hepatic impairment: Consider dose reduction
• Co-administration with allopurinol: Reduce azathioprine dose to 25%

For oral use. Azathioprine should be taken at least 1 hour before or 2 hours after milk or dairy products. Swallow tablets whole, do not chew or crush. Take with food to reduce stomach upset.

If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and continue with your regular schedule. Do not double the dose.

• Bone marrow suppression (leukopenia, thrombocytopenia)
• Nausea
• Increased risk of infections (viral, fungal, bacterial)
• Increased bleeding tendency
• Anorexia
• Lymphoproliferative disorders and malignancies (rare)
• Hypersensitivity reactions
• Hepatotoxicity (rare)

• Regular blood count monitoring during treatment (weekly for first 8 weeks, then monthly)
• Extreme caution in patients with TPMT enzyme deficiency
• Avoid live vaccines
• Protect skin from sunlight and UV exposure (skin cancer risk)
• Avoid use during pregnancy and breastfeeding
• Men and women of reproductive potential should use effective contraception

• Hypersensitivity to azathioprine or any component
• Hypersensitivity to 6-mercaptopurine
• Pregnancy (Category D)
• Lactation

• Allopurinol: Reduce azathioprine dose to 25% (due to xanthine oxidase inhibition)
• Warfarin: May reduce anticoagulant effect
• Aminosalicylates (mesalazine, sulfasalazine): Increase myelosuppression risk by inhibiting TPMT
• Methotrexate: Caution with co-administration
• Ribavirin: Severe myelosuppression may occur - avoid co-administration
• Live vaccines: Atypical and potentially deleterious response may occur

Do not take with milk or dairy products (xanthine oxidase in milk degrades 6-MP by 30% within 30 minutes). May be taken with food or on an empty stomach, but method of administration should be standardized.

[CONSULT YOUR DOCTOR] Azathioprine is unsafe during pregnancy (Category D). May have teratogenic effects on the fetus. Women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose.

[CONSULT YOUR DOCTOR] Azathioprine is excreted in breast milk (6-mercaptopurine has been identified in colostrum and breast milk). Mothers receiving azathioprine should not breastfeed.

Pediatric dose: 1-2.5 mg/kg/day (for juvenile idiopathic arthritis). Overweight children may require doses at the higher end of the range.

Elderly patients should start at the lower end of the dose range (limited experience).

[CAUTION] Consider dose reduction in renal impairment. Use is not recommended in serious kidney disease.

[CAUTION] Consider dose reduction in hepatic impairment. Use is not recommended in severe liver disease. Regular liver function tests should be monitored during treatment.

Symptoms: Unexplained infection, throat ulceration, bruising and bleeding (due to bone marrow depression, maximal after 9-14 days). More likely with chronic overdose. A single 7.5 g overdose caused nausea, vomiting, diarrhea, mild leukopenia and mild liver abnormalities.

Treatment: No specific antidote. Close blood count monitoring. Activated charcoal may be effective within 60 minutes. Azathioprine is partially dialysable.

Store below 25°C. Protect from light.

Azathioprine (C₉H₇N₇O₂S)