Adult: Initially, 3-5 mg/kg daily as a single dose starting on the day of transplantation, may be given 1-3 days prior to transplantation in some cases. Maintenance: 1-3 mg/kg daily. May convert to oral dosing as soon as tolerated. Child: Same as adult dose.
Intravenous Rheumatoid arthritis
Adult: Initially, 1 mg/kg daily in 1-2 divided doses for 6-8 wk, may increase by 0.5 mg/kg 4 wkly until response or up to 2.5 mg/kg daily. Maintenance: Reduce dose by 0.5 mg/kg 4 wkly to achieve lowest effective dose. Child: Same as adult dose.
Intravenous Prophylaxis of rejection in organ and tissue transplant
Adult: 1-5 mg/kg daily. Adjust according to clinical response and haematological tolerance. Child: Same as adult dose.
Intravenous Auto-immune diseases
Adult: 1-3 mg/kg daily. Discontinue treatment if there is no improvement after 3-6 mth. Child: Same as adult dose.
Oral Rheumatoid arthritis
Adult: Initially, 1 mg/kg daily in 1-2 divided doses for 6-8 wk, may increase by 0.5 mg/kg 4 wkly until response or up to 2.5 mg/kg daily. Maintenance: Reduce dose by 0.5 mg/kg 4 wkly to achieve lowest effective dose. Child: Same as adult dose.
Oral Prophylaxis of rejection in organ and tissue transplant
Adult: 1-5 mg/kg daily. Adjust according to clinical response and haematological tolerance. Child: Same as adult dose.
Oral Auto-immune diseases
Adult: 1-3 mg/kg daily. Discontinue treatment if there is no improvement after 3-6 mth. Child: Same as adult dose.
Oral Renal homotransplantation
Adult: Initially, 3-5 mg/kg daily as a single dose starting on the day of transplantation, may be given 1-3 days prior to transplantation in some cases. Maintenance: 1-3 mg/kg daily. Child: Same as adult dose.
Special Patient Group
Pharmacogenomics:
Azathioprine is a prodrug that forms thioguanine nucleotides (TGNs) which exerts cytotoxic effects. It is inactivated by thiopurine S-methyltransferase (TPMT). Genetic testing for TPMT prior to initiation of treatment with azathioprine is recommended.
TPMT intermediate metabolisers, heterozygous (carriers of 1 functional allele plus 1 non-functional allele e.g. *1/*2, *1*3A, *1*3B, *1/*3C, *1*4)
Patient has reduced TPMT-mediated metabolism leading to moderate to high concentrations of active TGN metabolites resulting to increased risk of myelosuppression. Use alternative agent or consider starting dose at 30-70% of usual dose and adjust according to individual safety or tolerability. Allow 2-4 weeks to reach steady state after each dose adjustment.
TPMT poor metabolisers, homozygous variant [(carriers of 2 nonfunctional alleles e.g. *3A/*3A, *2/*3A, *3C/*3A, *3C/*4, *3C/*2, *3A/*4)
Patient has reduced TPMT-mediated metabolism leading to extremely high concentrations of active TGN metabolites resulting to greater risk of developing life-threatening myelosuppression. Use alternative agent or drastically reduce daily dose by 10 folds and administer 3 times weekly instead of daily, adjust according to individual safety or tolerability. Allow 4-6 weeks to reach steady state after each dose adjustment.
NUDT15 rs116855232 variant
CC genotype
Patient treated by azathioprine for inflammatory bowel disease (IBD) or acute lymphoblastic leukaemia (ALL) with NUDT15 CC genotype may have reduced, but not absent risk of developing leucopenia, neutropenia or alopecia. Patient may be able to tolerate higher doses of azathioprine.
CT or TT genotype
Patient treated by azathioprine for IBD or ALL with NUDT15 CT or TT genotype are unable to tolerate usual dose of azathioprine and have higher risk of leucopenia, neutropenia or alopecia. They may require dose reduction. Close monitoring of blood count is necessary. The frequency of NUDT15 c.415C>T is at approx 10% of East Asians, 4% of Hispanics, and 0.2% in Europeans.
Renal Impairment
Reduce dose.
Hepatic Impairment
Reduce dose.
Administration
May be taken with or without food. Preferably taken w/ or after meals to reduce GI discomfort.
Reconstitution
Intravenous:
Add 10 mL of sterile water for inj to a vial containing 100 mg to produce a soln containing 10 mg/mL. May further dilute in NaCl 0.9% or dextrose 5% inj for IV infusion.
Contraindications
History of treatment w/ alkylating agents (e.g. chlorambucil, cyclophosphamide).
Special Precautions
Patient who are intermediate or poor thiopurine methyltransferase (TPMT) metabolisers. Patient with NUDT15 gene mutation. Renal and hepatic impairment. Pregnancy and lactation.
Monitor CBC w/ differential and platelet regularly, LFTs, total bilirubin, CrCl, symptoms of infection; TPMT genotyping or phenotyping.
Overdosage
Symptoms: Bleeding, unexplained infection, bruising, throat ulceration, nausea, vomiting, diarrhoea, mild leucopenia and liver function abnormalities. Management: Supportive treatment. Blood transfusion may be necessary.
Drug Interactions
Increased risk of infection w/ intra-uterine device and live vaccine. May potentiate neuromuscular blockade produced by depolarising agents (e.g. succinylcholine). May reduce neuromuscular blockade by non-depolarising agents (e.g. tubocurarine). May reduce anticoagulant effect of warfarin. Risk of haematologic abnormalities w/ ACE inhibitors, co-trimoxazole. Increased myelosuppressive effects w/ indometacin and cimetidine. Decreased rate of catabolism w/ xanthine oxidase inhibitors (e.g. allopurinol). Ribavirin may reduce efficacy and increase toxicity of azathioprine.
Action
Description: Mechanism of Action: Azathioprine is an imidazolyl derivative of mercaptopurine which inhibits RNA and DNA synthesis, and antagonises purine synthesis. It interferes w/ cellular metabolism by inhibiting coenzyme functioning and formation; may also inhibit mitosis. Pharmacokinetics: Absorption: Well absorbed from the GI tract. Time to peak plasma concentration: 1-2 hr (oral). Distribution: Enters breast milk (low concentration). Plasma protein binding: Approx 30%. Metabolism: Hepatically metabolised to 6-mercaptopurine via glutathione S-transferase (GST) reduction; further metabolised in the liver and GI tract via 3 main pathways: Hypoxanthine guanine phosphoribosyltransferase (to active metabolite: 6-thioguanine-nucleotides), xanthine oxidase (to inactive metabolite: 6-thiouric acid), and thiopurine methyltransferase (to inactive metabolite: 6-methylmercaptopurine). Excretion: Via urine (mainly as metabolites). Elimination half-life: Approx 2 hr.
Chemical Structure
Azathioprine Source: National Center for Biotechnology Information. PubChem Database. Azathioprine, CID=2265, https://pubchem.ncbi.nlm.nih.gov/compound/Azathioprine (accessed on Jan. 21, 2020)
Storage
Store between 15-25°C. Protect from light and moisture.
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