Azathioprine


Thông tin thuốc gốc
Chỉ định và Liều dùng
Intravenous
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. 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.
Cách dùng
May be taken with or without food. Preferably taken w/ or after meals to reduce GI discomfort.
Hướng dẫn pha thuốc
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.
Chống chỉ định
History of treatment w/ alkylating agents (e.g. chlorambucil, cyclophosphamide).
Thận trọng
Patient who are intermediate or poor thiopurine methyltransferase (TPMT) metabolisers. Patient with NUDT15 gene mutation. Renal and hepatic impairment. Pregnancy and lactation.
Phản ứng phụ
Bone marrow depression (dose-related) characterised by anaemia, leucopenia, thrombocytopenia and rarely, aplastic anaemia, agranulocytosis, pancytopenia; reversible myelosuppression, megaloblastic anaemia, myelotoxicity, liver damage, GI disturbances, reversible alopecia, rashes, muscle and joint pains, rigors, fever, pneumonitis, tachycardia, pancreatitis, renal dysfunction, hypotension, Sweet’s syndrome (acute febrile neutrophilic dermatosis). Rarely, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Potentially Fatal: Progressive multifocal leucoencephalopathy. Rarely, veno-occlusive liver disease, hepatosplenic T-cell lymphoma (HSTCL), post-transplant lymphoma.
IV/Parenteral/PO: D
MonitoringParameters
Monitor CBC w/ differential and platelet regularly, LFTs, total bilirubin, CrCl, symptoms of infection; TPMT genotyping or phenotyping.
Quá liều
Symptoms: Bleeding, unexplained infection, bruising, throat ulceration, nausea, vomiting, diarrhoea, mild leucopenia and liver function abnormalities. Management: Supportive treatment. Blood transfusion may be necessary.
Tương tác
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.
Tác dụng
Description: 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.
Đặc tính

Chemical Structure Image
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)

Bảo quản
Store between 15-25°C. Protect from light and moisture.
Phân loại ATC
L04AX01 - azathioprine ; Belongs to the class of other immunosuppressants.
References
Relling MV, Gardner EE, Sandborn et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update. CPIC Update. 2013 Feb. doi:10.1038/clpt.2013.4. Accessed 26/09/2018

Anon. Azathioprine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 23/10/2015.

Azathioprine Tablet (Mylan Institutional Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 23/10/2015.

Buckingham R (ed). Azathioprine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 23/10/2015.

Clinical Annotation for NUDT15; Azathioprine or Mercaptopurine; IBD and Precursor Cell Lymphoblastic Leukemia-Lymphoma (Level 1B Dosage, Toxicity/ADR). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 26/09/2018.

CPIC Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org/. Accessed 26/09/2018.

Imuran Tablets and Injection. U.S. FDA. https://www.fda.gov/. Accessed 23/10/2015.

Joint Formulary Committee. Azathioprine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 23/10/2015.

McEvoy GK, Snow EK, Miller J et al (eds). Azathioprine, Azathioprine Sodium. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 23/10/2015.

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