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Box 4 Methods of administering azathioprine

From: French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and ANCA-associated vasculitides)

Azathioprine is administered orally at a dose of 2 mg/kg/day in one, two, or three doses daily, without exceeding 200 mg/day (based on published therapeutic trials) and rounded up to the multiple dose of 25 mg higher (e.g., for a 70 kg patient, the dose will be 150 mg/day). This dose may be increased to 3 mg/kg/day by the doctor if he deems it useful (in the event of a partial response to 2 mg/kg/day), in the absence of studies having proven better efficacy of the drug azathioprine at a dose of 3 mg/kg/day, however. The maximum dose should not exceed 200 mg/day, regardless of the patient’s weight. Conversely, the doctor may reduce the daily dose by 25–50 mg in the event of a minor side effect in order to improve the digestive or hematological tolerance of the treatment. If this is not enough and/or if the side effect observed is serious from the start, the treatment must be definitively stopped
When deciding to introduce azathioprine, the doctor can now rely on recommendations from the National Pharmacogenetic Network (RNGx) published in 2017. A warning regarding the genetic deficit in TPMT (thiopurine methyltransferase) and the risk of rapid development of myelosuppression is present in the SPC for azathioprine. There are, however, no pharmacogenetic recommendations in the SPC, unlike the American SPC
The Clinical Pharmacogenetics Implementation Consortium and the RNGx recommend the search for a TPMT deficiency based on the identification of the allelic variants TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C or on the phenotyping of TPMT allowing classification of individuals based on their metabolic capacity and suggest dose adjustments based on the TPMT status
However, there is no study showing that an adjustment of the doses based on the genotypic study made it possible to reduce the risk of hematological events, in particular during chronic inflammatory diseases of the intestine. Thus, carrying out this test does not rule out strict hematological monitoring, especially in the first weeks of treatment
The concomitant prescription of a urate-lowering treatment with allopurinol or febuxostat is contraindicated (increase in spinal toxicity). If allopurinol or febuxostat cannot be interrupted, the choice should be made for another immunosuppressant
Azathioprine is usually prescribed for 12–24 months (optimal duration not defined)
In ANCA-associated vasculitides, the REMAIN study conducted by EUVAS recently demonstrated the superiority of a 4-year maintenance treatment compared to a 2-year treatment
Biological monitoring will include a regular complete blood count, platelets, and transaminases (AST or ALT), every week for the first month, then every month for 3 months, then every 3 months until it is stopped
 
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