Azathioprine (AZA) is approved by the Food and Drug Administration (FDA) for symptomatic treatment of active rheumatoid arthritis. It also has approval as adjunctive therapy for the prevention of kidney transplant rejection.
AZA used off-label for the treatment of inflammatory bowel disease, Churg-Strauss syndrome, autoimmune hepatitis (for maintenance treatment along with steroids), chronic ITP (second-line agent), lupus nephritis, connective tissue disease-associated ILD, multiple sclerosis, severe myasthenia gravis, recurrent pericarditis, psoriasis, non-infectious uveitis, relapsing polychondritis, dermatomyositis/polymyositis, erythema multiforme, severe and refractory atopic dermatitis, chronic actinic dermatitis, pyoderma gangrenosum, Behcet disease, cutaneous vasculitis, pityriasis rubra pilaris, lichen planus, bullous pemphigoid and pemphigus vulgaris. Of note, AZA or 6-MP are treatment options for Crohn disease in children as a maintenance treatment.
Azathioprine is a purine analog that converts to its active metabolites, mercaptopurine (6-MP) and thioguanine (6-TGN), by hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) enzymes, then inhibits purine synthesis. Its metabolites are incorporated into the replicating DNA and halt division. AZA metabolites may also mediate most of its immunosuppressive and toxic effects. AZA is absorbed rapidly through the GI system and does not penetrate the blood-brain barrier. It undergoes metabolism in the liver and excretion is via the kidneys, which increases its toxicity in renal failure.
The starting dose for AZA is 2 to 2.5 mg/kg/day, except for patients with TPMT or NUDT15 gene mutation, in which the starting dose is lower than normal. Dose adjustments are necessary for hepatic and kidney disease.
AZA tablets may be administered after meals to decrease adverse GI effects. Administration can be by IV push over 5 minutes, at a concentration not exceeding 5 mg/ml. It can be further diluted with NS or DW and administered by intermittent infusion over 30 to 60 minutes. However, it may also be infused over 5 minutes up to over 8 hours.
Complications occur in 15 to 28% of patients.
Relative contraindications are:
Toxicity symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity, myelosuppression. Acute toxicity usually happens when more than 1.5 times of daily dose taken by the patient.
In the acute setting, activated charcoal may help with decreasing the symptoms within 2 hours of ingestion. No specific antidote is known for AZA. In severe cases of toxicity, dialysis is permissible as AZA is dialysable.
In cases of hepatic sinusoidal obstruction syndrome, it must discontinue permanently. If severely leukopenic, thrombocytopenic, or infected, treatment should stop.
Azathioprine is an immunomodulator which is associated with several serious adverse effects. Susceptibility to its toxicity varies with age, genetic differences, and medication dosage. Its adverse effects are a limiting factor in the patient's compliance. Therefore regular follow-up and frequent laboratory workups are crucial to avoiding its complications. Physicians and pharmacists should be aware of potential adverse effects with AZA, even in asymptomatic patients. Pharmacists should verify dosing is appropriate to the condition treated, and report any discrepancies to the rest of the healthcare team. Nursing will often function at the "front lines" in seeing the patients and are often the first to know about adverse events, which they can report to the team as well. Nursing will also be in charge of administration, so they should verify dosing to ensure optimal therapeutic results with minimal adverse effects.
In summary, azathioprine therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]
|||Ladri�re M, [Current indications of azathioprine in nephrology]. Nephrologie [PubMed PMID: 23022291]|
|||Anstey AV,Wakelin S,Reynolds NJ, Guidelines for prescribing azathioprine in dermatology. The British journal of dermatology. 2004 Dec; [PubMed PMID: 15606506]|
|||Schmidt C,Herrlinger K,Siegmund B,Bokemeyer B,Schreiber S,Stallmach A, [Azathioprine in Crohn's disease therapy--guidance against the background of recent studies]. Zeitschrift fur Gastroenterologie. 2014 Dec; [PubMed PMID: 25474282]|
|||Outcomes in Pediatric Autoimmune Hepatitis and Significance of Azathioprine Metabolites., Sheiko MA,Sundaram SS,Capocelli KE,Pan Z,McCoy AM,Mack CL,, Journal of pediatric gastroenterology and nutrition, 2017 Mar 7 [PubMed PMID: 28272159]|
|||Aljumah AA,Al Jarallah B,Albenmousa A,Al Khathlan A,Al Zanbagi A,Al Quaiz M,Al-Judaibi B,Nabrawi K,Al Hamoudi W,Alghamdi M,Fallatah H, The Saudi association for the study of liver diseases and transplantation clinical practice guidelines for management of autoimmune hepatitis. Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association. 2018 Nov; [PubMed PMID: 30264737]|
|||Cooper N, State of the art - how I manage immune thrombocytopenia. British journal of haematology. 2017 Apr; [PubMed PMID: 28295192]|
|||Oldham JM,Lee C,Valenzi E,Witt LJ,Adegunsoye A,Hsu S,Chen L,Montner S,Chung JH,Noth I,Vij R,Strek ME, Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease. Respiratory medicine. 2016 Dec; [PubMed PMID: 27888985]|
|||Imazio M,Lazaros G,Brucato A,Gaita F, Recurrent pericarditis: new and emerging therapeutic options. Nature reviews. Cardiology. 2016 Feb; [PubMed PMID: 26259934]|
|||Touhami S,Diwo E,S�ve P,Trad S,Bielefeld P,S�ne D,Abad S,Br�zin A,Quartier P,Kon� Paut I,Weber M,Chiquet C,Errera MH,Sellam J,Cacoub P,Kaplanski G,Kodjikian L,Bodaghi B,Saadoun D, Expert opinion on the use of biological therapy in non-infectious uveitis. Expert opinion on biological therapy. 2019 Mar 19; [PubMed PMID: 30888881]|
|||Mathian A,Miyara M,Cohen-Aubart F,Haroche J,Hie M,Pha M,Grenier P,Amoura Z, Relapsing polychondritis: A 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best practice [PubMed PMID: 27886803]|
|||Meggitt SJ,Anstey AV,Mohd Mustapa MF,Reynolds NJ,Wakelin S, British Association of Dermatologists' guidelines for the safe and effective prescribing of azathioprine 2011. The British journal of dermatology. 2011 Oct; [PubMed PMID: 21950502]|
|||Ruemmele FM,Veres G,Kolho KL,Griffiths A,Levine A,Escher JC,Amil Dias J,Barabino A,Braegger CP,Bronsky J,Buderus S,Mart�n-de-Carpi J,De Ridder L,Fagerberg UL,Hugot JP,Kierkus J,Kolacek S,Koletzko S,Lionetti P,Miele E,Navas L�pez VM,Paerregaard A,Russell RK,Serban DE,Shaoul R,Van Rheenen P,Veereman G,Weiss B,Wilson D,Dignass A,Eliakim A,Winter H,Turner D, Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. Journal of Crohn's [PubMed PMID: 24909831]|
|||Wee JS,Marinaki A,Smith CH, Life threatening myelotoxicity secondary to azathioprine in a patient with atopic eczema and normal thiopurine methyltransferase activity. BMJ (Clinical research ed.). 2011 Mar 25; [PubMed PMID: 21441287]|
|||Trend towards dose reduction of azathioprine as monotherapy in inflammatory bowel disease patients: what about for combination therapy?, Williet N,Roblin X,, Therapeutic advances in gastroenterology, 2017 Jan [PubMed PMID: 28286554]|
|||Joshi R,Singh S, Plica Neuropathica (Plica polonica) Following Azathioprine-induced Pancytopenia. International journal of trichology. 2010 Jul; [PubMed PMID: 21712900]|
|||Steponaitiene R,Kupcinskas J,Survilaite S,Varkalaite G,Jonaitis L,Kiudelis G,Denapiene G,Valantinas J,Skieceviciene J,Kupcinskas L, TPMT and ITPA genetic variants in Lithuanian inflammatory bowel disease patients: Prevalence and azathioprine-related side effects. Advances in medical sciences. 2016 Mar; [PubMed PMID: 26674571]|
|||Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis and rheumatism. 1996 May; [PubMed PMID: 8639168]|
|||Melzer N,Ruck T,Fuhr P,Gold R,Hohlfeld R,Marx A,Melms A,Tackenberg B,Schalke B,Schneider-Gold C,Zimprich F,Meuth SG,Wiendl H, Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. Journal of neurology. 2016 Aug; [PubMed PMID: 26886206]|
|||Broekman MMTJ,Coenen MJH,van Marrewijk CJ,Wanten GJA,Wong DR,Verbeek ALM,Klungel OH,Hooymans PM,Guchelaar HJ,Scheffer H,Derijks LJJ,de Jong DJ, More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing. Inflammatory bowel diseases. 2017 Oct; [PubMed PMID: 28644183]|
|||Weinshilboum RM,Sladek SL, Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American journal of human genetics. 1980 Sep; [PubMed PMID: 7191632]|
|||Nielsen OH,Vainer B,Rask-Madsen J, Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Alimentary pharmacology [PubMed PMID: 11683683]|
|||Saway PA,Heck LW,Bonner JR,Kirklin JK, Azathioprine hypersensitivity. Case report and review of the literature. The American journal of medicine. 1988 May; [PubMed PMID: 3284343]|
|||Azathioprine-Induced Hypersensitivity Reaction Presenting as Erythema Nodosum., González-Olivares M,Khedaoui R,Martínez-Morán C,Borbujo J,, Actas dermo-sifiliograficas, 2017 Mar 2 [PubMed PMID: 28262113]|
|||Karaahmet F,Akinci H,Ayte R,Hamamci M,Coskun Y,Yuksel I, Tremor as dose dependent side-effect of azathioprine in remission patient with ileal Crohn's disease. Journal of Crohn's [PubMed PMID: 23623283]|
|||Fuggle NR,Bragoli W,Mahto A,Glover M,Martinez AE,Kinsler VA, The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. Journal of the American Academy of Dermatology. 2015 Jan; [PubMed PMID: 25440430]|
|||Trivedi CD,Pitchumoni CS, Drug-induced pancreatitis: an update. Journal of clinical gastroenterology. 2005 Sep; [PubMed PMID: 16082282]|
|||van Geenen EJ,de Boer NK,Stassen P,Linskens RK,Bruno MJ,Mulder CJ,Stegeman CA,van Bodegraven AA, Azathioprine or mercaptopurine-induced acute pancreatitis is not a disease-specific phenomenon. Alimentary pharmacology [PubMed PMID: 20222913]|
|||Gupta P,Shaffrali F, An unusual side effect of azathioprine. Clinical and experimental dermatology. 2015 Dec; [PubMed PMID: 25810100]|
|||van der Woude CJ,Ardizzone S,Bengtson MB,Fiorino G,Fraser G,Katsanos K,Kolacek S,Juillerat P,Mulders AG,Pedersen N,Selinger C,Sebastian S,Sturm A,Zelinkova Z,Magro F, The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. Journal of Crohn's [PubMed PMID: 25602023]|
|||Provan D,Stasi R,Newland AC,Blanchette VS,Bolton-Maggs P,Bussel JB,Chong BH,Cines DB,Gernsheimer TB,Godeau B,Grainger J,Greer I,Hunt BJ,Imbach PA,Lyons G,McMillan R,Rodeghiero F,Sanz MA,Tarantino M,Watson S,Young J,Kuter DJ, International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010 Jan 14; [PubMed PMID: 19846889]|
|||Petri M, Immunosuppressive drug use in pregnancy. Autoimmunity. 2003 Feb; [PubMed PMID: 12765471]|
|||Menter A,Korman NJ,Elmets CA,Feldman SR,Gelfand JM,Gordon KB,Gottlieb AB,Koo JY,Lebwohl M,Lim HW,Van Voorhees AS,Beutner KR,Bhushan R, Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. Journal of the American Academy of Dermatology. 2009 Sep; [PubMed PMID: 19493586]|
|||Jack KL,Koopman WJ,Hulley D,Nicolle MW, A Review of Azathioprine-Associated Hepatotoxicity and Myelosuppression in Myasthenia Gravis. Journal of clinical neuromuscular disease. 2016 Sep; [PubMed PMID: 27552384]|
|||Gregoriano C,Ceschi A,Rauber-Lüthy C,Kupferschmidt H,Banner NR,Krähenbühl S,Taegtmeyer AB, Acute thiopurine overdose: analysis of reports to a National Poison Centre 1995-2013. PloS one. 2014; [PubMed PMID: 24489721]|