Azathioprine


Article Author:
Oranus Mohammadi


Article Editor:
Thamer Kassim


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
7/17/2019 8:40:22 AM

Indications

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.[1][2]

AZA used off-label for the treatment of inflammatory bowel disease,[3] Churg-Strauss syndrome, autoimmune hepatitis (for maintenance treatment along with steroids),[4][5] chronic ITP (second-line agent),[6] lupus nephritis,[1] connective tissue disease-associated ILD,[7] multiple sclerosis, severe myasthenia gravis, recurrent pericarditis,[8] psoriasis, non-infectious uveitis,[9] relapsing polychondritis,[10] 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.[2][11] Of note, AZA or 6-MP are treatment options for Crohn disease in children as a maintenance treatment.[12]

Mechanism of Action

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.[13] 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.[2]

Administration

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.[14] Dose adjustments are necessary for hepatic and kidney disease.[11]

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.

Adverse Effects

Complications occur in 15 to 28% of patients.[2]

Frequent side effects[15][16][13][4][17][18][19][20][21][22][23][24][4]:

  • Nausea; is the most frequent side effect
    • Dose-dependent.
    • Early-onset nausea usually resolves without dose alteration
  • Fever
  • Fatigue
  • Arthralgias/myalgia
  • Bone marrow suppression causing pancytopenia, thrombocytopenia, leukopenia - there are reports of dose-dependent, life-threatening case
    • This complication correlates with the 6-TGN level
    • There is a higher risk of myelosuppression in patients who take allopurinol or ACEI and in renal insufficiency
    • Increase in mean corpuscular volume of the red blood cells is also an expected side effect
  • Rash
  • Hepatotoxicity: Hepatic injury correlates with 6-MMP level more than 5700 pmol/8 x 10^8 RBC.
  • Hepatotoxicity categorizes into two groups
    • Acute idiosyncratic liver injury happens in the early course and resolves with stopping the medication  
    • Nodular regenerative hyperplasia occurs in IBD and organ transplant patients several years after therapy
  • Infections (7.4%): Concomitant use of AZA and steroids will increase the risk of PCP in leukopenic patients
  • Hypersensitivity: symptoms including fever, chills, arthralgia/myalgia, liver abnormalities, erythema nodosum
  • Kidney damage

Rare side effects[25][26][27][21][28][15][11][24]:

  • Diarrhea
  • Carcinogenesis: cutaneous hyperkeratosis and nonmelanoma skin cancer (SCC) in myasthenia gravis (most likely due to increased risk of photosensitivity), solid-organ transplant and IBD patients/ lymphoma in transplant and IBD patients
  • Pancreatitis (3.3%): more in females with Crohn disease
    • Dose-dependent
    • Usually happens in the first 6 weeks
    • In the case of pancreatitis, discontinue AZA
  • Alopecia including telogen effluvium, anagen effluvium, and plica neuropathica
  • Macrocytic anemia
  • Sweet syndrome (acute febrile neutrophilic dermatosis)
  • Pneumonitis: in IBD and renal transplant patients
  • Upper airway edema
  • Tremor: in transplant and Crohn patient: dose-dependent

Contraindications

Contraindications[29][30][31][2][32]:

  1. Hypersensitivity
  2. Pregnancy or plan for pregnancy: Contraception recommended. AZA can increase the risk of spontaneous miscarriage, low birth-weight, and preterm delivery. Although data in systemic lupus erythematosus (SLE) and renal transplant patients showed safety in pregnancy. In some specific conditions like SLE and antiphospholipid antibody syndrome, the benefits of taking immunosuppressive medications are more than harm to keep the mother safe.
  3. Breastfeeding as 6-MP was present in breast-milk of women who take azathioprine
  4. Unknown TPMT status or very low TPMT activity due to the high risk of myelosuppression 
  5. Known malignancy
  6. Clinically active infection

Relative contraindications are[32]:

  1. Allopurinol intake concomitantly with AZA due to severe myelosuppression 
  2. Cyclophosphamide or chlorambucil treatment in the past

Monitoring

  • It usually requires 6 to 8 weeks for AZA to work. It is recommended to consider stopping the medication if there is no improvement in 3 months.[2]
  • Checking TPMT activity is suggested before starting the medication. Misclassification of TMPT phenotype can occur by prior blood transfusion.[12]
  • Test the patient for hepatitis B and C and PPD. Pregnancy test before treatment initiation is also a recommendation.[32]
  • Complete blood count (CBC) and liver function test (LFT) monitoring weekly are recommended initially for the first 4 to 8 weeks. When maintenance dose achieved, CBC and LFT should get checked every 3 months for the rest of the treatment. Although it is advised to check CBC and LFT more frequently in patients with kidney or renal diseases or, elderly, patients on high dosages of AZA or with low TPMT activity. If labs show leukopenia (WBC less than 3 x 10^9/L), thrombocytopenia (platelet less than 120 x 10^9/L) or transaminitis (liver biochemistry more than half of the normal upper limit), the medication should be stopped.[21]
  • If patients have abdominal pain or severe nausea/vomiting, serum amylase should be checked to rule out pancreatitis. Lymph node and skin examination should be biannual.[32] If generalized wart occurs, AZA dose should be reduced or switched to another agent.
  • Some studies suggested monitoring the level of AZA metabolites (e.g., 6-TGN and 6-MP) to avoid specific complications.[4]

Toxicity

Toxicity symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity, myelosuppression.[33] 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.[34] 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. 

Enhancing Healthcare Team Outcomes

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]


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Azathioprine - Questions

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Because of its liver toxicity, azathioprine, for the prevention of transplant rejection, is now often replaced by which of the following?



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A 42-year-old obese female with twice yearly flares of Crohn disease previously managed well with steroids is now readmitted with another flare. She has recently found out that she has diabetes and is tired of the side effects of weight gain. She wishes to be on a single treatment throughout that will have minimal side effects. She is up to date with all her vaccinations, and her titers are within normal limits. Which of the following investigations would be most important to check prior to starting her on azathioprine?



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A patient is on azathioprine for rheumatoid arthritis. He was having problems with hyperuricemia gout and was started on allopurinol. Over the next few days, he becomes profoundly neutropenic, anemic, and thrombocytopenic. What is the most likely reason for the pancytopenia?



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A 68-year-old female with a past medical history of rheumatoid arthritis was recommended to start on azathioprine by her rheumatologist. Before initiating therapy with azathioprine, which of the following test is recommended to perform?



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A 66-year-old female with a history of Crohn disease is being evaluated in the clinic for follow-up. Lab studies showed white blood cell count 5000/microL, hemoglobin 11.2 g/dL, and platelets 59000/microL. The only current medication is azathioprine. She complains of mild diffuse abdominal pain. Her temperature is 37.1 C (98.8 F), blood pressure is 125/70 mmHg, pulse rate is 80/min, and respiratory rate is 12/min. The physical examination is unremarkable. Which of the following drug-related complications would be most expected in this patient?



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A 38-year-old female is being evaluated at follow-up after starting azathioprine (AZA) therapy for myasthenia gravis. Patient denies any new symptoms. Physical examination, including a neurological exam, is unremarkable. Labs show a white blood cell count of 2500/microL, platelets 150000/microL, aspartate transaminase 59 IU/L, alanine transaminase 100 IU/L, and alkaline phosphatase 109 IU/L. Which of the following is the next best step in the management of this patient?



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Azathioprine - References

References

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