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Azathioprine

Author: Oranus Mohammadi Editor: Thamer A. Kassim Updated: 5/1/2023 7:22:48 PM

Indications

Azathioprine (AZA) is approved by the Food and Drug Administration (FDA) for the 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

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Mechanism of Action

Azathioprine is a purine analog that converts to its active metabolites, mercaptopurine (6-MP) and thioguanine (6-TGN), by the action of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) enzymes. It 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]

  • 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 cases.
    • 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
    • An increase in the mean corpuscular volume of the red blood cells is also an expected side effect
  • Rash
  • Hepatotoxicity: Hepatic injury correlates with a 6-MMP level of 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 six 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 harms in keeping the mother safe.
  3. Breastfeeding as 6-MP was present in breast-milk of women who take azathioprine
  4. Unknown TPMT status or deficient TPMT activity due to the high risk of myelosuppression 
  5. Known malignancy
  6. Clinically active infection

Relative Contraindications[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. The recommendation is 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. A 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. CBC and LFT should get checked every three months for the rest of the treatment once the maintenance dose is achieved. However, it is advisable to check CBC and LFT more frequently in patients with kidney or renal diseases or elderly patients on high dosages of AZA or 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 requires checking to rule out pancreatitis. Lymph node and skin examination should be biannual.[32] If a generalized wart occurs, the 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 is taken by the patient. 

In the acute setting, activated charcoal may help with decreasing the symptoms within two 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 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. Clinicians and pharmacists should be aware of potential adverse effects of 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. 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 clinicians, specialists, mid-level practitioners, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]

References

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