Azathioprine (AZA)

Azathioprine (AZA)

  • Prodrug of 6-MP (6-mercaptopurin)
  • Pregnancy category D
  • Easily crosses placenta & mammary glands (avoid breastfeeding within 4 hours post azathioprine dose; when majority of 6-MP in breast milk is excreted)

Based on Thiopurine Methyltransferase (TPMT) level

  • High TPMT >15:  2-2.5 mg/kg/day
  • Intermediate TPMT 6.3-15: 1mg/kg/day
  • Low TPMT <6.3: avoid
  • Orally, twice daily 
  • Takes 4-6 weeks for effect to be seen, maximum effect at 8-12 weeks
  • Azathioprine effect is continued up to 6 weeks post discontinuation

Antimetabolite effect

  • Azathioprine is rapidly converted by Glutathione transferase in erythrocytes to 6-MP (6-mercaptopurine) which is then is metabolized via 3 pathways:
    1. Xanthine oxidase (XO): inactive metabolites
    2. TPMT:  inactive metabolites
    3. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT): active metabolite 6-TG (6-Thioguanine), a purine analog to adenine & guanine, incorporates into DNA/RNA during S- phase of cell cycle, inhibiting purine metabolism & cellular division

Other mechanisms (less understood)

  • Decrease T cell & B cell functions, decrease antibody production 
  • Decrease langerhan cells

Metabolism

Via 3 pathways

  • Xanthine oxidase 
  • Thiopurine Methyltransferase (TPMT)
  • Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) 
  • Decrease activity of degradative pathways (xanthine oxidase, TPMT) will shift metabolism to the active pathway (HGPRT) leading to more cytotoxic effects (immune suppression/ myelosuppression) 
  • 88% orally bioavailable

Excretion

  • Negligible 

Note

  • Azathioprine does not cross blood brain barrier
  • Renal insufficiency requires dose reduction

FDA (food & drug administration)

  • Organ transplant
  • Rheumatoid arthritis 

Off label

  • Dermatitis
  • Papulosquamous diseases
  • Immunobullous
  • Vasculitis
  • Neutrophilic dermatoses
  • Autoimmune connective tissue disease (especially palmoplantar discoid lupus)
  • Photodermatoses
  • Sarcoidosis
  • Persistent erythema multiforme
  • Chronic graft-versus-host disease

Absolute

  • Hypersensitivity
  • Pregnancy
  • Significant active infection
  • Low Thiopurine Methyltransferase (TPMT)

Relative

  • Allopurinol use 
  • Prior use of alkylating agents (risk of malignancy)
  • Vaccines: caution with live vaccines, may have atypical response

Myelosuppression  

  • Correlates with Thiopurine Methyltransferase (TPMT) level (discontinue azathioprine if white blood cells <3500, hemoglobin < 10 g/dL, platelets <100 000/mm 

Infections 

  • Increase risk at higher doses & if on multiple immunosuppressants e.g. human herpes virus, human papilloma virus, scabies
  • Potential for latent infection reactivation e.g.  tuberculosis, hepatitis B virus

Carcinogenesis 

  • Increase risk of lymphoproliferative diseases (especially Non-Hodgkin lymphoma) & squamous cell carcinomas

Hypersensitivity syndrome

  • Wide range of symptoms (cardiovascular collapse, pneumonitis, pancreatitis, arthralgias, polymorphous skin eruptions), occurs 1-4 weeks after starting azathioprine
  • More common with concomitant use of cyclosporine or methotrexate
  • Discontinue azathioprine, & re-challenge is contraindicated

Reproductive

  • Pregnancy category D, temporarily depresses spermatogenesis

Gastrointestinal

  • Nausea, vomiting, diarrhea common, to ↓ symptoms give azathioprine as a twice daily dose +/- with food

Hepatic

  • Life-threatening hepatic failure – uncommon

Xanthine oxidase inhibitors

  • Allopurinol
  • Febuxostat (if needed to be used concomitantly, azathioprine dose should be ↓ by 75%)

TMPT

  • Genetics 
  • Sulfasalazine

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

  • Lesch-Nyhan syndrome

↑ Myelosuppression & hypersensitivity 

  • Methotrexate
  • Cyclosporine

Other important interactions

  • Angiotensin converting enzyme (ACE) inhibitors: ↓ white blood cells
  • Anticoagulants: decrease Warfarin 
  • Decrease Neuromuscular blockers
  • Tumor necrosis factor (TNF) inhibitors: Increase risk of aggressive hepatosplenic T-cell lymphoma & other T-cell lymphomas

Baseline

  • History & physical examination
  • Complete blood count, chemistry profile, liver function tests, urinalysis
  • If glomerular filtration rate <10, decrease azathioprine by 50%, if 10-50 decrease by 25%
  • Pregnancy test
  • Tuberculin skin test (if indicated) 
  • Thiopurine Methyltransferase (TPMT) level

Follow-up

  • Complete blood count + liver function tests every 2weeks x 2 months then every 3 months
  • Annual skin exam & cancer screen

Guidelines for use in dermatology

  • Life threatening condition
  • Patient dermatosis was unresponsive to less risky treatments
  • Dermatoses should be controllable & reversible
  • Physician should have methods to evaluate improvement (clinical/laboratory)
  • Risks, side effects, & alternative options must be discussed with the patient
  • Patient should be compliant with monitoring & follow up