What are the contraindications for using Azathioprine in a patient with refractory Immune Thrombocytopenic Purpura (ITP)?

Contraindications of Azathioprine in ITP

Azathioprine should not be used in ITP patients with absent or very low TPMT activity, known hypersensitivity to azathioprine or 6-mercaptopurine, concurrent allopurinol or febuxostat use, pregnancy (unless benefits outweigh risks), active breastfeeding, severe infections, severely impaired hepatic or bone marrow function, active pancreatitis, or active malignancy. 1, 2

Absolute Contraindications

TPMT Deficiency

• Very low or absent TPMT activity is an absolute contraindication due to the high risk of life-threatening pancytopenia and profound myelosuppression 1
• Approximately 0.3% (1:300) of patients have two loss-of-function TPMT alleles with little or no TPMT activity (homozygous deficient) 2
• TPMT status must be checked before initiating azathioprine therapy—it is strongly recommended that azathioprine should not be used in patients whose TPMT status is unknown 1
• Patients with intermediate TPMT activity (approximately 10% of population) require dose reduction to approximately 50% of standard dosing 1, 2

NUDT15 Deficiency

• NUDT15 deficiency also increases risk of severe myelosuppression and should be considered, particularly in patients of East Asian ancestry where 2% have two loss-of-function alleles 2
• Consider genotyping for NUDT15 deficiency in patients with severe myelosuppression 2

Known Hypersensitivity

• Known hypersensitivity to azathioprine or 6-mercaptopurine is an absolute contraindication 1, 2
• Hypersensitivity reactions can manifest as fever, rash, malaise, myalgias, severe nausea and vomiting, diarrhea, and potentially hypotension 2, 3
• These reactions can be severe and potentially fatal, often occurring within the first several weeks of therapy 2, 3

Concurrent Drug Interactions

• Concurrent allopurinol treatment is contraindicated—if unavoidable, azathioprine dose must be reduced to approximately 1/3 to 1/4 the usual dose due to severe myelosuppression risk 1, 2
• Concomitant use with febuxostat is not recommended due to similar xanthine oxidase inhibition leading to toxicity 2
• Xanthine oxidase inhibitors block one of the major inactivation pathways of azathioprine, causing accumulation of toxic metabolites 2

Relative Contraindications

Pregnancy and Lactation

• Azathioprine is contraindicated in pregnancy except where benefit may outweigh risk (such as in allograft recipients) 1
• Adequate contraceptive precautions are advised when either partner is taking azathioprine 1
• Women on azathioprine should not breastfeed their babies—6-mercaptopurine has been identified in colostrum and breast milk 1, 2

Active Malignancy

• Azathioprine treatment should not usually be initiated or continued in patients with known malignancy, as immunosuppression may increase the risk of disease progression 1
• There are concerns about increased malignancy risk with prolonged azathioprine use, though the absolute risk appears to be low 1

Severe Organ Dysfunction

• Severely impaired hepatic or bone marrow function is a contraindication per FDA labeling 2
• Renal or hepatic insufficiency represents a relative contraindication requiring dose adjustment and more frequent monitoring 1
• Doses at the lower end of the range (1 mg/kg/day) are recommended in patients with renal and/or hepatic impairment 1

Active Infections and Pancreatitis

• Severe infections are a contraindication to azathioprine initiation 1, 2
• Active pancreatitis is a contraindication—acute pancreatitis is a rare but well-recognized side effect of azathioprine 1, 2
• Live vaccines are contraindicated in patients receiving azathioprine due to immunosuppression 1, 2

Special Considerations for ITP Patients

Pre-existing Cytopenias

• While ITP itself causes thrombocytopenia, patients with additional severe baseline cytopenias (severe leukopenia or anemia) require careful consideration 1
• Moderate leucopenia common in cirrhosis probably does not increase the risk of azathioprine-related marrow depression per se, but complicates haematological monitoring 1

Concurrent Medications

• Aminosalicylate derivatives (sulphasalazine, mesalazine, olsalazine) inhibit TPMT enzyme—concomitant use should be done with caution 2
• Ribavirin use is contraindicated with azathioprine due to severe pancytopenia risk 2
• Warfarin effect may be inhibited by azathioprine, requiring careful monitoring 2
• Angiotensin-converting enzyme inhibitors may induce anemia and severe leukopenia when used with azathioprine 2

Common Pitfalls to Avoid

• Do not start azathioprine without checking TPMT status first—this is a critical safety measure that cannot be skipped 1
• Do not rechallenge patients who experienced hypersensitivity reactions—these can be severe and potentially fatal upon re-exposure 2, 3
• Do not forget to adjust dose or avoid azathioprine entirely in patients on xanthine oxidase inhibitors—this interaction can be life-threatening 1, 2
• Elderly patients require doses at the lower end of the recommended range with additional haematological monitoring due to higher incidence of side effects 1