What are the common side effects of restarting azathioprine?

Common Side Effects When Restarting Azathioprine

The most common side effects when restarting azathioprine are dose-dependent nausea, gastrointestinal disturbances, myelotoxicity (particularly neutropenia), and hepatotoxicity. 1

Gastrointestinal Side Effects

• Early, mild nausea is extremely common when restarting azathioprine and often self-resolves after a few weeks without dose adjustment 1
• Nausea and vomiting occur in approximately 12% of patients and typically appear within the first few months of therapy 2
• Gastrointestinal symptoms may be severe in some patients and accompanied by diarrhea, fever, malaise, and myalgias 2
• Vomiting with abdominal pain may rarely indicate hypersensitivity pancreatitis, which requires immediate discontinuation 2

Management of Gastrointestinal Side Effects

• Taking azathioprine after food can reduce nausea 1
• Using divided daily doses rather than a single dose can minimize gastrointestinal side effects 1
• Temporary dose reduction may help manage moderate nausea 1
• Antiemetics can be prescribed for symptomatic relief 1
• If these strategies fail, switching to 6-mercaptopurine may reduce gastrointestinal side effects 1

Hematologic Toxicity

• Bone marrow suppression, particularly neutropenia, is a potentially serious and dose-dependent side effect 1
• The incidence of azathioprine-induced neutropenia ranges from 5-30% with a mean of 19% 1
• Myelotoxicity can occur at any stage during therapy, including when restarting the medication 1
• Pancytopenia may occur in patients with thiopurine methyltransferase (TPMT) deficiency 3

Management of Hematologic Toxicity

• Regular monitoring of complete blood counts is essential when restarting azathioprine 1
• If total white cell count falls below 3.5×10⁹/L or neutrophils below 2×10⁹/L, withhold azathioprine until counts normalize 1
• If neutrophils fall below 1×10⁹/L, patients should be warned to seek medical attention if febrile 1
• Once abnormalities resolve, azathioprine can be restarted at a lower dose with careful monitoring 1

Hepatotoxicity

• Mild derangement of liver function tests is not uncommon and usually has no serious clinical implications 1
• Hepatotoxicity manifests as elevation of serum alkaline phosphatase, bilirubin, and/or transaminases 2
• Severe hepatotoxicity is rare but can occur in two patterns: acute idiosyncratic drug-induced liver injury or nodular regenerative hyperplasia 1

Management of Hepatotoxicity

• Monitor liver function tests regularly when restarting azathioprine 1
• Detection of abnormal liver tests should prompt careful evaluation and increased frequency of monitoring 1
• Dose reduction or drug withdrawal may be necessary if liver function deteriorates significantly 1

Hypersensitivity Reactions

• Idiosyncratic hypersensitivity reactions are rare but can occur when restarting azathioprine 1
• Manifestations include fever, hypotension, nausea, vomiting, diarrhea, rash, and potentially circulatory collapse 1, 4
• Nausea associated with fever, myalgia, or arthralgia suggests hypersensitivity rather than simple dose-dependent nausea 1
• These reactions can be life-threatening and require immediate discontinuation of the drug 4

Increased Susceptibility to Infection

• Patients may have increased susceptibility to infection even without neutropenia 1
• Mild lymphopenia is commonly seen in patients receiving thiopurines 1
• Varicella zoster virus (VZV) infections occur more commonly in patients receiving azathioprine 1
• Reactivation of latent infections such as tuberculosis has been reported 1

Special Considerations When Restarting

• Gradual dose escalation when restarting may minimize initial nausea 1
• Patients who previously experienced severe hypersensitivity reactions should not be rechallenged with azathioprine 4
• Patients with previous hematologic or hepatic toxicity may tolerate retreatment with azathioprine, but those with systemic toxicity often do not 5
• Toxicity can be delayed as long as 56 weeks after starting azathioprine in some patients 5

Monitoring Recommendations

• Complete blood counts should be performed weekly during the first month after restarting 1
• Continue monitoring twice monthly for the second and third months, then monthly or more frequently if dosage alterations are necessary 2
• Regular liver function tests are recommended to detect hepatotoxicity early 1
• Prompt dose reduction or temporary withdrawal may be necessary if there is evidence of bone marrow depression 2