Azathioprine

The frequency of gastrointestinal adverse effects (nausea and vomiting) may be decreased with dividing dose or administering after meals. Gastrointestinal hypersensitivity with severe nausea and vomiting has been reported; diarrhea, rash, fever, malaise, myalgia, hypotension, and liver enzyme abnormalities may also occur. Symptoms usually develop within the first several weeks of treatment and are generally reversible upon discontinuation; may recur upon rechallenge.

Dose-related hematologic toxicities (leukopenia, thrombocytopenia, and anemias, including macrocytic anemia and/or pancytopenia) may occur; may be severe and/or delayed. Thiopurine methyltransferase (TPMT) genotyping or phenotyping may help to identify patients who are at an increased risk for developing azathioprine toxicity. Patients with intermediate TPMT activity may be at increased risk for hematologic toxicity at conventional azathioprine doses; patients with low or absent TPMT activity are at risk for severe, life-threatening myelotoxicity. Myelosuppression may be more severe with renal transplants undergoing rejection. Monitor CBC with differential and platelets weekly during the first month, then twice a month for 2 months, then monthly (or more frequently if clinically indicated). May require treatment interruption or dose reduction. Leukopenia does not correlate with therapeutic effect and the dose should not be increased intentionally to lower the white blood cell count.

Hepatotoxicity (transaminase, bilirubin, and/or alkaline phosphatase elevations) may occur, usually in renal transplant patients. Usually occurs within 6 months of transplant and is normally reversible with discontinuation. Monitor liver function periodically. Rarely, hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported; discontinue if hepatic SOS is suspected.

Chronic immunosuppression increases the risk of serious, sometimes fatal, infections (bacterial, viral, fungal, protozoal, and opportunistic), including reactivation of latent infections.

Chronic immunosuppression with azathioprine (a purine antimetabolite), increases the risk of malignancy. Malignancies reported have included post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Health care providers using this medication should be very familiar with this risk, as well as with the mutagenic potential to both men and women, and with possible hematologic toxicities. Patients should be informed of the risk for malignancy development. HSTCL is a rare white blood cell cancer that is usually fatal and has predominantly occurred in adolescents and young adults treated for Crohn disease or ulcerative colitis and receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. Most cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents, although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy. Renal transplant patients are known to be at increased risk for malignancy (eg, skin cancer, lymphoma), the risk is increased with aggressive immunosuppression. Limit sun and ultraviolet light exposure and use appropriate sun protection.

Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including azathioprine (some cases have been fatal). Risk factors for PML include treatment with immunosuppressants and immune system impairment. Consider a diagnosis of PML in any patient presenting with new-onset neurological manifestations; consultation with a neurologist as clinically indicated may be warranted. Consider decreasing the degree of immunosuppression with respect to the risk of organ rejection in transplant patients. Disease-related concerns:

Use with caution in patients with hepatic impairment.

Use with caution in patients with renal impairment; dosage reductions may be necessary.

Patients with genetic deficiency of TPMT are more sensitive to myelosuppressive effects. Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity are at risk for developing severe and life-threatening hematologic toxicity. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity. Consider TPMT testing in patients with abnormally low CBC unresponsive to dose reduction. TPMT testing does not substitute for CBC monitoring. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Azathioprine is metabolized to mercaptopurine; concomitant use may result in profound myelosuppression and should be avoided.

Patients on concurrent therapy with drugs which may inhibit TPMT (eg, olsalazine) or xanthine oxidase (eg, allopurinol) may be sensitive to myelosuppressive effects. Dose adjustment of azathioprine may be recommended when used concurrently with allopurinol; patients with low or absent TPMT activity may require further dose reductions or discontinuation.

Immune response to vaccines may be diminished. Other warnings/precautions:

Should be prescribed by health care providers familiar with the risks, including hematologic toxicities and mutagenic potential.