Azathioprine for preventing kidney transplant rejection and treating rheumatoid arthritis

Azathioprine is an oral immunosuppressive medication used primarily to prevent rejection in kidney transplant patients and to reduce symptoms in active rheumatoid arthritis. It works by suppressing parts of the immune system involved in graft rejection and inflammation. Azathioprine tablets are scored and available in 75 mg and 100 mg strengths.

Azathioprine tablets are approved for:

• Prevention of rejection in renal homotransplantation: Used as an adjunct therapy starting at the time of transplant to help the body accept the new kidney and reduce immune-mediated rejection.
• Treatment of active rheumatoid arthritis: To reduce signs and symptoms of active rheumatoid arthritis. Concomitant treatment with aspirin, NSAIDs, or low-dose glucocorticoids may continue. Use with other DMARDs has not been studied or recommended.

Azathioprine

Azathioprine is a purine antimetabolite that is metabolized in the body to 6-mercaptopurine, which then inhibits DNA synthesis in immune cells. This selectively suppresses T-cell mediated immune responses involved in transplant rejection and autoimmune inflammation. Its effects arise from incorporation of active metabolites into DNA, leading to cytotoxicity in immune cells. The drug acts slowly and its effects may persist after stopping therapy.

Renal transplant patients

The initial dose is usually 3 to 5 mg/kg orally once daily, starting at the time of transplantation or up to 1–3 days before. After initial therapy, the dose is typically reduced to a maintenance dose of 1 to 3 mg/kg daily. The dose should not be increased to toxic levels if rejection threatens, and discontinuation may be required for severe hematologic toxicity.

Rheumatoid arthritis

Specific dosing for rheumatoid arthritis is not detailed in the supplied evidence. Concomitant use of aspirin, NSAIDs, or low dose glucocorticoids may continue, but use with other DMARDs is not recommended due to lack of studied safety and efficacy.

Special populations and adjustments

• Patients with genetic deficiencies in TPMT or NUDT15 enzymes require dose reduction or alternative therapy owing to risk of severe myelosuppression.
• Concomitant use with xanthine oxidase inhibitors (e.g., allopurinol) requires dose reduction of azathioprine to about one third to one quarter the usual dose. Concurrent use with febuxostat is not recommended.

Monitoring

Complete blood counts including platelets should be obtained weekly for the first month, twice monthly for months 2 and 3, then monthly or more frequently if dose changes are made. Monitor liver enzymes periodically due to possible hepatotoxicity.

• Known hypersensitivity to azathioprine.
• Use in pregnant women for treatment of rheumatoid arthritis.
• Patients with rheumatoid arthritis previously treated with alkylating agents due to increased malignancy risk.

Malignancy risk

Chronic immunosuppression with azathioprine increases the risk of malignancies, including lymphomas and skin cancers. Post-transplant lymphoma and rare hepatosplenic T-cell lymphoma have been reported, especially in inflammatory bowel disease patients. Physicians should inform patients about these risks and advise sun protection.

Hematologic toxicity

Severe leukopenia, thrombocytopenia, anemia (including macrocytic anemia), and pancytopenia may occur and are dose-related. Bone marrow suppression requires close monitoring with blood counts and possible dose adjustment or drug withdrawal.

Infections

Increased risk of serious bacterial, viral, fungal, protozoal, and opportunistic infections including reactivation of latent infections. This risk may be fatal.

Pregnancy and reproductive risks

Azathioprine is teratogenic in animal studies and can cause fetal harm. It should be avoided in pregnancy unless benefits outweigh risks. It is contraindicated for rheumatoid arthritis treatment during pregnancy.

Hypersensitivity reactions

Severe gastrointestinal hypersensitivity with nausea, vomiting, diarrhea, rash, fever, malaise, and occasionally hypotension can occur early in therapy and recur upon rechallenge.

Common adverse reactions

• Nausea and vomiting occur in about 12% of rheumatoid arthritis patients, often reduced by dosing after meals or divided doses.
• Gastrointestinal disturbances such as diarrhea and abdominal pain.
• Leukopenia and thrombocytopenia may develop, sometimes late in therapy.

Serious adverse reactions

• Severe bone marrow suppression leading to infections and bleeding.
• Hepatotoxicity, including rare veno-occlusive disease.
• Rare skin rashes, alopecia, fever, arthralgia, interstitial pneumonitis.
• Rarely, Sweet’s Syndrome and hepatosplenic T-cell lymphoma.

• Xanthine oxidase inhibitors (allopurinol, febuxostat): Increase azathioprine toxicity by inhibiting its metabolism. Dose reduction of azathioprine to one third or one quarter is required with allopurinol; combination with febuxostat is not recommended.
• Aminosalicylates (sulphasalazine, mesalazine, olsalazine): May inhibit TPMT enzyme and increase azathioprine toxicity. Caution advised.
• Other myelosuppressive drugs (e.g., co-trimoxazole): May worsen leukopenia.
• ACE inhibitors: Reported to induce anemia and severe leukopenia with azathioprine.
• Warfarin: Azathioprine may reduce anticoagulant effect.
• Ribavirin: May increase risk of severe pancytopenia and myelotoxicity. Requires close blood count monitoring.

Pregnancy

Azathioprine is teratogenic in animals, causing skeletal and visceral malformations, and can harm the fetus. It should be avoided during pregnancy unless benefits outweigh risks. Use is contraindicated for rheumatoid arthritis in pregnant women. Cases of intrahepatic cholestasis of pregnancy have been reported and resolved after stopping drug.

Lactation

Azathioprine and its metabolites pass into breast milk in low amounts. Use during breastfeeding is not recommended because of potential tumorigenic risks.

Overdose can lead to bone marrow suppression causing bleeding, infection, and may be fatal. Symptoms include nausea, vomiting, diarrhea, mild leukopenia, and abnormal liver function tests. Azathioprine is partially removed by hemodialysis. Supportive care and monitoring are advised.