How is AZA used?
- • Available formulations: 50-mg tablets (Imuran), 75-mg tablets (Azasan), 100-mg/20-mL vial.
- • Side effects: bone marrow depression, nausea, vomiting, skin rash, malignancy (some studies show lymphoma increased two times), hepatotoxicity (liver enzymes mildly increased in 33%, isolated hyperbilirubinemia , severe toxicity is rare), infections (herpes zoster, cytomegalovirus [CMV]), pancreatitis, hypersensitivity syndrome (rash, fever, hepatitis, renal failure within first 2 weeks of use).
- • Dosage: 50 to 200 mg/day (1–2.5 mg/kg per day). Start 25 to 50 mg/day and increase by 25 to 50 mg every 1 to 2 weeks to desired dose.
- • Cost (150 mg/day): generic ($120/month); Azasan ($1000/month); Imuran ($650/month). TPMT testing:
- genetic ($395) and phenotypic or functional enzyme ($220) testing for TPMT are commercially available. TPMT is the enzyme responsible for the metabolism of thiopurines, including AZA and 6-mercaptopurine (6-MP). Genetic polymorphisms can result in functional inactivation of the enzyme and lead to potentially fatal myelosuppression. The US Food and Drug Administration (FDA) recommends that “consideration be given to either genotype or phenotype patients for TPMT” prior to initiating therapy with AZA. Some practitioners routinely order the TPMT test prior to administration of AZA or 6-MP, but this has not been universally adopted. With a lack of cost-effective data and optimal clinical circumstances for which the test should be ordered, other practitioners do not routinely check TPMT and elect for slow dose escalation with close monitoring of the blood counts. Even in the absence of TPMT genetic polymorphisms, close monitoring should occur for anyone taking AZA or 6-MP.
- • Monitoring: a complete blood count (CBC) and platelet count should be monitored every 2 weeks during dose escalation and every 4 to 6 weeks after dose stability. Liver transaminases should be checked every 6 to 8 weeks during therapy. If leukopenia or thrombocytopenia occurs, the dose should be reduced by 50% or the drug discontinued. Patients developing macrocytosis require closer monitoring once alternative causes have been excluded.
- • Precautions: AZA has been used in pregnancy without demonstration of teratogenicity or serious harm to the fetus; AZA is metabolized by xanthine oxidase (XO), and XO inhibitors can lead to fatal bone marrow suppression. Use of AZA or 6-MP with allopurinol or febuxostat requires a reduction of AZA dose by 75%. Many would advocate to not use this combination at all. Sulfasalazine and trimethoprim/sulfamethoxazole increase the risk of leukopenia. AZA may cause warfarin resistance. Patients more likely (3×) to get a rash if treated with ampicillin or amoxicillin.
Pearl: patients who cannot tolerate AZA due to nausea, vomiting, or rash may be able to tolerate 6-MP (Purinethol), which is the active product of AZA. However, 6-MP cannot be used in patients who develop pancreatitis or liver toxicity on AZA. The effective dose of 6-MP is half the dose of AZA (i.e., 50 mg 6-MP = 100 mg AZA).