Azathioprine dosing

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

When azathioprine is administered concomitantly with allopurinol, there is a risk of enhanced effects and increased toxicity of azathioprine. Doses of azathioprine should be reduced to one quarter of the usual dose. Both allopurinol and azathioprine may cause hypersensitivity reactions. 

Drug Interactions Xanthine oxidase, a key enzyme in the catabolism of azathioprine metabolites, is blocked by aUopurinol. If azathioprine and allopurinol are used concurrently, the azathioprine dose must be decreased to 25-33% of the usual dose it is best not to use these two drugs together. Adverse effects resulting from coadministration of azathioprine with other myelosuppres-sive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression. 

A number of other reports similarly describe reversible bone marrow toxicity associated with anaemia, pancytopenia, leucocytopenia and thrombocytopenia in patients given azathioprine with allopurinol, " and in one case a fatality occurred as a result of neutropenia and septicaemia. In a retrospective analysis of 24 patients who had received both azathioprine and allopurinol, 11 developed leucopenia, 7 developed moderate anaemia, and 5 developed thrombocytopenia. Only 14 of the patients had received a greater than two-thirds reduction in their azathioprine dose when allopurinol was started, but despite this, some of these patients still developed haematological toxicity." ... 

Conversely, in an early study, there was no difference in the incidence of leucopenia when renal transplant recipients were given co-trimoxazole or other antibacterials. Similarly, in 252 renal transplant patients given continuous prophylaxis with co-trimoxazole or sulfafurazole for 12 to 25 months, toxicity was minimal leucopenia occurred only occasionally and was reversed by temporarily withholding azathioprine. This was needed in a similar number of patients with each antibacterial. In another placebo-controlled study in cardiac transplant recipients taking triple therapy including azathioprine, co-trimoxazole prophylaxis for 4 months did not alter total white blood cell counts leucopenia did not occur and no change in azathioprine dose was required. ... 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

Left-sided disease Mesalamine enema 1 g rectally at bedtime daily, or Mesalamine 24-4.8 g/day or sulfasalazine 4-6 g/day orally May reduce enema frequency to 1 g 3 times/week if symptoms permit May reduce dose of oral agents if symptoms permit Consider adding azathioprine or 6-MP 1.5-2.5 mg/kg per day orally... 

Oral corticosteroids may be used for patients who are unresponsive to sulfasalazine or mesalamine. Prednisone doses of 40 to 60 mg per day (or equivalent) are recommended.1 Azathioprine or 6-MP is used for patients unresponsive to corticosteroids or those who become steroid-dependent. Over a 12-month period, these agents have been shown to reduce the relapse rate to 36% versus 59% seen with placebo.1 Infliximab 5 mg/kg may also be used for patients who are unresponsive to conventional oral therapies and may reduce the need for colectomy after 3 months of treatment.35... 

Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. Remission may be maintained in up to 58% of patients after 5 years of treatment.1,25 Intermittent infliximab dosing (5 mg/kg IV every 8 weeks) may be used to maintain disease remission and reduce the need for corticosteroids in patients with moderate to severe UC. Colectomy is an option for patients with progressive disease who cannot be maintained on drug therapy alone. 

Azathioprine and 6-MP in oral doses up to 2.5 mg/kg per day have been shown to maintain remission in 45% of patients for up to 5 years.2,25,26 These drugs may be used to prevent disease recurrence after surgically-induced remission. Methotrexate in doses ranging from 12.5 to 25 mg per week given orally, intramuscularly, or subcutaneously has resulted in remission rates of up to 52% at 3 years.26,27... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

The answer is b. (Hardmanr pp 1296-1299.) Cyclosporine is the preferred agent because it is a specific T cell inhibitor, and its success rate in protecting against rejection is considerably better than that of any other agent. All of the other agents listed in the question are cytotoxic. Because of the severe adverse reactions with cyclosporine, it is used in conjunction with azathioprine, which reduces the required dose. Prednisone is also used in conjunction with cyclosporine. 

The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when toxic doses are required. The usual dose of azathioprine is 2 to 3 mg/kg/day and 1 to 1.5 mg/kg/day for mercaptopurine. Up to 3 to 4 months may be required to observe a response. Starting doses are typically 50 mg/day and increased at 2-week intervals while monitoring complete blood count with differential. 

The number of drugs susceptible to S-methylation is still limited but greater than the number turned over by COMT. Thiopurine methyl transferase (TPMT) is an important enzyme responsible for detoxifying mercaptopurine—a drug used to treat leukemia— as well as azathioprine —a prodrug that is metabolized to mercaptopurine (Fig. 7.12). This enzyme is polymorphic and patients who are homozygous for the deficient enzyme experience severe toxicity when given usual doses of mercaptopurine (19). Similar aromatic and heterocyclic sulfhydryls can also be substrates for TPMT. The similar thiol... 

Tests for the TPMT genotype and phenotype are commercially available. Attention should be paid for those patients who test negative for TPMT status. Patients with poor or intermediate TPMT activity may tolerate only 1/10 to 1/2 of the average 6-MP dose. A pharmacoeconomic model has been developed to analyze the potential cost of screening to prevent azathioprine toxicity. In this model, it was assumed that TPMT deficiency is present in 0.3% of the population, that intermediate activity is present in 11%, and that both groups have an increased risk of developing myelosuppression. Under these circumstances, the model predicted that the costs per Caucasian patient for the first 6 mo of therapy with screening are lower... 

Q64 The dose of allopurinol should be reduced in patients receiving aza-thioprine. Both allopurinol and azathioprine may cause hypersensitivity reactions. 

Mercaptopurine results from biotransformation of the inactive precursor azathioprine (p. 37). The uricostatic allo-purinol inhibits the degradation of 6-mercaptopurine such that co-adminis-tration of the two drugs permits dose reduction of the latter. 

Use with allopurinol Reduce dose of azathioprine to approximately 25% to 33% of the usual dose. 

Hematoiogic effects Severe leukopenia or thrombocytopenia, macrocytic anemia, severe bone marrow depression, and selective erythrocyte aplasia may occur in patients on azathioprine. Hematologic toxicities are dose-related, may occur late in the... 

For immunosuppressive effects methotrexate is most frequently used in RA but also azathioprine and cyclosporin are employed. Methotrexate doses for this indication can be lower than those used for cancer chemotherapy but significant toxicity such as nausea, cytopenias and mucosal lesions, and with longterm therapy slowly progressive hepatotoxicity may still be seen. 

Azathioprine can be administered both orally and intravenously. It is well absorbed orally and after its rapid conversion to 6-mercaptopurine it is inactivated by xanthine oxidase which converts 6-mercaptopurine to 6-thiouric acid. This final metabolite is then excreted in the urine. In combination with the xanthine oxidase inhibitor allopurinol dose adjustments of azathioprine are needed. Renal disease also raises 6-mercaptopurine concentrations and can make dose adjustments necessary. Azathioprine is still used in organ transplantation programs and for the management of several autoimmune diseases. Its adverse effects include nausea, vomiting, diarrhea and, more seriously, bone marrow suppression and hepatotoxicity. Azathioprine is not thought to cause fetal malformation. 

Patients with frequent relapses despite apparently adequate prophylactic treatment should be reviewed carefully. Associated milk intolerance or coeliac disease need treatment on their merits. Colonoscopic evidence of dysplasia raises the question of undiagnosed malignancy. Occasionally the prophylactic agents themselves can cause watery diarrhoea (particularly olsalazine) or a hypersensitivity colitic disease. Prophylactic azathioprin should be considered in those in whom relapse is frequent despite use of aminosalicylates or if they are poorly tolerated. In the effective dose of 2 mg/kg adverse effects of bone marrow depression are uncommon, but still occur, and regular haematological review is essential (monthly or bi-monthly). Azathioprin-induced pancreatitis is an uncommon but well-recognised entity. 

IX.b.3.3. Immunosuppressants. As in ulcerative colitis low doses of azathioprine (2 mg/kg) are effective in preventing recurrence, but have little value in treating acute disease. 

For auto-immune hepatitis relatively low doses of oral corticosteroids are effective, and concurrent azathioprin (2 mg/kg) is steroid sparing. Those in remission for two years can stop treatment, but relapse is common. 

Since allopurinol is metabolized by the hepatic microsomal drug-metabohzing enzymes, coadministration of drugs also metabohzed by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cytotoxic drugs (e.g., vidarabine). The actions of allopurinol are not antagonized by the coadministration of salicylates. 

Idiopathic thrombocytopenic purpura (ITP) Prednisone,1 vincristine, occasionally cyclophosphamide, mercaptopurine, or azathioprine commonly high-dose gamma globulin, plasma immunoadsorption or plasma exchange Usually good... 

Autoimmune hemolytic anemia Prednisone,1 cyclophosphamide, chlorambucil, mercaptopurine, azathioprine, high-dose gamma globulin Usually good... 

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity. 

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