Azathioprine with allopurinol

The risk of bone marrow depression by cytostatic drugs is potentiated by allopurinol, which also appears to potentiate the therapeutic effect of purine cytostatic drugs, since it competitively inhibits their metabolic breakdown. Studies in animals suggest that this reaction occurs only with oral mercaptopurine (28), although there is older evidence that the toxicity of cyclophosphamide and other cytostatic drugs can be increased by allopurinol (SED-9, 156). The danger of combining allopurinol with azathioprine has been confirmed by cases of bone marrow suppression, particularly in patients with impaired renal function (SEDA-16,114). 

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. 

The special risk is observed in patients with hepatic or renal impairment. It is not advised to use allopurinol in acute attacks of gout, but it is useful in chronic gout. Excretion of allopurinol and its active metabolite oxypurinol is primarily via the kidneys and therefore the dosage should be reduced if renal function is impaired. The adverse effects have been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function. The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one-quarter to one-third of the usual dose when either of them is given with allopurinol to avoid potentially life-threatening toxicity.27-29... 

Because of the possible risks of reduced immunosuppression if the dose of azathioprine is reduced when allopurinol is given, cyclic urate oxidase can be given instead, as has been shown in six hjq)eruricemic transplant patients treated with azathioprine (101). 

Brooks RJ, Dorr RT, Durie BGM, Interaction of allopurinol with 6-mercaptopurine and azathioprine. Biomedicine (1982) 36, 217-22. 

Cummins D, Sekar M, Halil C, Banner N. Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation. Transplantation (1996) 61,1661-2. 

Twenty-five kidney transplant patients taking eielosporin were given benzbromarone 100 mg daily to treat hyperurieaemia. The plasma uric acid levels decreased from 579 to 313 micromol/L and the 24-hour urinary uric acid secretion rose from 2082 to 3233 micromol after 4 weeks of treatment. The plasma uric acid levels normalised in 21 of the patients who had creatinine clearances of over 25 mL/minute. No significant adverse effects developed and the ciclosporin serum levels remained unchanged. The authors of the report emphasise the advantages of benzbromarone over allop-urinol because of its efficacy, lack of significant adverse effects and because, unlike allopurinol, it does not interact with azathioprine, which often accompanies ciclosporin treatment. ... 

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. 

There are several important drug-drug interactions with allopurinol. The effects of both theophylline and warfarin may be potentiated by allopurinol. Azathioprine and 6-mercaptopurine are purines whose metabolism is inhibited... 

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

Absorption of thioguanine is incomplete and erratic. It is eliminated mainly by S-methylation. Thioguanine can be administered concurrently with allopurinol without reduction in dosage, unlike mercaptopurine and azathioprine. 

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. 

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. 

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants... 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

Allopurinol is used not only in treating the hyperuricemia associated with gout, but also in the secondary hyperuricemia associated with the use of antineoplastic agents. However, allopurinol may interfere with the metabolism of antineoplastic agents such as azathioprine and 6-mercaptopurine. 

MERCAPTOPURINE ANTIGOUT DRUGS -ALLOPURINOL t mercaptopurine levels with risk of toxicity (e.g. myelosuppression, pancreatitis) Azathioprine is metabolized to mercaptopurine. Allopurinol inhibits hepatic metabolism of mercaptopurine 1 doses of azathioprine and mercaptopurine by up to three-quarters and monitor FBC, LFTs and amylase carefully... 

Allopurinol specifically inhibits xanthine oxidase and thus prevents metabolism of azathioprine to mercaptopurine (with potentially dangerous toxicity). 

Clinically important, potentially hazardous interactions with allopurinol, azathioprine, procainamide... 

Certain drugs inhibit non-microsomal metabolic pathways. Metronidazole, like disulfiram, inhibits aldehyde dehydrogenase, the enzyme that normally oxidizes acetaldehyde to acetic acid in the metabolic pathway for ethanol. Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Because azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase, the dosage of these drugs (synthetic xanthine analogues), when used concomitantly with... 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions. Azathioprine causes bone marrow suppression and has been associated with lymphomas (in renal transplant patients), skin cancer, and pancreatitis (about 3% of patients). Some investigators believe that induction of leukopenia may be necessary for therapeutic effect. Mercaptopurine causes adverse reactions similarly to azathioprine however, there are fewer reports of lymphomas with this agent. In one cohort of IBD patients, adverse effects from mercaptopurine were as follows pancreatitis, 1.2% allergic reactions, 3.9%, significant leukopenia, 11.5% and infectious complications, 14%. Ten percent of patients who received azathioprine or mercaptopurine required discontinuation of treatment because of adverse effects. Allopurinol inhibits the metabolism of mercaptopurine, and a dosage reduction of the latter is required when the two are used in combination. 

Allopurinol inhibits the enzymatic inactivation of mercaptopurine and its derivative azathio-prine by xanthine oxidase. Thus, when allopurinol is used concomitantly with oral mercaptopurine or azathioprine, dosage of the antineoplastic agent must be reduced by 25-33% (see Chapters 38 and 51). This is of importance when treating gout in the transplant recipient. The risk of bone marrow suppression also is increased when allopurinol is administered with cytotoxic agents that are not metabolized by xanthine oxidase, particularly cyclophosphamide. 

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. 

These interaetions are not elearly established, and the reaction appears to he rare and unpredictable. All that can he constructively said is that patients taking both drugs should he very closely monitored for any signs of hypersensitivity (e.g. skin reactions) or low white cell count (sore throat, fever), especially if they have renal impairment. The UK manufacturer of captopril recommends that diffeiential white hlood cell counts should be performed before adding allopurinol, then every 2 weeks during the first 3 months of treatment, and periodically thereafter. Similar caution and advice is given by the UK manufacturers of several other ACE inhibitors. For other possible interactions with ACE inhihitors that might result in an increased risk of leucopenia see also ACE inhihitors + Azathioprine , p.l8 and ACE inhibitors + Procainamide , p.33. 

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." ... 

Two clinical studies in renal transplant patients taking ciclosporin, aza-thioprine and prednisolone with low-dose allopurinol 25 mg daily or on alternate days found a reduction in ciclosporin levels (significant in one group), as well as a beneficial reduction in the acute rejection rate. Note that azathioprine levels can be raised significantly by allopurinol usually requiring a dose reduction, see Thiopurines + Allopurinol , p.664. The case reports above and the clinical studies are probably insufficient to recommend increased monitoring of ciclosporin levels in all patients given allopurinol, but bear them in mind in the event of an unexpected response to treatment. 

A study in 5 kidney transplant patients with gouty arthritis, who were switched from azathioprine to myeophenolate mofetil 2 g daily (to avoid the risk of an azathioprine/allopurinol interaction), found that no adverse effects occurred when they were given allopurinol 100 or 200 mg daily. On average, 10 weeks after the switch had taken place, uricaemia had fall-... 

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