Allopurinol adverse effects

The initial dose of allopurinol is based on the patient s renal function. Patients with creatinine clearances of 50 mL/minute or less should receive a starting dose of less than 300 mg/day to minimize adverse effects. The relationship between dose of allopurinol and its most severe side effects is controversial. However, the dose can be adjusted upward as needed and tolerated. It is reasonable to reduce the dose temporarily in patients who develop reversible acute renal failure. 

Evaluate the patient for drug interactions, allergies, and adverse effects of allopurinol or rasburicase. 

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. 

If properly controlled, simple gout may have few adverse effects. However, the severe neurological symptoms of Lesch-Nyhan syndrome (Section E,2 of text)6 cannot be corrected by medication. Colchicine (Box 7-D), in a manner which is not understood, alleviates the painful symptoms of gout caused by the deposits of sodium urate in joints and tissues. It is also important to keep the dietary purine intake low and it is often necessary to inhibit xanthine oxidase. A widely used and effective inhibitor is the isomer of hypoxanthine known as allopurinol, which is taken daily in amounts of 100 -600 mg or more. 

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... 

Allopurinol and some antibiotics increase plasma concentrations of theophylline and increase the risk of adverse effects of theophylline. 

Allopurinol and meglumine antimoniate (Glucantime) have been evaluated in a randomized controlled trial in 150 patients with cutaneous leishmaniasis (2). They received oral allopurinol (15 mg/kg/day) for 3 weeks or intramuscular meglumine antimoniate (30 mg/kg/day, corresponding to 8 mg/kg/day of pentavalent antimony, for 2 weeks), or combined therapy. There were a few adverse effects in those who used allopurinol nausea, heartburn (n = 3), and mild increases in transaminases (n = 2). These symptoms subsided on drug withdrawal. 

Apart from headache and vertigo, adverse effects of allopurinol involving the nervous system are rare. Transient peripheral neuropathy has been reported (SEDA-18,107). 

Since allopurinol blocks xanthine conversion to uric acid, urinary xanthine excretion is increased, creating a risk of xanthine crystal formation in the urinary system or even in muscles this can result in nephrolithiasis (12). It is still an open question whether a predisposition to renal disease or renal disease itself is required to precipitate these adverse effects. It is also not known whether increased excretion of orotic acid, due to an interaction of allopurinol with pyrimidine formation, has any consequences for these adverse effects or for its role in reducing glucose tolerance. 

Thiazides enhance the excretion of orotic acid, which is already increased during allopurinol treatment, but the implications for the frequency of adverse effects are not known. 

Tlie clinical utility of another first-generation, non-nitrogen-containing bisphosphonate, tiludronate, has been limited because of concern over renal adverse effects observed in early trials. In a dose-finding study for the treatment of HCM, 19 patients received i.v. drug followed by oral maintenance therapy [70]. Three patients had elevated serum creatinine levels after i.v. drug administration of 4.5 or 6.0 mg/kg, 1 of whom developed acute renal insufficiency and subsequently died, most probably due to tiludronate, although renal infection and allopurinol therapy could have played a contributory role. 

Allopurinol 300 mg q. 24 hr 30% 75% 50% 25% Adverse effects interstitial nephritis, exfoliative dermatitis, and rarely, xanthine stones renal excretion of active metabolite with half life of 25 hr in normal renal function, half life 1 wk in patients with ESRD Half dose No data Dose for GFR 10-50 ml/min... 

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. 

Chronic gout is treated with allopurinol, a suicide inhibitor of xanthine oxidase the goal is to reduce the uric acid pool by inhibiting its formation from purines. The adverse effects of allopurinol are j considered. 

Allopurinol is tolerated well by most patients. The most common adverse effects are hypersensitivity reactions that may occur cffter months or years of medication. The fffects usually subside within a few days after medication is discontinued. Serious reactions preclude further use of the drug. 

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. 

In a retrospective study of the adverse effects of allopurinol in 1835 patients, 3 patients were identified who had developed excessive anticoagulation while taking warfarin and allopurinol. One of them developed extensive intrapulmonary haemorrhage and had a prothrombin time of 71 seconds. An increase in prothrombin time was seen in an 82-year-old woman stabilised on warfarin when given both allopurinol 3(X) mg daily and indometacin , (p.432), but the precise role of allopurinol in this case is unclear. ... 

The UK manufacturer recommends close monitoring for adverse effects if allopurinol is used with didanosine, but the US manufaeturer says that coadministration is not recommended. ... 

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. ... 

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-... 

Evidence appears to be limited to a single case report and the studies in healthy subjects. The interaction only appears to be of moderate importance. Nevertheless, it would seem prudent to check for any signs of theophylline adverse effects (headache, nausea, tremor) during concurrent use, particularly in situations where the metabolism of the theophylline may already be reduced (other drugs or diseases), or where high doses of allopurinol are used. For mention that allopurinol may invalidate the results of phenotyping tests using caffeine, see Caffeine + Allopurinol ,... 

Two phase III studies versus aUopurinol (n = 762 and 1067), and two long-term, open-label extension studies (n= 116 and 1086) have been reported. In a published 52-week phase III study, more febuxostat recipients achieved the primary endpoint of serum urate concentration (sUA, < 0.36mmol/L) compared to allopurinol. Despite the greater effect on sUA, there was no difference between treatments in more clinically important outcomes such as gout flares and tophi reduction (secondary endpoints). The adverse event profiles of febuxostat and allopurinol were similar over the 52-week period. Longterm adverse event data for febuxostat (1) is limited. 

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