Summary for UKPID Allopurinol Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. Name Proprietary Zyloric(R), Zyloric-300(R) Generic Allopurinol Chemical group / family Antigout agents - xanthine oxidase inhibitor BNF 10.1.4 Reference number CAS 315-30-3 CAS 17795-21-0 Manufacturer / supplier Wellcome UK The Wellcome Foundation Ltd Hale Court Greencourts Business Park Styal Road Manchester M22 5LQ Tel: 0161 435 9372 01707 398085 (24hr emergencies) Fax: 0161 435 9363 Presentation Tablets 100mg bottle of 100 tablets Tablets 300mg calendar pack of 2x14 tablets Also available from generic drug companies in various pack sizes. Physico-chemical properties: Chemical structure 1H-Pyrazolo[3,4-d]pyrimidin-4-ol, C5H4N4O Physical state at room temp white / almost white crystalline powder, odourless Molecular weight 136.1 pKa 10.2 Solubility in alcohol >1 in 10 000 in water >1 in 10 000 Uses Indications Prophylaxis of gout and of uric acid and calcium oxalate renal stones. Therapeutic Dosage Initially 100mg daily as a single dose, after food, gradually increased over 1-3 weeks according to the plasma or urinary uric acid concentration to about 300mg daily. Usual maintenance dose 200-600mg, rarely 900mg daily, divided into doses of not more than 300mg. Child (in neoplastic conditions, enzyme disorders) 10-20mg/kg daily. Contra-indications Known intolerance of allopurinol. Not for treatment of the acute attack of gout. Hazard / risk classification None Pharmacokinetics Absorption 80-90% Volume of distribution 1.6 Lkg-1 Metabolism approx 80% Elimination 10% excreted in urine unchanged, 70% excreted as allopurinol Plasma half-life allopurinol 0.5-2h oxypurinol 10-40h Special populations Pregnancy - little data available, avoid use. Hepatic disease - patients may have a higher risk of adverse reactions Renal disease - Reduce dose in renal impairment as increased risk of adverse reactions. Reduced rate of elimination and possible precipitation of oxypurinol or xanthine calculi. Reduce risks of calculi by maintaining sufficient hydration to maintain daily urinary output above 2l and ensuring that the urine remains slightly alkaline. Breast milk - Allopurinol and oxypurinol are excreted in breast milk. The effects on the infant are unknown. Toxicokinetics NK Adverse effects Skin rashes are the most common side-effect. These are generally maculopapular or pruritic, but more serious hypersensitivity reactions may occur and include exfoliative rashes, the Stevens-Johnson syndrome, and toxic epidermal necrolysis. Further symptoms of hypersensitivity include fever, chills, leucopenia or leucocytosis, eosinophilia, arthralgia, and vasculitis leading to renal and hepatic damage. These hypersensitivity reactions may be severe, even fatal, and patients with hepatic or renal impairment are at special risk. Interactions ACE Inhibitors Increased risk of toxicity with captopril, especially in patients with renal impairment. Adenine arabinoside Enhanced toxic effects as half-life increased. Salicylates and Decreased therapeutic activity of uricosuric agents allopurinol. Chlorpropamide Increased risk of prolonged hypoglycaemic activity in patients with poor renal function. Coumarin anticoagulants Effects of anticoagulants possibly enhanced. Cyclosporin Plasma levels possibly increased - risk of nephrotoxicity. Cytotoxics Effects of azathioprine and mercaptopurine enhanced with increased toxicity. Phenytoin Inhibition of hepatic oxidation may occur, but may not be clinically significant. Theophylline No clinical reports of interactions. Mechanism of action / toxicity Acute ingestion Accidental or deliberate ingestion of up to 5g (Manufacturer's data sheet), and in one case 22.5g (Ferner et al, 1988), has been reported, with low toxicity. Chronic ingestion Toxicity on therapeutic doses is more common in patients with renal failure. Features Nausea, vomiting, diarrhoea, dizziness, headache, somnolence and abdominal pain. Rarely renal insufficiency and hepatitis. Management Unlikely to be required. Recovery follows general supportive measures. In cases of massive overdose the patient's renal and hepatic function should be evaluated. Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its metabolites. Case data 1. A 15 year old girl ingested 22.5g (416mg/kg) of allopurinol, received gastric lavage within 3 hours of ingestion and 50g of activated charcoal. No signs of toxicity developed. Minor increases in plasma phosphate (to 1.43 mmol/L) and alkaline phosphatase (to 129 IU) were noted over the next 4 days. The half-life of allopurinol was 3.6 hours, and oxypurinol 26 hours. (Ferner et al, 1988). 2. An 11 year old boy with acute lymphoblastic leukaemia presented in renal failure after having been treated with allopurinol 900mg/day for 3 months. He failed to respond to peritoneal dialysis, and died on the seventh day post-admission. Autopsy revealed an obstructive uropathy, focal ephrocalcinosis, and multiple small stones in the calyces of both kidneys. The stones were found to contain 82% xanthine, 15% oxypurinol, and 3% hypoxanthine. Uric acid and allopurinol were not detected (Potter & Silvidi, 1987). 3. A 79 year old man taking allopurinol of unknown dosage and duration developed general malaise, weakness and anorexia. The initial impression was acute hepatitis. Liver function tests revealed the following: Total bilirubin 1.3mg/dL, LDH 1957 IU/L, SGOT 1487 IU/L, SGPT 535 IU/L, and alkaline phosphatase 331 IU/L. Despite aggressive treatment, the patient died on the third hospital day. Autopsy showed hepatic toxic centrilobular necrosis. An antemortum blood sample was found to contain allopurinol 230.8mcg/ml; normal peak serum levels after a typical 300mg dose are 3 to 9mcg/ml ( Tam & Carroll, 1989). Other toxicological data Carcinogenicity Longterm studies in rodents showed no carcinogenicity. Mutagenicity No mutagenicity showed in human lymphocytes Teratogenicity There are no controlled studies on the use of allopurinol in human pregnancy or possible effects on fertility / male reproduction. There are 2 published reports of normal outcomes following exposure during pregnancy. Animal studies: Facial clefts and minor skeletal defects have been reported in mice exposed to allopurinol, but no teratogenic effects were reported after administration of high doses in rats and rabbits. Author Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph was produced by the staff of the Newcastle Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. Last updated January 1997 References: Books: 1. ABPI Compendium of Data Sheets and Summaries of Product Characteristics. Datapharm Publications Ltd. 1996-97. 2. AHFS Drug Information. McEvoy GK (Ed.) 1996. 3. British National Formulary. Number 32 (September 1996). British Medical Association and Royal Pharmaceutical Society. 4. Dollery C. Therapeutic Drugs. Churchill Livingstone. 1991. 5. Ellenhorn MJ. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd Edition 1997. Williams & Wilkins. 6. Martindale : The Extra Pharmacopoeia. 31st Edition. Reynolds JEF (Ed.) Pharmaceutical Press. 1996. Papers: 1. Ferner RE, Simmonds HA, Bateman DN. Allopurinol kinetics after massive overdosage. Hum Toxicol 1988; 7: 293-4. 2. Potter JL and Silvidi AA. Xanthine lithiasis, nephrocalcinosis, and renal failure in a leukaemia patient treated with allopurinol. Clin Chem 1987; 33: 2314-6. 3. Tam S and Carroll W. Allopurinol hepatotoxicity. Am J Med 1989; 86:357-8. Computer databases 1. Poisindex System(R), Micromedex inc., Denver Colorado, Edition Expires 3/97. 2. Reprotox System(R), Micromedex inc., Denver Colorado, Edition Expires 3/97. 3. TOXBASE, National Poisons Information Service, 1996.