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.