Adult: In patients with leukaemia, lymphoma, and solid tumour malignancies at risk for tumour lysis syndrome who cannot tolerate oral therapy: 200-400 mg/m2 daily as a single infusion or in equally divided infusions at 6-, 8- or 12-hour intervals. Max: 600 mg daily. Initiate treatment 24-48 hours before starting chemotherapy. Child: Initially, 200 mg/m2 daily as a single infusion or in equally divided infusions at 6-, 8- or 12-hour intervals. Max: 400 mg daily. Initiate treatment 24-48 hours before starting chemotherapy. Dosage and treatment recommendations may vary among countries or individual products (refer to local or specific product guidelines).
Oral Gout
Adult: For the management of primary and secondary gout: Initially, 100 mg daily, gradually increased by 100 mg at weekly intervals until urate concentration in plasma is decreased to 0.36 mmol/L (6 mg/dL) or less. Dose range: 100-300 mg daily (mild gout); up to 600 mg daily (moderately severe tophaceous gout). Max: 800 mg or 900 mg daily. Doses >300 mg daily should be taken in divided doses. Prophylactic dose of colchicine or an anti-inflammatory agent according to clinical guidelines is recommended upon starting treatment. Dosage and treatment recommendations may vary among countries or individual products (refer to local or specific product guidelines).
Oral Cancer therapy-induced hyperuricaemia
Adult: For prevention of uric acid nephropathy in patients with leukaemia, lymphoma, and solid tumour malignancies at risk for tumour lysis syndrome: 600-800 mg daily for 2-3 days, begin treatment 24-48 hours before the start of cancer therapy. Dosage or treatment recommendations may vary among countries or individual products (refer to local or specific product guidelines). Child: <6 years 150 mg daily; 6-10 years 300 mg daily. Adjust dose after 48 hours, if needed. Alternative dosing: <15 years 10-20 mg/kg daily, up to a Max of 400 mg daily. Dosage recommendations may vary among countries or individual products (refer to local or specific product guidelines).
Oral Recurrent calcium oxalate stones
Adult: In patients with hyperuricosuria (uric acid excretion >800 mg/day in men and >750 mg/day in women) who persistently experience active disease despite attempted dietary modification: 200-300 mg daily as a single dose or in divided doses. Adjust dose based on resultant control of hyperuricosuria using 24-hour urinary urate excretion determinations.
Special Patient Group
Patients receiving mercaptopurine or azathioprine: Reduce mercaptopurine or azathioprine dose to 1/3 to 1/4 of the usual dose. Refer to the respective product guidelines for detailed dosing information.
Pharmacogenomics:
Human leucocyte antigen (HLA)-B*58:01 Allopurinol is one of the most common causes of severe cutaneous adverse reaction (SCAR) and one of the most serious, up to 25% mortality. HLA-B*58:01 allele is a genetic marker that is strongly associated with allopurinol-induced SCAR. The prevalence of HLA-B*58:01 allele varies widely among different ethnic or racial origin. It has been estimated that up to 20% in Han Chinese population, 8-15% in Thai, approx 12% in Korean population carry the allele, while only 1-2% in Japanese or European origin. Consider HLA-B*58:01 screening prior to initiation of therapy in genetically at-risk populations.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of February 2013:
Genotype
Implications
Recommendations
Noncarrier of HLA-B*58:01
Patients with no copies of HLA-B*58:01 (reported as "negative" on genotyping test).
Low or reduced risk of allopurinol-induced SCAR.
Use allopurinol standard dosing guidelines. Negative HLA-B*58:01 on a genotyping test does not rule out the possibility of allopurinol-induced SCAR, patients must still be monitored for SCAR.
Carrier of HLA-B*58:01
Patients with at least 1 copy of the HLA-B*58:01 allele e.g. HLA-B*58:01/HLA-B*58:01, *58:01/any HLA-B genotype other than HLA-B*58:01 (reported as "positive" on genotyping test).
Significantly increased risk of allopurinol-induced SCAR.
Use of allopurinol is contraindicated.
ATP-binding cassette subfamily G member 2 (ABCG2)
Allopurinol is rapidly metabolised to oxipurinol, the main active metabolite which is responsible for most of the uric acid lowering effect. ABCG2 encodes breast cancer resistance protein (BCRP) which is a known efflux pump for uric acid and oxipurinol is a substrate of this transporter. The rs2231142 variant (141KK and 141QK genotype), a single nucleotide polymorphism of ABCG2 gene, was associated with poor response to allopurinol. Genetic testing may be potentially beneficial for drug effectiveness and may be considered on an individual patient basis.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of May 2021:
Genotype
Description
Recommendations
141KK (TT genotype)
Effectiveness of allopurinol is reduced in patients with 141KK genotype, which means higher dose is necessary. This gene variation decreases uric acid secretion by the kidneys and intestines, therefore stronger inhibition of uric acid production by allopurinol is needed to attain desired uric acid concentration.
Use 1.4 times the standard allopurinol dose, this is equivalent to a dose titration schedule of 100 mg, 300 mg, 400 mg, 600 mg, and 700 mg daily instead of the usual schedule of 100 mg, 200 mg, 300 mg, 400 mg, and 500 mg daily.
141QK (GT genotype)
Effectiveness of allopurinol is reduced in patients with 141QK genotype, which means higher dose is necessary. This gene variation decreases uric acid secretion by the kidneys and intestines, therefore stronger inhibition of uric acid production by allopurinol is needed to attain desired uric acid concentration.
Use 1.25 times the standard allopurinol dose, this is equivalent to a dose titration schedule of 100 mg, 200 mg, 400 mg, and 500 mg daily instead of the usual schedule of 100 mg, 200 mg, 300 mg, and 400 mg daily.
Treatment recommendations may vary among countries. Refer to local guidelines for the latest recommendations.
Renal Impairment
Oral:
CrCl (mL/min)
Dosage
<10
100 mg daily or longer dose intervals.
10-20
100-200 mg daily.
Max initial dose: 100 mg daily, increase only if response is inadequate. In severe insufficiency, doses <100 mg daily or single doses of 100 mg at intervals longer than 1 day may be advisable. If facilities are available for monitoring, adjust dose to maintain plasma oxipurinol concentration <100 micromole/L (15.2 mcg/mL). In patients requiring dialysis for 2 or 3 times weekly, consider an alternative dose of 300-400 mg immediately after each dialysis with none in the interim. Dosage recommendations may vary among countries or individual products (refer to local or specific product guidelines).
Intravenous:
Patient on dialysis: 50 mg 12 hourly or 100 mg 24 hourly.
CrCl (mL/min)
Dosage
<10
100 mg daily.
10-20
200 mg daily.
Dosage recommendations may vary among local guidelines (refer to specific country guidelines).
Hepatic Impairment
Oral:
Dose reduction may be needed.
Administration
Should be taken with food. Take immediately after meals.
Reconstitution
IV: Reconstitute vial labelled as 500 mg with 25 mL of sterile water for inj to provide a solution containing 20 mg/mL. Further dilute with NaCl 0.9% or dextrose 5% inj to a final concentration not exceeding 6 mg/mL.
Patient with thyroid disorder; undergoing treatment for cardiac insufficiency or hypertension. Patient receiving mercaptopurine or azathioprine. Not intended for the treatment of an acute gout attack. Not recommended for treatment of asymptomatic hyperuricaemia. Patient with ABCG2 polymorphism. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Acute attacks of gout (during early stages of administration), reversible hepatotoxicity, renal insufficiency or failure, myelosuppression (e.g. anaemia, leucopenia, thrombocytopenia), impaction of uric acid renal stones in the ureter. Ear and labyrinth disorders: Vertigo. Gastrointestinal disorders: Nausea, vomiting, diarrhoea. General disorders and administration site conditions: Fever, malaise; local inj site reaction (IV). Investigations: Increased blood TSH, alkaline phosphatase, ALT, or AST. Nervous system disorders: Drowsiness, ataxia. Skin and subcutaneous tissue disorders: Rash, maculopapular rash. Potentially Fatal: Hypersensitivity reactions including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, toxic epidermal necrolysis.
This drug may cause drowsiness, vertigo, and ataxia, if affected, do not drive or operate machinery. Ensure adequate fluid intake.
Monitoring Parameters
Consider screening for HLA-B*58:01 allele before treatment in patients at increased risk for developing severe cutaneous adverse reactions (e.g. patients of Asian descent [e.g. Thai, Korean, Han Chinese], African American patients). Monitor CBC; serum uric acid levels (at least 2-4 weeks after every dose titration until desired level is reached, then every 6 months [for symptomatic patients] or every 12 months [for all patients regardless of symptoms]); LFTs (periodically in patients with preexisting liver disease), and renal function (BUN, serum creatinine, or CrCl [before starting treatment and periodically]), hydration status, frequency and severity of gouty attacks. Monitor for signs or symptoms of hypersensitivity reactions and hepatotoxicity.
Overdosage
Symptoms: Nausea, vomiting, diarrhoea, and dizziness. Management: Supportive treatment. Maintain optimum diuresis through adequate hydration. May perform haemodialysis, if needed.
Drug Interactions
Increased serum concentrations of azathioprine and mercaptopurine, which may increase the risk of myelosuppression. May increase the plasma half-life of vidarabine. Uricosuric agents (e.g. probenecid) and large doses of salicylates may accelerate oxipurinol (major active metabolite) excretion. May increase the risk of hypersensitivity reactions when given with ACE inhibitors and thiazide diuretics, particularly in patients with renal impairment. May inhibit the hepatic oxidation of phenytoin. Concurrent use with bendamustine, ampicillin or amoxicillin may increase the incidence of skin rash. May enhance the anticoagulant effect of warfarin and other coumarin anticoagulants. Prolongs the half-life of chlorpropamide, which may increase the risk of hypoglycaemia particularly in patients with renal impairment. May inhibit the metabolism of theophylline. May increase the risk of bone marrow suppression with cytotoxic agents (e.g. cyclophosphamide, bleomycin, doxorubicin, procarbazine, chlormethine). May increase the serum concentration of ciclosporin and didanosine. Concomitant administration with aluminium hydroxide may attenuate the effect of allopurinol. May decrease the concentration of the active metabolites of capecitabine, which may reduce capecitabine efficacy.
Action
Description: Mechanism of Action: Allopurinol is a structural analogue of hypoxanthine that acts on purine catabolism without disrupting the biosynthesis of vital purines. It inhibits xanthine oxidase, the enzyme that catalyses the conversion of hypoxanthine to xanthine and xanthine to uric acid, thus decreasing serum and urinary uric acid concentrations. In addition to the purine catabolism inhibition in some patients, the de novo purine biosynthesis is reduced through feedback inhibition of hypoxanthine-guanine phosphoribosyltransferase. Pharmacokinetics: Absorption: Oral: Rapidly absorbed from the gastrointestinal tract (up to 90%). Bioavailability: 67-90%. Time to peak plasma concentration: 1.5 hours (allopurinol); 3-5 hours (oxipurinol). Distribution: Uniformly distributed in total tissue water except in the brain (where drug concentrations are approx 50% those of other tissues); small amounts of allopurinol and oxipurinol crystals have been found within the muscle. Crosses the placenta (allopurinol) and enters breast milk (allopurinol and oxipurinol). Metabolism: Rapidly metabolised via oxidation to oxipurinol (major active metabolite). Excretion: Mainly via urine (approx 70% as oxipurinol, approx 10% as allopurinol); faeces (approx 20%). Elimination half-life: Oral: Approx 1-2 hours (allopurinol); approx ≥15 hours (oxipurinol). IV: 1.21 ± 0.33 hours (allopurinol); 23.5 ± 4.5 hours (oxipurinol).
Chemical Structure
Allopurinol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 135401907, Allopurinol. https://pubchem.ncbi.nlm.nih.gov/compound/Allopurinol. Accessed Feb. 23, 2024.
Storage
Tab: Store below 30°C. Protect from light and moisture. Inj: Store between 20-25°C. Diluted solution may be stored for up to 10 hours between 20-25°C. Do not refrigerate reconstituted and/or diluted solution.
M04AA01 - allopurinol ; Belongs to the class of preparations inhibiting uric acid production. Used in the treatment of gout.
References
Hershfield MS, Callaghan JT, Tassaneeyakul W et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotype and Allopurinol Dosing. Clinical Pharmacology and Therapeutics. 2013 Feb;93(2):153-158. doi: 10.1038/clpt.2012.209. Accessed 01/02/2023Roberts RL, Wallace MC, Phipps-Green AJ et al. ABCG2 Loss-of-Function Polymorphism Predicts Poor Response to Allopurinol in Patients with Gout. Pharmacogenomics Journal. 2017 Mar;17(2). doi: 10.1038/tpj.2015.101. Accessed 08/02/2024Wen CC, Yee SW, Liang X et al. Genome-Wide Association Study Identifies ABCG2 (BCRP) as an Allopurinol Transporter and a Determinant of Drug Response. Clinical Pharmacology and Therapeutics. 2015 May;97(5). doi: 10.1002/CPT.89. Accessed 08/02/2024Allopurinol 100 mg Tablets (Teva UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 03/01/2024.Allopurinol Injection, Powder, Lyophilized, for Solution (Fresenius Kabi USA, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/01/2024.Allopurinol Tablet (Accord Healthcare Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/02/2024.Allopurinol Tablet (Camber Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/02/2024.Allopurinol Tablet (Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/01/2024.Allopurinol. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 03/01/2024.Annotation of CPIC Guideline for Allopurinol and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 05/01/2024.Annotation of DPWG Guideline for Allopurinol and ABCG2. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 05/01/2024.Annotation of FDA Label for Allopurinol and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 01/02/2023.Annotation of PMDA Label for Allopurinol and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 01/02/2023.Annotation of Swissmedic Label for Allopurinol and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 05/01/2024.Anon. ABCG2 - Allopurinol (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/02/2023.Anon. Allopurinol. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 01/02/2023.Anon. Allopurinol. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 03/01/2024.Anon. HLA-B - Allopurinol (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/02/2023.Buckingham R (ed). Allopurinol. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/01/2024.Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotype and Allopurinol Dosing. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 01/02/2023.Douglas Pharmaceuticals Ltd. DP-Allopurinol 100 mg and 300 mg Tablets data sheet 01 June 2022. Medsafe. http://www.medsafe.govt.nz. Accessed 01/02/2023.Joint Formulary Committee. Allopurinol. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/02/2023.Zyloric 100 mg and 300 mg Tablet (Aspen Medical Products Malaysia Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 01/02/2023.
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