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allopurinol (Zyloprim, Lopurin, Zurinol)

Tradenames: Zyloprim, Lopurin, Zurinol. Indications: 1) hyperuricemia 2) gout maintenance therapy: a) do not use as lone therapy during an acute attack of gout b) allopurinol may precipitate an attack of gout c) drug of choice if patient has history of renal stones or renal insufficiency d) improves clinical outcomes (reduction in flares, tophi, joint damage) [5] e) improves mortality in patients with chronic renal failure [21] e) 200-300 mg PO QD/BID* [1,2] f) maximum dose 800 mg QD 3) prevention of chemotherapy-induced acute tumor lysis syndrome 4) improves exercise tolerance in patients with chronic stable angina pectoris [8] 5) may improve outcomes in patients with heart failure & gout [9] 6) APRT deficiency 7) phosphoribosyl pyrophosphate synthetase deficiency 8) phosphoribosyl pyrophosphate synthetase superactivity 9) may reduce recurrence of hepatic cirrhosis-related complications [23] Contraindication: - concurrent use of purine analogs (theophylline, mercaptopurine, azathioprine) [4] - HLA-B*5801 allele-positive Hans Chinese or Thai persons - does not provide renal protection for patients with diabetes mellitus [20] Dosage: - gout: a) start: 100 mg PO QD; 50 mg PO QD if eGFR < 60 mL/min [22] - start: 1.5 X GFR in mL/min/1.73 m2 QD [10] - maximum: 800 mg QD b) do not initiate during acute exacerbation of gout c) titrate to achieve serum urate level of < 6.0 mg/dL [4] - mean daily dose required = 460 mg QD [19] - tumor lysis syndrome - 600-800 mg QD with maintenance of high fluid intake - chronic stable angina pectoris - 600 mg PO QD [8] - hepatic cirrhosis - 300 mg/day * use in combination with colchicine 0.6 mg QD# during 1st 3-6 months of therapy # dose reduction with renal failure [6] Tabs: 100 & 300 mg. Injection: Pharmacokinetics: 1) bioavailability following oral administration is 80-90% 2) peak plasma levels occur 2-6 hours after oral administration 3) peak plasma leves 30 minutes after IV administration 4) serum urate levels a) generally decrease within 24-48 hours - delay may occur due to dissolution of urate crystals b) normal serum urate levels generally within 1-3 weeks 5) widely distributed to body tissues, including breast milk) 6) metabolized in liver to active metabolite oxypurinol 7) 1/2life of allopurinol is 1-3 hours 8) 1/2life of oxypurinol is 18-30 hours 9) allopurinol (12%) & oxypurinol excreted in the urine Dosage adjustment in renal failure: - some controversy here (see below)* creatinine clearance dosage 60 mL/min 200 mg QD 40 mL/min 150 mg QD 20 mL/min 100 mg QD 10 mL/min 100 mg QOD < 10 mL/min 100 mg 3 x/week * some controversy here * limiting allopurinol dosing to <= 300 mg/day suboptimally controls hyperuricemia & fails to adequately prevent hypersensitivity reactions. [12] * using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. - monitor for drug toxicity (pruritus, rash, increased ALT) - dosage of 400 mg/day with creatinine clearance of 35 mL/min recommended in [5] - doses higher than those based on creatinine clearance well tolerated in patients with mild renal insufficiency [15] Monitor: - serum creatinine every 6 months [7] - serum ALT renal insufficiency Adverse effects: 1) common (> 10%) a) rash*, generally maculopapular (not itchy) [6] b) exfoliative, urticarial or purpuric lesions 2) less common (1-10%)# - drowsiness, fever/chills, nausea/vomiting, diarrhea, abdominal pain, gastritis, dyspepsia, alopecia, increased LFTs (ALP, AST, ALT, bilirubin), jaundice, hepatomegaly 3) uncommon (< 1%) - hepatic necrosis, vasculitis, headache, somnolence, toxic epidermal necrolysis, Stevens-Johnson syndrome, bone marrow suppression, idiosyncratic reaction (fever/ chills, nausea/vomiting, eosinophilia, arthralgias), thrombophlebitis, peripheral neuropathy, paresthesias, neuritis, cataracts, renal impairment, epistaxis - allopurinol is associated with less chronic renal failure than febuxostat [17] 4) can worsen acute attack of gout with initiation of therapy 5) drug reaction with eosinophilia & systemic symptoms (DRESS) [4] - late reactions begin 2-8 weeks after starting medication - low SaO2, pulmonary crackles - bilateral interstitial infiltrates & lower lobe atelectasis - maculopapular eruptions, burning skin pain, morbilliform exanthem 6) potentially fatal hypersensitivity reaction - severe dermatitis, fever, eosinophilia, hepatic necrosis, acute nephritis - not clear how this is distinguished from DRESS or idiosyncratic reaction described above * discontinue allopurinol immediately if rash develops [4]; * increased incidence of cutaneous & generalized hypersensitivity reactions in the elderly [5] & in patients with renal failure or cardiovascular disease [14] # risk of adverse effects is greater with renal failure Drug interactions: 1) ampicillin & amoxicillin: increase in incidence of rash 2) cyclophosphamide: increase in myelosuppression 3) avoid use in combination with theophylline, mercaptopurine, or azathioprine; these drugs are metabolized by xanthine oxidase, thus may accumulate to toxic levels 5) thiazide diuretics: increase in incidence of skin reactions Laboratory: - HLA-B*5801 allele testing - increased risk of allopurinol-induced SCAR* in individuals with the HLA-B*5801 allele - screening for HLA-B*5801 prior to starting allopurinol may be cost-effective in blacks & Asians, but not in whites or Hispanics [16] - allopurinol in CSF - allopurinol in serum/plasma - allopurinol/creatinine in urine * SCAR = severe cutaneous skin reaction - Stevens-Johnson syndrome - toxic epidermal necrolysis Mechanism of action: 1) structural analog of hypoxanthine 2) reversibly inhibits xanthine dehydrogenase & xanthine oxidase 3) diminishes formation of uric acid* 4) diminished renal tubular resorption of uric acid a) increased renal tubular resorption of Ca+2 b) reduced hypercalciuria c) attenuation of hypocalcemia 5) xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume [8] 6) may reduce bacterial translocation & inflammation [23] * clearance of hypoxanthine & xanthine at least 10 times that of uric acid

Interactions

drug interactions

General

anti-inflammatory agent enzyme inhibitor hypouricemic agent metabolic agent (metabolic modifier)

Properties

INHIBITS: xanthine dehydrogenase xanthine oxidase MISC-INFO: elimination route KIDNEY pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2022.
  5. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  6. Journal Watch 25(3):24, 2005 Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol. 2004 Dec;31(12):2429-32. PMID: 15570646
  7. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  8. Noman A et al Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial Lancet 8 June 2010 PMID: 20542554 doi:10.1016/S0140-6736(10)60391-1 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60391-1/fulltext
  9. Thanassoulis G et al. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010 Aug 9; 170:1358. PMID: 20696962
  10. Stamp LK et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: A proposed safe starting dose of allopurinol. Arthritis Rheum 2012 Aug; 64:2529. PMID: 22488501
  11. Deprecated Reference
  12. Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep. 2009 Apr;11(2):135-40. PMID: 19296886
  13. Stamp LK, O'Donnell JL, Zhang M et al Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum. 2011 Feb;63(2):412-21. PMID: 21279998
  14. Yang CY, Chen CH, Deng ST et al Allopurinol Use and Risk of Fatal Hypersensitivity Reactions: A Nationwide Population-Based Study in Taiwan. JAMA Intern Med. Published online July 20, 2015 PMID: 26193384 http://archinte.jamanetwork.com/article.aspx?articleID=2397733
  15. Stamp LK, Chapman PT, Barclay ML et al. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout. Ann Rheum Dis 2017 Mar 17; PMID: 28314755 http://ard.bmj.com/content/early/2017/03/17/annrheumdis-2016-210872
  16. Jutkowitz E, Dubreuil M, Lu N, Kuntz KM, Choi HK. The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the United States. Semin Arthritis Rheum 2017 Apr; 46:594 PMID: 27916277 http://www.semarthritisrheumatism.com/article/S0049-0172(16)30114-7/fulltext
  17. Singh JA, Cleveland JD. Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: An analysis of Medicare claims data. Ann Rheum Dis 2017 Jun 5 PMID: 28584186
  18. Saokaew S, Tassaneeyakul W, Maenthaisong R, Chaiyakunapruk N. Cost-effectiveness analysis of HLA-B*5801 testing in preventing allopurinol-induced SJS/TEN in Thai population. PLoS One. 2014 Apr 14;9(4):e94294. eCollection 2014. PMID: 24732692 Free PMC Article
  19. Doherty M, Jenkins W, Richardson H et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: A randomised controlled trial. Lancet 2018 Oct 20; 392:1403. PMID: 30343856 Free PMC Article
  20. Doria A, Galecki AT, Spino C et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med 2020 Jun 25; 382:2493. PMID: 32579810 https://www.nejm.org/doi/10.1056/NEJMoa1916624 - Badve SV, Pascoe EM, Tiku A et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med 2020 Jun 25; 382:2504. PMID: 32579811 https://www.nejm.org/doi/10.1056/NEJMoa1915833
  21. Wei J et al. Allopurinol initiation and all-cause mortality among patients with gout and concurrent chronic kidney disease: A population-based cohort study. Ann Intern Med 2022 Jan 25; [e-pub]. PMID: 35073156 https://www.acpjournals.org/doi/10.7326/M21-2347
  22. Bathini L et al. Initiation dose of allopurinol and the risk of severe cutaneous reactions in older adults with CKD: A population-based cohort study. Am J Kidney Dis 2022 Dec; 80:730-739 PMID: 35644439 https://www.ajkd.org/article/S0272-6386(22)00704-1/fulltext
  23. Glal KAM, El-Haggar SM, Abd-Elsalam SM et al. Allopurinol Prevents Cirrhosis-Related Complications: A Quadruple Blind Placebo- Controlled Trial. Am J Med. 2023 Oct 11:S0002-9343(23)00607-1. PMID: 37832758
  24. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information for allopurinol and HLA-B. https://www.pharmgkb.org/guideline/PA166105003

Component-of

allopurinol/lesinurad (Duzallo)