Drug Monograph
Allopurinol
Zyloprim, Lopurin, Aloprim (IV)
Pharmacokinetic Profile
Half-Life
Allopurinol: 1–2 h; Oxypurinol: ~23 h
Metabolism
Xanthine oxidase → oxypurinol (active)
Protein Binding
Negligible
Bioavailability
~79%
Volume of Distribution
1.3 L/kg (allopurinol); 0.6 L/kg (oxypurinol)
Clinical Information
Drug Class
Xanthine oxidase inhibitor (XOI)
Available Doses
100 mg, 200 mg, 300 mg tablets; 500 mg IV vial
Route
Oral (primary); IV (cancer therapy only)
Renal Adjustment
Yes — lower starting dose; titrate cautiously
Hepatic Adjustment
Monitor LFTs; no specific dose adjustment in PI
Pregnancy
May cause fetal harm
Lactation
Advise not to breastfeed
Schedule
Not a controlled substance; Rx only
Pharmacogenomics
HLA-B*58:01 screening recommended in at-risk populations
Generic Available
Yes
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Gout management (primary or secondary: acute attacks, tophi, joint destruction, uric acid lithiasis, nephropathy) | Adults | Long-term urate-lowering monotherapy | FDA Approved |
| Hyperuricemia secondary to cancer therapy | Adults and paediatric patients | Prophylactic (pre-chemotherapy) | FDA Approved |
| Recurrent calcium oxalate calculi with hyperuricosuria | Adults | Adjunctive to dietary measures | FDA Approved |
Allopurinol, first approved in 1966, remains the most widely prescribed urate-lowering therapy worldwide. The American College of Rheumatology (2020) conditionally recommends allopurinol as the preferred first-line agent for urate-lowering therapy in gout, including in patients with moderate-to-severe chronic kidney disease (stage ≥3). It is not indicated for asymptomatic hyperuricaemia alone. An important pre-treatment consideration is pharmacogenomic screening for HLA-B*58:01 in genetically at-risk populations to mitigate the risk of severe cutaneous adverse reactions.
Off-Label Uses
Lesch-Nyhan syndrome — Management of hyperuricaemia in this X-linked purine metabolism disorder. Evidence quality: Moderate.
Recurrent uric acid nephrolithiasis — Prevention in patients without hyperuricosuria-related calcium oxalate stones. Evidence quality: Moderate.
Ischaemia-reperfusion injury — Investigational use based on xanthine oxidase free-radical generation inhibition. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Gout — initiating urate-lowering therapy (normal renal function) | 100 mg once daily | 200–300 mg once daily | 800 mg/day | Titrate by 100 mg every 2–5 weeks to target SUA <6 mg/dL ACR 2020: start low, go slow |
| Tophaceous gout — aggressive urate lowering | 100 mg once daily | 300–600 mg/day | 800 mg/day | Target SUA <5 mg/dL; doses >300 mg should be divided May take months to years for tophus resolution |
| Hyperuricaemia from cancer therapy — adults | 200–400 mg/day (moderate); 600–800 mg/day (severe) | Adjust based on uric acid levels and disease severity | 800 mg/day | Start 24–48 h before chemotherapy; ensure adequate hydration and alkaline urine Doses >300 mg should be divided |
| Recurrent calcium oxalate calculi with hyperuricosuria | 200–300 mg/day | 200–300 mg/day | 300 mg/day (typical) | Adjunctive to high fluid intake and dietary modification |
Paediatric Dosing (Cancer Therapy Hyperuricaemia Only)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Cancer therapy-induced hyperuricaemia | 10 mg/kg/day or 100 mg/m² q8–12h | Adjust to response | 800 mg/day | BSA <0.5 m²: consider alternative formulation Maintain urinary output ≥100 mL/m²/h |
Renal Impairment Adjustments (Gout)
| Creatinine Clearance | Starting Dose | Titration | Notes | Source |
|---|---|---|---|---|
| >60 mL/min | 100 mg/day | Increase by 100 mg q2–5wk to target SUA | Standard titration | FDA PI / ACR 2020 |
| 30–60 mL/min | 50 mg/day | Lower increments until target SUA ≤6 mg/dL | Monitor renal function during titration | FDA PI 2024 |
| 15–29 mL/min | 50 mg/day | Titrate cautiously; close monitoring | ACR 2020 supports cautious dose escalation above traditional limits if needed | FDA PI / ACR 2020 |
| <15 mL/min or dialysis | 50 mg every other day or 100 mg 3 times/week | Titrate with extreme caution | Oxypurinol accumulates; not dialyzable effectively; monitor for toxicity | FDA PI |
Clinical Pearl: Treat-to-Target Dosing
The ACR 2020 guideline conditionally recommends a treat-to-target strategy for allopurinol in gout: start at ≤100 mg/day (lower in CKD), titrate upward every 2–5 weeks, and target a serum uric acid <6 mg/dL (or <5 mg/dL for tophaceous disease). Doses above the traditional renal-adjusted ceiling may be necessary and are supported by the ACR when accompanied by close monitoring, as undertreating hyperuricaemia leaves patients at risk for ongoing crystal deposition.
Pharmacology
Mechanism of Action
Allopurinol is a structural analogue of hypoxanthine that acts as a substrate and inhibitor of xanthine oxidase (XO), the enzyme responsible for the final two steps in purine catabolism: the conversion of hypoxanthine to xanthine and xanthine to uric acid. By blocking this pathway, allopurinol reduces both serum and urinary uric acid concentrations. Its primary active metabolite, oxypurinol, is itself a potent XO inhibitor with a much longer half-life, and is responsible for the sustained urate-lowering effect of allopurinol during chronic therapy.
By reducing uric acid production rather than increasing its excretion, allopurinol also decreases the urinary uric acid load, making it suitable for patients with uric acid nephrolithiasis or urate nephropathy. The inhibition of xanthine oxidase additionally suppresses the generation of reactive oxygen species, which has generated interest in potential cardioprotective and antioxidant applications, though these remain investigational.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability ~79%; Tmax ~1.5 h (allopurinol), 3–5 h (oxypurinol); food does not significantly affect absorption | May be taken with or after meals to reduce GI upset |
| Distribution | Vd ~1.3 L/kg (allopurinol), ~0.6 L/kg (oxypurinol); negligible protein binding for both | Widely distributed; no displacement interactions expected |
| Metabolism | Rapidly metabolised by xanthine oxidase to oxypurinol (active); ~90% conversion; also a substrate of BCRP (ABCG2) | Oxypurinol is responsible for sustained efficacy; BCRP Q141K variant may affect response |
| Elimination | t½ 1–2 h (allopurinol), ~23 h (oxypurinol); ~80% excreted in urine (primarily as oxypurinol); ~20% faecal | Oxypurinol half-life prolonged in renal impairment, requiring dose reduction; not effectively removed by dialysis |
Side Effects
≥1%
Most Common (≥1%)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Skin rash (maculopapular) | 1–10% | Most frequent adverse reaction overall; any rash warrants immediate discontinuation to exclude evolving hypersensitivity |
| Acute gout flares | ~6% (historical); <1% with slow titration + prophylaxis | Due to urate mobilisation from tissue deposits; co-prescribe flare prophylaxis (colchicine or NSAID) |
| Nausea | >1% | Taking with food may reduce GI discomfort |
| Diarrhoea | >1% | Generally mild; dose-related |
| Elevated LFTs (ALP, AST/ALT) | >1% (up to ~6%) | Usually asymptomatic and reversible; monitor LFTs and discontinue if persistent |
<1%
Less Common (<1%)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | <1% | Reported in postmarketing data |
| Drowsiness / somnolence | <1% | May impair driving; additive with alcohol and CNS depressants |
| Fever / malaise | <1% | May be early sign of hypersensitivity; evaluate promptly |
| Myalgia / arthralgia | <1% | Distinguish from gout flare |
Serious
Serious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| SJS / TEN | ~0.05% (5 in 10,000); mortality up to 25–30% | First few weeks to 3 months | Immediate permanent discontinuation; dermatology and ICU as needed; strongly associated with HLA-B*58:01 |
| DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) | Rare (included in 0.05% SCAR rate) | 2–8 weeks | Permanent discontinuation; systemic corticosteroids; multiorgan monitoring |
| Allopurinol hypersensitivity syndrome (AHS) | Rare; mortality up to 25% | Weeks to months after initiation | Permanent discontinuation; supportive care; check renal function, LFTs, eosinophils |
| Hepatotoxicity (hepatic necrosis, granulomatous hepatitis) | Rare; sometimes irreversible | Variable; weeks to months | Discontinue; monitor LFTs; hepatology referral if severe |
| Myelosuppression (leukopenia, thrombocytopenia, aplastic anaemia) | Rare; 6 weeks to 6 years after initiation | 6 weeks–6 years | Discontinue; urgent CBC; haematology referral; higher risk with concurrent cytotoxic agents |
| Nephrotoxicity (interstitial nephritis) | Rare | Variable | Monitor renal function; discontinue and investigate if persistent abnormalities |
| Vasculitis (generalised) | Very rare | Variable | Discontinue; rheumatology/dermatology assessment |
Discontinuation
Discontinuation Rates
Overall
Low overall discontinuation rate
Primary reason: Skin rash (any grade) — mandates permanent discontinuation per PI
Real-World Adherence
Suboptimal adherence is common
Key barrier: Early gout flares during titration phase lead many patients to discontinue prematurely
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Skin rash | Most frequent reason for mandatory discontinuation | Any rash requires permanent cessation to exclude SJS/TEN/DRESS |
| Acute gout flare | Common early in therapy | Not a reason to stop; continue allopurinol and manage flare; counsel patients proactively |
| GI intolerance | Uncommon reason for discontinuation | Usually manageable by taking with meals or dose adjustment |
Managing Skin Reactions: The Critical First 3 Months
The risk of SJS/TEN/DRESS is highest during the first few months of therapy. Any skin rash, however mild, requires immediate and permanent discontinuation of allopurinol. Do not rechallenge. Educate patients at initiation to stop the drug and seek urgent evaluation if they develop rash, mouth sores, skin blistering, fever, or facial swelling. Starting low and titrating slowly reduces but does not eliminate this risk.
Drug Interactions
Allopurinol’s interaction profile centres on its inhibition of xanthine oxidase, which is involved in the metabolism of several important drugs. It also affects purine metabolism pathways that influence the activation and clearance of thiopurines and certain cytotoxic agents.
Major
Azathioprine / Mercaptopurine
MechanismAllopurinol inhibits xanthine oxidase-mediated metabolism of 6-MP (active metabolite of azathioprine)
EffectDramatically increased 6-MP levels causing severe myelosuppression and pancytopenia
ManagementReduce mercaptopurine or azathioprine dose to approximately one-third to one-quarter of usual dose per their respective PIs
FDA PI
Major
Capecitabine
MechanismInhibition of capecitabine activation pathway
EffectReduced efficacy of capecitabine; potential for altered toxicity
ManagementAvoid concomitant use
FDA PI
Major
Pegloticase
MechanismAllopurinol masks the uric acid flare that serves as a biomarker for anti-drug antibody development
EffectInability to detect loss of pegloticase efficacy, increasing anaphylaxis and infusion reaction risk
ManagementDiscontinue allopurinol before and during pegloticase therapy
FDA PI
Moderate
Ampicillin / Amoxicillin
MechanismUnknown; possibly immunological
EffectIncreased incidence of skin rash compared to either drug alone
ManagementUse alternative antibiotics when possible; discontinue allopurinol at first sign of rash
FDA PI
Moderate
Thiazide Diuretics
MechanismReduced renal clearance of oxypurinol; additive renal impairment
EffectIncreased risk of allopurinol hypersensitivity syndrome, particularly with concurrent renal impairment
ManagementMonitor renal function; reduce allopurinol dose if renal function declines; heightened vigilance for skin reactions
FDA PI
Moderate
Warfarin
MechanismPossible inhibition of warfarin metabolism (clinical significance debated)
EffectEnhanced anticoagulant effect reported in some cases
ManagementMonitor INR more frequently when initiating or adjusting allopurinol
FDA PI / Lexicomp
Moderate
ACE Inhibitors (captopril, enalapril)
MechanismUnknown immunological interaction
EffectCase reports of increased risk of hypersensitivity reactions including SJS
ManagementMonitor for hypersensitivity symptoms; consider alternative antihypertensive if feasible
Medscape / Case reports
Minor
Aluminium Hydroxide
MechanismReduced GI absorption of allopurinol
EffectDecreased allopurinol bioavailability
ManagementSeparate administration by at least 2 hours
MedscapeMonitoring
-
HLA-B*58:01
Before initiation (in at-risk populations)
Routine Screen patients of Southeast Asian, African American, Native Hawaiian/Pacific Islander, and Korean descent. Do not initiate in HLA-B*58:01-positive patients unless benefits clearly outweigh risks. ACR 2020 conditionally recommends testing prior to allopurinol in these populations. -
Serum Uric Acid
Baseline, then every 2–5 weeks during titration; q6 months at maintenance
Routine Target <6 mg/dL for gout; <5 mg/dL for tophaceous disease. Continue checking even at stable doses to confirm sustained target attainment. -
Renal Function
Baseline, then every 2–5 weeks during titration; periodically thereafter
Routine Serum creatinine and eGFR. Oxypurinol accumulates in renal impairment. Dose adjustments required if renal function declines. Monitor especially during early stages of treatment. -
Liver Function Tests
Baseline, then every 2–5 weeks during titration; periodically thereafter
Routine ALT, AST, ALP, total bilirubin. Reversible hepatotoxicity reported; discontinue if persistent elevations or clinical hepatitis develops. -
CBC
Baseline, then every 2–5 weeks during titration; q6 months
Routine Monitor for myelosuppression (leukopenia, thrombocytopenia, anaemia). More frequently if concurrent cytotoxic therapy. -
Skin Assessment
Every visit, especially in the first 3 months
Routine Any rash requires immediate discontinuation. Educate patient to self-monitor and contact prescriber at first sign of cutaneous changes. -
Drug Interaction Review
At initiation and every prescription change
Trigger-based Screen for thiopurines, capecitabine, pegloticase, ampicillin/amoxicillin, thiazides, and ACE inhibitors.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to allopurinol or history of severe reaction (SJS/TEN/DRESS/AHS) to any formulation.
- HLA-B*58:01 positive — not recommended unless benefits clearly outweigh risks (FDA PI 2024).
Relative Contraindications (Specialist Input Recommended)
- Severe renal impairment (CrCl <15 mL/min) — oxypurinol accumulation increases toxicity risk; if used, start at very low dose with specialist supervision.
- Concurrent thiazide diuretics with renal impairment — significantly increased risk of allopurinol hypersensitivity; documented cases of fatal AHS.
- Concurrent azathioprine or mercaptopurine without dose reduction — predictable life-threatening myelosuppression.
Use with Caution
- Mild-to-moderate renal impairment — start at lower doses and titrate slowly.
- Hepatic disease — monitor LFTs closely; reversible and irreversible hepatotoxicity reported.
- Pregnancy — may cause fetal harm based on animal data; use only if clearly needed.
- Lactation — allopurinol and oxypurinol present in breast milk; advise not to breastfeed.
- Elderly — more likely to have renal impairment; start with lower doses.
FDA Safety Warning
Severe Cutaneous Adverse Reactions (SCAR) and HLA-B*58:01
Serious and sometimes fatal dermatologic reactions, including SJS, TEN, and DRESS, occur in approximately 0.05% of patients taking allopurinol. The HLA-B*58:01 allele is a strong genetic marker for these reactions. This allele is more prevalent in individuals of African, Asian (Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry. Consider testing for HLA-B*58:01 before starting allopurinol in genetically at-risk populations. Discontinue allopurinol permanently at the first appearance of skin rash or other signs of hypersensitivity.
Patient Counselling
Purpose of Therapy
Allopurinol works by reducing the amount of uric acid the body produces. It is taken daily on an ongoing basis to prevent gout attacks, kidney stones, and joint damage. It does not treat a gout attack that is already happening, and it may actually cause more frequent attacks during the first few months of use — this is expected and does not mean the medicine is not working.
How to Take
Take allopurinol once daily (or in divided doses if prescribed more than 300 mg per day) with or after a meal to reduce stomach upset. Drink plenty of water (at least 8–10 glasses per day) to help prevent kidney stones. Your doctor will likely start you on a low dose and increase it gradually. Continue taking allopurinol even if you have a gout flare — stopping may make the flare worse.
Skin Rash — Critical Safety Warning
Tell patient
This is the single most important safety message. Any skin rash, no matter how mild, requires you to stop taking allopurinol immediately and contact your doctor the same day. A rash can be the first sign of a rare but potentially life-threatening allergic reaction.
Call prescriber
Immediately for any rash, blistering or peeling skin, mouth sores, eye redness, swelling of the face or lips, or fever with skin changes. Go to the emergency department if breathing is affected.
Gout Flares During Early Treatment
Tell patient
Gout attacks may increase in the first few months as uric acid levels change. This is a normal part of the process and does not mean the medicine is failing. Your doctor may prescribe a separate anti-inflammatory medicine (such as colchicine or an NSAID) to take alongside allopurinol to prevent these flares.
Call prescriber
If gout flares are frequent or severe despite prophylactic medication, or if you are unsure whether symptoms represent a flare or something else.
Drowsiness
Tell patient
Allopurinol may cause drowsiness or dizziness, especially when starting treatment or increasing the dose. Avoid driving or operating heavy machinery until you know how it affects you. Alcohol may worsen drowsiness and can also raise uric acid levels.
Call prescriber
If drowsiness is persistent or interferes with daily activities.
Kidney & Liver Health
Tell patient
Regular blood tests will be needed to monitor kidney and liver function, especially during dose adjustments. Stay well hydrated to protect the kidneys.
Call prescriber
If you notice dark urine, yellowing of the skin or eyes, loss of appetite, upper right-side stomach pain, unusual fatigue, blood in the urine, or decreased urination.
Drug Interactions
Tell patient
Inform every healthcare provider that you take allopurinol, especially before starting antibiotics (particularly ampicillin or amoxicillin), blood thinners, or medications for autoimmune conditions. Some common medications interact dangerously with allopurinol.
Call prescriber
Before starting any new medication, including over-the-counter drugs.
Sources
Regulatory (PI / SmPC)
- Allopurinol Tablets Prescribing Information. Sun Pharmaceutical Industries, Inc. Revised April 2024. FDA Current FDA-approved PI for oral allopurinol; source for dosing, renal adjustments, HLA-B*58:01 guidance, and adverse reaction data.
- Zyloprim (allopurinol) Prescribing Information. Takeda Pharmaceuticals/Casper Pharma. 2018. FDA Historical reference PI providing additional adverse reaction detail and drug interaction guidance.
- Aloprim (allopurinol) for Injection Prescribing Information. Fresenius Kabi USA, LLC. Revised 2022. FDA FDA-approved PI for IV allopurinol; source for tumour lysis syndrome dosing and renal adjustment table.
Key Clinical Trials
- Stamp LK, Taylor WJ, Jones PB, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012;64(8):2529–2536. doi:10.1002/art.34488 Key study establishing that low starting doses reduce hypersensitivity risk; supported the start-low, go-slow approach.
- 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;76(9):1522–1528. doi:10.1136/annrheumdis-2016-210872 RCT demonstrating safety of dose escalation above creatinine clearance-based limits when guided by serum urate targets and monitoring.
- Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396(10264):1745–1757. doi:10.1016/S0140-6736(20)32234-0 FAST trial: confirmed cardiovascular safety of allopurinol versus febuxostat in gout patients; no excess CV risk with allopurinol.
Guidelines
- FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for management of gout. Arthritis Care Res. 2020;72(6):744–760. doi:10.1002/acr.24180 Current ACR guideline conditionally recommending allopurinol as first-line ULT; provides treat-to-target dosing strategy and HLA-B*58:01 screening recommendations.
- Khanna D, FitzGerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431–1446. doi:10.1002/acr.21772 Prior ACR guideline establishing allopurinol as first-line and providing dose escalation framework; superseded but historically important.
Mechanistic / Basic Science
- Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58(1):87–114. doi:10.1124/pr.58.1.6 Comprehensive review of xanthine oxidase biology and the pharmacology of allopurinol beyond gout, including antioxidant properties.
- Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005;102(11):4134–4139. doi:10.1073/pnas.0409500102 Landmark study identifying HLA-B*58:01 as a strong genetic marker for allopurinol-induced SJS/TEN/DRESS in Han Chinese.
Pharmacokinetics / Special Populations
- Day RO, Graham GG, Hicks M, et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet. 2007;46(8):623–644. doi:10.2165/00003088-200746080-00001 Definitive PK/PD review establishing key parameters: bioavailability 79%, allopurinol t½ 1.2 h, oxypurinol t½ 23.3 h, and renal clearance relationships.
- Stocker SL, Williams KM, McLachlan AJ, et al. The population pharmacokinetics of allopurinol and oxypurinol in patients with gout. Eur J Clin Pharmacol. 2013;69(6):1411–1421. doi:10.1007/s00228-013-1478-1 Population PK model demonstrating how renal function, fat-free mass, and diuretic use predict oxypurinol exposure and inform dose individualisation.
- Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984;76(1):47–56. doi:10.1016/0002-9343(84)90743-5 Historical study establishing creatinine clearance-based dosing guidelines for allopurinol in renal impairment; basis for traditional dose ceilings.