A Comprehensive Clinical and Pharmacological Monograph of Allopurinol (DB00437)

Executive Summary

Allopurinol is a cornerstone therapeutic agent in the long-term management of disorders caused by hyperuricemia. As a first-line xanthine oxidase inhibitor, its primary function is to decrease the production of uric acid in the body. The therapeutic efficacy of allopurinol is predominantly mediated by its principal active metabolite, oxipurinol, which possesses a significantly longer half-life and provides sustained inhibition of the terminal enzymatic steps in purine catabolism.

The United States Food and Drug Administration (FDA) has approved allopurinol for three primary clinical indications: the management of chronic gout, including gouty arthritis and tophaceous disease; the prevention of acute uric acid nephropathy and severe hyperuricemia associated with tumor lysis syndrome (TLS) during cancer chemotherapy; and the management of recurrent calcium oxalate kidney stones in patients with hyperuricosuria.

Despite its widespread use and established efficacy, the safety profile of allopurinol requires careful clinical consideration. The most critical safety concern is the risk of rare but potentially fatal Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). A strong pharmacogenomic association has been established between the risk of these reactions and the presence of the Human Leukocyte Antigen (HLA)-B*58:01 allele, which is found with higher prevalence in individuals of certain Asian and African ancestries.

Clinically, two considerations are paramount for the safe use of allopurinol. First, dose adjustment is mandatory in patients with renal impairment. The active metabolite, oxipurinol, is cleared by the kidneys, and its accumulation in patients with chronic kidney disease significantly elevates the risk of toxicity. Second, allopurinol engages in a life-threatening drug-drug interaction with the thiopurine agents azathioprine and 6-mercaptopurine, necessitating significant dose reduction or avoidance of the combination.

In modern clinical practice, allopurinol remains the foundational urate-lowering therapy, valued for its proven efficacy, convenient once-daily dosing, and low cost. Its use demands a nuanced approach that balances these benefits against a well-defined risk profile, mandating careful patient selection, risk stratification, vigilant monitoring, and comprehensive patient education.

Chemical Identity and Physicochemical Properties

Allopurinol is a small molecule drug that is a structural isomer of the natural purine base hypoxanthine.[1] This structural similarity is fundamental to its mechanism of action as a competitive inhibitor in the purine metabolic pathway.

Nomenclature and Identifiers

The compound is universally known by its generic name, Allopurinol.[1] Its systematic chemical name, according to the International Union of Pure and Applied Chemistry (IUPAC), is 1H-pyrazolo[3,4-d]pyrimidin-4-ol.[3] It is also frequently referred to by synonyms such as 1,5-Dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one and 4-Hydroxypyrazolo[3,4-d]pyrimidine.[3] For database and regulatory tracking, it is assigned the DrugBank accession number DB00437 and the Chemical Abstracts Service (CAS) number 315-30-0.[2]

Chemical Structure and Formula

Chemically, allopurinol is classified as a purine analog and a nucleobase analogue.[3] Its molecular architecture consists of an organic heterobicyclic structure where a pyrazole ring is fused to a hydroxy-substituted pyrimidine ring.[3]

• Molecular Formula: C5​H4​N4​O [1]
• Molecular Weight: 136.11 g/mol [3]
• Standard InChI: InChI=1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10) [1]
• Standard InChIKey: OFCNXPDARWKPPY-UHFFFAOYSA-N [1]
• SMILES: Oc1ncnc2[nH]ncc12 [2]

Physical Properties

Allopurinol presents as a white to off-white, odorless crystalline solid or powder at room temperature.[4] It has a very high melting point, recorded as >300 °C and in some instances >340 °C, which is indicative of a highly stable crystalline lattice structure.[4]

The compound is a polar molecule with limited solubility. It is described as slightly soluble in water and ethanol.[6] Its solubility in dimethyl sulfoxide (DMSO) is noted for laboratory purposes.[2] The acid dissociation constant, or pKa, of allopurinol is 10.2, reflecting its weakly acidic nature.[6]

Table 1: Physicochemical and Identification Data for Allopurinol

Property	Value	Source(s)
IUPAC Name	1H-pyrazolo[3,4-d]pyrimidin-4-ol	3
Generic Name	Allopurinol	1
CAS Number	315-30-0	5
DrugBank ID	DB00437	[User Query]
Molecular Formula	C5​H4​N4​O	1
Molecular Weight	136.11 g/mol	3
Appearance	White to off-white crystalline solid	4
Melting Point	>300 °C	4
pKa	10.2	6
Solubility	Slightly soluble in water and ethanol	6
InChIKey	OFCNXPDARWKPPY-UHFFFAOYSA-N	1

Clinical Pharmacology

The clinical effects of allopurinol are dictated by its unique pharmacological profile, which includes a multi-faceted mechanism of action and a pharmacokinetic profile dominated by its long-acting, renally cleared active metabolite.

3.1. Mechanism of Action

Allopurinol exerts its therapeutic effects through several interrelated mechanisms that collectively reduce the total body burden of uric acid.

Primary Mechanism: Xanthine Oxidase Inhibition

The principal mechanism of allopurinol is the inhibition of xanthine oxidase (XO), an enzyme that plays a pivotal role in purine metabolism.[1] Allopurinol is a structural isomer of hypoxanthine, and its primary active metabolite, oxipurinol (also known as alloxanthine), is a structural analogue of xanthine.[1] This structural mimicry allows both allopurinol and oxipurinol to bind to the active site of XO, acting as competitive inhibitors.[6]

XO is responsible for catalyzing the final two steps in the synthesis of uric acid: the oxidation of hypoxanthine to xanthine, and the subsequent oxidation of xanthine to uric acid.[1] By blocking this enzyme, allopurinol and oxipurinol effectively halt the production of uric acid, leading to a decrease in both serum and urinary concentrations of urate.[4] This reduction in urate concentration below the saturation point facilitates the dissolution of existing urate crystal deposits (tophi) in joints and other tissues.[4]

Role of the Active Metabolite, Oxipurinol

While allopurinol itself contributes to XO inhibition, its therapeutic effect is overwhelmingly attributed to its metabolite, oxipurinol.[1] Allopurinol is rapidly metabolized in the body to oxipurinol.[1] Oxipurinol is also a potent inhibitor of XO, but it binds more tightly and is considered a non-competitive inhibitor.[1] Crucially, oxipurinol has a much longer elimination half-life than the parent drug.[1] This extended duration of action is what allows for convenient once-daily dosing and provides the sustained urate-lowering effect that is essential for the long-term management of gout.[1] Therefore, oxipurinol is considered the primary "workhorse" of allopurinol therapy.[1]

Secondary Mechanism: Inhibition of De Novo Purine Biosynthesis

Beyond simply blocking the final steps of uric acid formation, allopurinol also reduces the overall production of purines. The inhibition of XO leads to an accumulation of its substrates, hypoxanthine and xanthine.[1] These purine bases are not merely waste products; they can be re-utilized by the body through a "salvage pathway" mediated by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase).[6] HGPRTase converts hypoxanthine and xanthine back into their corresponding ribonucleotides (inosine monophosphate and xanthosine monophosphate), which can then be used for nucleic acid synthesis.[6]

The resulting increase in the intracellular pool of purine ribonucleotides is believed to exert a negative feedback inhibition on amidophosphoribosyl transferase, the first and rate-limiting enzyme in the de novo (from scratch) purine biosynthesis pathway.[6] This feedback mechanism effectively throttles the body's overall production of new purines, thereby reducing the total amount of purine substrate available for catabolism into uric acid. Evidence for this secondary mechanism comes from studies showing that allopurinol therapy reduces total daily purine excretion in healthy individuals, an effect that is absent in patients with Lesch-Nyhan syndrome, who have a congenital deficiency of the HGPRTase enzyme.[6] This dual action—blocking the final conversion to uric acid and reducing the initial synthesis of its precursors—makes allopurinol a highly effective agent, particularly in conditions of massive purine overproduction like TLS.

Additional Pharmacodynamic Effects

Allopurinol and its metabolite exhibit other biological activities that may contribute to their therapeutic and adverse effect profiles.

• Antioxidant and Radical Scavenging Properties: Xanthine oxidase is a significant biological source of reactive oxygen species (ROS), such as superoxide radicals, during its catalytic cycle.[8] By inhibiting XO, allopurinol effectively reduces the production of these pro-inflammatory and damaging molecules.[8] This antioxidant effect has been proposed as a mechanism for its potential cardioprotective benefits.[1] However, the picture is complex, as some evidence suggests that the enzymatic conversion of allopurinol to oxipurinol by XO can, paradoxically, generate superoxide radicals itself, adding a layer of complexity to its net effect on oxidative stress.[3]
• Adenosine Modulation and Anti-Nociception: Preclinical research has demonstrated that allopurinol can produce a modest pain-relieving (anti-nociceptive) effect.[8] This is thought to occur because the buildup of hypoxanthine resulting from XO inhibition leads to increased salvage and subsequent elevation of adenosine levels in the central nervous system.[8] This effect appears to be specifically mediated by adenosine A1 receptors and offers a potential mechanism for analgesia in certain chronic pain states that is independent of its urate-lowering and anti-inflammatory properties.[8]

3.2. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical behavior of allopurinol is characterized by the rapid absorption and clearance of the parent drug and the slow elimination of its long-acting active metabolite, oxipurinol. This dichotomy is central to both its efficacy and its primary safety concerns.

Absorption

Following oral administration, allopurinol is absorbed rapidly and extensively from the gastrointestinal tract, with reports of oral bioavailability ranging from 67% to as high as 90%.[6] Peak plasma concentrations (

Cmax​) of the parent drug are typically achieved within 1 to 1.5 hours post-dose.[6] In contrast, peak plasma levels of the metabolite oxipurinol are reached more slowly, at approximately 3 to 4.5 hours.[6] Administration via the rectal route results in negligible absorption and is not a viable clinical option.[6]

Distribution

Allopurinol is widely distributed throughout the body tissues. Its apparent volume of distribution (Vd​/F) is approximately 1.3 to 1.6 L/kg, which is significantly larger than the volume of total body water, indicating extensive extravascular distribution.[7] Its active metabolite, oxipurinol, has a smaller volume of distribution of about 0.6 L/kg, suggesting it is less extensively distributed into tissues and remains more confined to the body's water content.[9] A key feature of both compounds is that they are negligibly bound to plasma proteins, meaning they are freely available to distribute into tissues and interact with their target enzyme.[6] Animal studies have shown the highest concentrations of allopurinol in highly perfused tissues such as the liver, intestine, heart, and blood.[6]

Metabolism

Allopurinol functions as a prodrug, undergoing rapid and nearly complete metabolism to its pharmacologically active metabolite, oxipurinol.[1] This conversion is efficient, occurring within about two hours of an oral dose.[1] While xanthine oxidase itself can catalyze this reaction, it is a common misconception that it is the primary enzyme responsible. The principal catalyst for the conversion of allopurinol to oxipurinol is aldehyde oxidase (AOR).[1]

Excretion

The elimination kinetics of allopurinol and oxipurinol are starkly different and are central to understanding the drug's clinical use.

• Allopurinol: The parent drug has a very short elimination half-life (t1/2​) of only 1 to 2 hours.[9] This rapid clearance is due to its swift metabolic conversion to oxipurinol.
• Oxipurinol: The active metabolite is eliminated slowly and almost exclusively via renal excretion.[1] In individuals with normal renal function, oxipurinol has a long elimination half-life ranging from 15 to 30 hours.[1] This prolonged half-life is what provides sustained xanthine oxidase inhibition and allows for effective once-daily dosing.

Overall, approximately 80% of an administered oral dose is recovered in the urine, with about 70% as oxipurinol and only 10% as unchanged allopurinol.[6] The remaining 20% of the dose is eliminated in the feces.[13]

The pharmacokinetic profile of allopurinol presents a classic "double-edged sword." The therapeutic success of the drug is built upon the rapid conversion of the short-lived parent compound into the long-acting active metabolite, oxipurinol. This metabolic conversion is what transforms a drug that would otherwise require frequent, inconvenient dosing into a highly effective once-daily therapy. The sustained high levels of oxipurinol ensure continuous inhibition of xanthine oxidase throughout the dosing interval. However, this very same property is the root of the drug's most significant safety liability. The near-total reliance on the kidneys for the elimination of oxipurinol means that in any patient with impaired renal function, the metabolite cannot be cleared effectively. As its formation from allopurinol continues with each dose, oxipurinol levels accumulate, often to a degree far exceeding the therapeutic range. This accumulation is directly implicated as a primary risk factor for the development of severe and life-threatening adverse reactions, most notably the allopurinol hypersensitivity syndrome. Thus, the pharmacokinetic feature that confers therapeutic convenience is inextricably linked to its potential for toxicity in vulnerable populations.

Table 2: Comparative Pharmacokinetic Parameters of Allopurinol and Oxipurinol

Parameter	Allopurinol	Oxipurinol	Clinical Significance
Oral Bioavailability	~80% 7	N/A (Metabolite)	High absorption of the parent prodrug ensures reliable delivery.
Time to Peak (Tmax)	~1.5 hours 13	~4.5 hours 13	Rapid conversion to the active form begins shortly after ingestion.
Elimination Half-Life (t½)	1-2 hours 9	15-30 hours 1	The long half-life of oxipurinol allows for once-daily dosing and provides sustained therapeutic effect.
Volume of Distribution (Vd)	~1.6 L/kg 7	~0.6 L/kg 9	Allopurinol distributes more widely into tissues than its metabolite.
Plasma Protein Binding	Negligible 6	Negligible 6	High free fraction of both compounds allows for ready interaction with target enzymes and tissues.
Primary Metabolizing Enzyme	Aldehyde Oxidase 1	N/A	Metabolism is rapid and efficient, primarily driven by AOR.
Primary Route of Elimination	Metabolism to oxipurinol	Renal Excretion 1	Oxipurinol's renal clearance is the rate-limiting step and the reason for dose adjustment in CKD.

Clinical Indications and Therapeutic Use

Allopurinol is a widely prescribed medication with specific, well-defined indications for conditions driven by the overproduction or deposition of uric acid.

4.1. Approved (On-Label) Indications

The U.S. FDA has approved allopurinol for the following conditions [10]:

• Management of Chronic Gout: Allopurinol is established as a first-line, long-term maintenance therapy for patients with primary or secondary gout.[1] Its use is indicated in patients who exhibit signs and symptoms of the disease, such as recurrent acute attacks (gouty arthritis), the presence of subcutaneous urate deposits (tophi), joint destruction visible on radiography, or uric acid nephrolithiasis.[1] The therapeutic goal is to lower serum urate levels sufficiently to prevent the formation of new crystals and promote the dissolution of existing ones, thereby reducing the frequency of painful gout flares over time.[17] It is critical to emphasize that allopurinol is a prophylactic agent and is not indicated for the treatment of an acute gout attack.[17] Therapy should not be initiated during an acute flare, and if a patient already on allopurinol experiences a flare, the medication should be continued at the same dose without interruption.[1]
• Prevention of Tumor Lysis Syndrome (TLS): Allopurinol is used to manage the severe hyperuricemia that can result from the rapid breakdown of malignant cells during cytotoxic cancer therapy.[1] This is particularly relevant in the treatment of hematologic malignancies like leukemias and lymphomas, as well as other solid tumors with high cell turnover rates.[1] The massive release of purines from dying cancer cells can overwhelm the metabolic pathway, leading to acute uric acid nephropathy and renal failure. Allopurinol is typically initiated 2 to 3 days prior to the start of chemotherapy to preemptively lower uric acid production.[10] While it has been a mainstay for TLS prophylaxis, in some high-risk scenarios, it has been supplanted by urate oxidase agents like rasburicase, which directly catabolize existing uric acid.[1]
• Management of Recurrent Calcium Oxalate Calculi: Allopurinol is indicated for the prevention of recurrent calcium oxalate kidney stones in patients who also have hyperuricosuria.[10] This indication is specifically for patients whose 24-hour urinary uric acid excretion exceeds 800 mg/day (for males) or 750 mg/day (for females), despite lifestyle modifications.[20] By reducing the production of uric acid, allopurinol lowers its concentration in the urine, which in turn reduces the risk of uric acid crystals acting as a nidus for calcium oxalate stone formation.

A significant limitation of use stated on the drug's label is that allopurinol is not recommended for the treatment of asymptomatic hyperuricemia (elevated uric acid levels without symptoms of gout or kidney stones).[21]

4.2. Off-Label and Investigational Applications

Beyond its approved indications, the pharmacological properties of allopurinol have led to its investigation and use in a variety of other clinical contexts.

• Inflammatory Bowel Disease (IBD): Allopurinol is used as an adjunctive therapy in combination with thiopurine drugs (azathioprine or 6-mercaptopurine) for patients with IBD, such as Crohn's disease or ulcerative colitis, who have an inadequate response to thiopurine monotherapy.[1] The addition of low-dose allopurinol inhibits the xanthine oxidase-mediated metabolism of thiopurines, shunting their metabolic pathway towards the production of the active, therapeutic 6-thioguanine nucleotide (6-TGN) metabolites and away from the 6-methylmercaptopurine (6-MMP) metabolites, which are associated with hepatotoxicity.[1] This strategy allows for a reduction in the thiopurine dose, thereby improving both efficacy and the safety profile, particularly concerning liver toxicity.[1]
• Cardiovascular Disease: A substantial body of research has explored the potential role of allopurinol in cardiovascular protection. This interest is driven by the observed correlation between elevated serum uric acid and increased cardiovascular risk, as well as allopurinol's ability to reduce oxidative stress by inhibiting XO.[1] Some observational studies and smaller trials have suggested that allopurinol may have a cardioprotective effect, potentially reducing the risk of events like myocardial infarction.[3] However, the evidence remains inconclusive. Notably, a large randomized controlled trial in high-risk heart failure patients, the EXACT-HF study, found that allopurinol did not improve clinical outcomes.[24] Research in this area is ongoing.
• Dermatologic Disorders: Allopurinol has been used off-label in dermatology to treat a number of rare or recalcitrant skin conditions.[25] These include acquired reactive perforating collagenosis, cutaneous sarcoidosis, psoriasis, and foreign-body granulomas (e.g., from silicone or tattoo ink).[1] The therapeutic benefit in these disorders is not related to urate lowering but is hypothesized to stem from its anti-inflammatory, antioxidant, or vasculoprotective properties.[25]
• Chronic Kidney Disease (CKD): Given the link between hyperuricemia and the progression of CKD, allopurinol has been investigated for a potential renoprotective effect.[10] Clinical trials have explored whether lowering uric acid with allopurinol can slow the decline of kidney function in patients with CKD.[10] Some studies have suggested a benefit compared to other agents, but its role in this context is still being defined, especially given the need for careful dose adjustment in this very population.[10]

Dosage, Administration, and Therapeutic Monitoring

The safe and effective use of allopurinol requires adherence to specific guidelines for dosing, administration, and monitoring, with particular attention paid to patients with impaired organ function.

5.1. Formulations and Standard Dosing Regimens

Allopurinol is available in two primary formulations:

• Oral Tablets: The most common form, available in strengths of 100 mg, 200 mg, and 300 mg.[19] Common brand names include Zyloprim, Lopurin, and Uricto.[5]
• Intravenous (IV) Solution: Available for injection, typically under the brand name Aloprim, for patients who cannot tolerate oral therapy, primarily in the setting of TLS prevention.[1]

For oral administration, it is recommended that tablets be taken after a meal to minimize the potential for gastric irritation.[12] While once-daily dosing is common, total daily doses exceeding 300 mg should be administered in divided doses (e.g., twice daily).[20] A critical component of therapy is maintaining adequate hydration; patients should be counseled to drink plenty of fluids, aiming for a daily urine output of at least 2 to 3 liters, to help prevent the formation of xanthine or urate kidney stones.[12]

Table 3: Dosing Guidelines for Allopurinol in Key Indications

Indication	Patient Population	Starting Dose	Titration Schedule	Maintenance Dose	Maximum Dose	Key Comments
Chronic Gout	Adults	100 mg/day 12	Increase by 100 mg every 2-5 weeks 19	Mild: 200-300 mg/daySevere: 400-600 mg/day 19	800 mg/day 12	Initiate flare prophylaxis with colchicine or an NSAID for several months.12 Titrate to target serum uric acid <6 mg/dL.19
Tumor Lysis Syndrome	Adults	Oral: 600-800 mg/day in divided doses 19	IV: 200-400 mg/m²/day 10	N/A (Short-term use)	As per initial dose	Oral: 800 mg/dayIV: 600 mg/day 20
Tumor Lysis Syndrome	Pediatrics (6-10 years)	Oral: 300 mg/day 19	IV: 200 mg/m²/day 10	N/A (Short-term use)	As per initial dose	Oral: 800 mg/dayIV: 400 mg/day 10
Recurrent Calcium Oxalate Stones	Adults	200-300 mg/day (single or divided doses) 12	N/A	As per initial dose	800 mg/day 12	Dose should be adjusted based on 24-hour urinary urate levels.20 Ensure adequate hydration.12

5.2. Special Populations: Renal and Hepatic Impairment

Dose adjustment in patients with organ dysfunction is critical to prevent drug accumulation and toxicity.

Renal Impairment

This is the most important consideration for allopurinol dosing. Because the active metabolite oxipurinol is eliminated by the kidneys, renal impairment leads to its accumulation and a significantly increased risk of adverse effects, including SCARs.[6]

Historically, dosing was strictly capped based on creatinine clearance (CrCl). However, modern guidelines, such as those from the American College of Rheumatology (ACR), advocate for a more flexible "start low, go slow" titration strategy.[29] This approach involves initiating allopurinol at a very low dose (e.g., 50 mg/day for CKD stage 4 or worse) and titrating upwards cautiously every 2 to 5 weeks, guided by serum uric acid levels and close monitoring for toxicity.[10] This allows patients with CKD to potentially reach the target uric acid level, even if the final dose exceeds the old CrCl-based caps, provided they are well-educated on the risks.[29] For patients on dialysis, allopurinol is dialyzable, and the dose should be administered after the dialysis session.[10]

Table 4: Recommended Allopurinol Dose Adjustments in Renal Impairment

eGFR / CrCl (mL/min)	Recommended Starting Dose	Traditional Max Dose	Clinical Guidance Notes
>60	100 mg/day	800 mg/day	No initial adjustment needed. Standard titration.
30 to <60	50 mg/day 20	Varies	Start low and titrate cautiously based on serum uric acid and tolerance.
10 to <30	50 mg every other day or 100-200 mg/day 20	200 mg/day 30	Significant risk of accumulation. Very cautious titration is essential.
<10	50 mg weekly or 100 mg at extended intervals 20	100 mg/day 30	Highest risk. Use only if necessary. Consider alternatives.
Hemodialysis	50 mg on alternate days or after dialysis 10	Varies	Administer post-dialysis. Titrate based on pre-dialysis uric acid levels.

Hepatic Impairment

Allopurinol should be used with caution in patients with pre-existing liver disease.[12] Reduced initial doses should be considered, and liver function tests (LFTs) should be monitored periodically throughout therapy, as hepatotoxicity can occur.[21]

5.3. Therapeutic Monitoring

Regular monitoring is essential to ensure both the efficacy and safety of allopurinol therapy.

• Baseline Assessment: Prior to initiating treatment, a comprehensive baseline evaluation should be performed, including serum uric acid level, complete blood count (CBC), a chemistry panel including LFTs (ALT, AST, alkaline phosphatase, bilirubin), and renal function tests (serum creatinine and eGFR).[10]
• Titration Phase: During the initial dose titration period, serum uric acid levels should be checked every 2 to 5 weeks to guide dose adjustments.[10]
• Maintenance Phase: Once the target uric acid level is achieved and the dose is stable, monitoring can be performed less frequently, for example, every 6 months, to ensure continued efficacy and to screen for long-term adverse effects on renal, hepatic, and hematologic function.[10]
• Target Uric Acid Level: For the management of gout, the primary therapeutic goal is to achieve and maintain a serum uric acid concentration below 6 mg/dL.[19] In patients with severe tophaceous gout, a more aggressive target of less than 5 mg/dL may be pursued to promote the resolution of tophi.[10]

Safety Profile and Tolerability

While generally well-tolerated, allopurinol is associated with a spectrum of adverse effects ranging from minor intolerances to rare, life-threatening reactions. A thorough understanding of this safety profile is critical for its appropriate clinical use.

6.1. Common and Minor Adverse Effects

The most frequently reported adverse reactions are generally mild and may resolve with continued use. These include [1]:

• Skin Rash: The most common adverse effect is a mild to moderate pruritic (itchy) or maculopapular (flat or slightly raised lesions) skin rash.[1] However, any rash must be taken seriously as it can be an early sign of a more severe hypersensitivity reaction.
• Gastrointestinal Upset: Nausea and diarrhea are common, particularly at the beginning of therapy. Taking the medication with food can help mitigate these effects.[21]
• Elevated Liver Enzymes: Asymptomatic and transient increases in serum aminotransferases (ALT, AST) are observed in over 1% of patients.[21]
• Gout Flares: Paradoxically, initiating urate-lowering therapy can trigger an acute gout flare. This occurs as the rapid drop in serum uric acid mobilizes urate crystals from tissue deposits, causing an inflammatory response.[21] This is an expected phenomenon and not a reason to discontinue therapy. Prophylactic treatment with colchicine or an NSAID is recommended for the first several months of allopurinol treatment to prevent these flares.[12]
• Other Effects: Less common side effects include headache, drowsiness, somnolence, and a metallic taste in the mouth.[21]

6.2. Severe Cutaneous Adverse Reactions (SCARs) and Hypersensitivity

The most significant safety concern with allopurinol is its association with rare but potentially fatal SCARs. Allopurinol is one of the most common drugs implicated in these reactions, which have a reported mortality rate of 20-25%.[1] These are understood to be delayed, T-cell-mediated immune reactions directed against the drug's metabolite, oxipurinol.[10] The highest risk is within the first few months of initiating therapy.[34]

The clinical manifestations of SCARs include:

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): This syndrome, also known as Allopurinol Hypersensitivity Syndrome (AHS), is a severe, multi-organ reaction. It is characterized by a triad of fever, extensive skin rash (often morbilliform or exfoliative), and internal organ involvement. Common systemic features include marked eosinophilia, atypical lymphocytosis, hepatitis, and acute interstitial nephritis leading to renal failure.[1]
• Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): These represent a spectrum of the same life-threatening mucocutaneous disease. They are characterized by the rapid development of painful, dusky red or purpuric macules that progress to widespread blistering, full-thickness epidermal necrosis, and detachment, resembling a severe burn.[1] Severe mucosal erosion (affecting the mouth, eyes, and genitalia) is a hallmark feature.[36]

Clinical Management: Due to the severity of these reactions, it is imperative to discontinue allopurinol immediately at the first appearance of any skin rash, fever, or other signs of hypersensitivity. Prompt withdrawal is the single most important step in management and can significantly improve prognosis.[21]

6.3. Pharmacogenomics: The Role of HLA-B*58:01

A major advance in the safe use of allopurinol has been the discovery of a strong pharmacogenomic association between SCARs and a specific genetic marker.

• Strong Association: The presence of the Human Leukocyte Antigen (HLA) allele HLA-B*58:01 is a powerful predictor of risk for allopurinol-induced SJS/TEN and DRESS.[3] The odds ratio for developing SCARs in carriers of this allele can be 100-fold or higher compared to non-carriers.[34]
• Population Prevalence: The frequency of the HLA-B*58:01 allele varies significantly among ethnic groups. It is relatively common in certain Asian populations, with a prevalence of approximately 18.5% in Singaporean Chinese (about 1 in 5), and is also found at higher frequencies in Korean, Thai, and individuals of African descent.[34] In contrast, it is much rarer in Caucasian and Japanese populations.[34]
• Screening Recommendations: Based on this strong evidence, the FDA label and major clinical guidelines recommend considering pre-treatment genetic screening for HLA-B*58:01 in patients from genetically at-risk populations.[29] Allopurinol is not recommended and should generally be avoided in patients who test positive for the allele, unless the potential benefits are deemed to clearly outweigh the substantial risks.[35] It is important to note that while a positive test indicates high risk, a negative test does not completely eliminate the risk, as SCARs can still occur in HLA-B*58:01-negative individuals, albeit much less frequently.[34]

The safety profile of allopurinol is best understood as a confluence of interacting risk factors. The HLA-B*58:01 allele acts as a genetic "switch," predisposing an individual's immune system to recognize oxipurinol as a foreign threat and mount a potentially catastrophic T-cell response. Renal impairment serves as a pharmacokinetic "amplifier." By reducing the clearance of oxipurinol, it leads to higher and more sustained levels of the drug, increasing the antigenic load presented to the immune system. This is why renal impairment is itself an independent risk factor for SCARs. Finally, the initial dosing strategy can act as the "trigger." Starting with a high dose of allopurinol causes a rapid spike in oxipurinol levels, which may be more likely to initiate a hypersensitivity reaction compared to a "start low, go slow" approach that allows for gradual adaptation. The patient at the absolute highest risk embodies a "perfect storm" of these factors: an individual of Han Chinese or Thai descent (high HLA-B*58:01 prevalence) with underlying chronic kidney disease who is initiated on a standard 300 mg dose. This integrated understanding elevates clinical practice from simple prescribing to a sophisticated, multi-faceted risk stratification that must simultaneously account for a patient's genetics, organ function, and the chosen dosing philosophy.

6.4. Other Serious Adverse Reactions

Beyond SCARs, allopurinol can cause other significant organ toxicity.

• Hepatotoxicity: Cases of severe liver injury, including reversible hepatotoxicity, granulomatous hepatitis, and rare instances of fatal hepatic necrosis, have been documented.[1] Periodic monitoring of LFTs is recommended.[27]
• Nephrotoxicity: Allopurinol can adversely affect kidney function, causing or worsening renal dysfunction.[21] An acute interstitial nephritis is a common feature of the DRESS/AHS syndrome and can lead to permanent kidney damage.[1]
• Myelosuppression: Although uncommon, bone marrow suppression has been reported with allopurinol use, sometimes occurring months or even years after initiation of therapy.[21] Manifestations can include aplastic anemia, agranulocytosis, and thrombocytopenia, leading to increased risk of infection and bleeding.[12] This risk is dramatically potentiated by the co-administration of azathioprine or 6-mercaptopurine.[39]

6.5. FDA Label Warnings (Clarification)

It is a point of frequent confusion and critical clinical importance to distinguish the regulatory warnings for allopurinol from those of its main alternative, febuxostat.

• Allopurinol: In the United States, the FDA-approved label for allopurinol does not contain a "Black Box Warning." It does, however, feature prominent warnings and precautions detailing the risks of serious skin reactions (SCARs), the association with HLA-B*58:01, hepatotoxicity, nephrotoxicity, and myelosuppression.[21]
• Febuxostat (Uloric): In stark contrast, febuxostat does carry an FDA Black Box Warning. This warning highlights an increased risk of cardiovascular death associated with febuxostat compared to allopurinol, a finding that emerged from a large post-marketing safety trial (the CARES trial).[41] This distinction is a pivotal factor in clinical decision-making and positions allopurinol as the preferred first-line agent for most patients.

Clinically Significant Drug-Drug Interactions

Allopurinol's inhibition of xanthine oxidase and its effects on renal function can lead to several clinically important drug-drug interactions.

7.1. Critical Interaction: Azathioprine and 6-Mercaptopurine (6-MP)

This is the most dangerous and well-documented interaction with allopurinol.

• Mechanism: Azathioprine is a prodrug that is metabolized to 6-mercaptopurine (6-MP). A major inactivation pathway for 6-MP is oxidation by the enzyme xanthine oxidase (XO).[23] Allopurinol, a potent inhibitor of XO, effectively blocks this metabolic clearance route. This blockade causes the active thiopurine metabolites to be shunted down other pathways and accumulate to dangerously high, toxic concentrations.[10]
• Consequence: The resulting toxicity manifests as profound, severe, and potentially fatal myelosuppression (bone marrow suppression), leading to pancytopenia, severe leukopenia, and thrombocytopenia.[23]
• Management: Co-administration of allopurinol and azathioprine or 6-MP should be avoided whenever possible.[39] In situations where the combination is deemed clinically necessary (e.g., in select IBD patients to optimize thiopurine therapy), it requires extreme caution. The dose of azathioprine or 6-MP must be reduced dramatically, typically to 25-33% of the standard dose, and must be accompanied by frequent and intensive monitoring of blood counts to detect early signs of bone marrow suppression.[6]

7.2. Other Important Interactions

Allopurinol can interact with several other classes of drugs, requiring increased monitoring or dose adjustments.

Table 5: Management of Key Drug-Drug Interactions with Allopurinol

Interacting Drug(s)	Mechanism of Interaction	Clinical Consequence	Management Recommendation
Thiazide & Loop Diuretics (e.g., hydrochlorothiazide, furosemide)	May reduce renal clearance of oxipurinol, increasing its concentration.10	Increased risk of allopurinol hypersensitivity reactions and SCARs.10	Use combination with caution. Monitor closely for any signs of rash or hypersensitivity, especially during the initial months of therapy.
Ampicillin / Amoxicillin	Mechanism is not well understood.	A significantly increased incidence of skin rash is reported when these antibiotics are given with allopurinol.33	Advise patients of the increased likelihood of a non-allergic rash. Differentiate from a true hypersensitivity reaction if possible.
Warfarin	Allopurinol may inhibit the hepatic metabolism (CYP2C9) of warfarin.33	Potentiation of anticoagulant effect, leading to an increased risk of bleeding.	Monitor the International Normalized Ratio (INR) more frequently, especially when initiating, discontinuing, or changing the dose of allopurinol. Adjust warfarin dose as needed.
Cyclosporine	Allopurinol may inhibit the metabolism of cyclosporine, leading to increased plasma levels.44	Increased risk of cyclosporine-related toxicity (e.g., nephrotoxicity, neurotoxicity).	Monitor cyclosporine trough concentrations closely when allopurinol is initiated or its dose is adjusted. Adjust cyclosporine dose accordingly.
Pegloticase	Allopurinol lowers serum uric acid, masking the loss of response to pegloticase.21	A rise in uric acid is a key signal of antibody formation and impending risk of a severe infusion reaction to pegloticase. Allopurinol masks this signal.	Concomitant use is contraindicated. Allopurinol must be discontinued before initiating pegloticase therapy.21

Comparative Analysis with Alternative Hyperuricemic Agents

The treatment landscape for hyperuricemia includes several agents, with allopurinol, febuxostat, and probenecid being the most prominent. Choosing among them depends on a careful comparison of their mechanisms, efficacy, safety profiles, and patient-specific factors.

8.1. Allopurinol vs. Febuxostat (Uloric)

Allopurinol and febuxostat are the two available xanthine oxidase inhibitors in many regions.

• Mechanism: Both drugs share the same fundamental mechanism of action: they inhibit the enzyme xanthine oxidase to reduce the production of uric acid.[45]
• Efficacy: Multiple head-to-head clinical trials have demonstrated that both agents are effective in lowering serum uric acid to the target level of <6 mg/dL.[45] Some evidence suggests that febuxostat, particularly at higher doses (80 mg or 120 mg daily), may be more potent than standard-dose allopurinol (300 mg daily) in achieving this target.[46]
• Safety Profile: This is the most critical point of differentiation.
• Allopurinol's primary serious risk is hypersensitivity, specifically SCARs, which is strongly linked to the HLA-B*58:01 allele.[35]
• Febuxostat's primary serious risk is cardiovascular. The FDA has mandated a Black Box Warning for febuxostat due to a demonstrated increased risk of cardiovascular-related death compared to allopurinol in a large post-marketing safety trial (CARES).[41]
• Place in Therapy: Due to the cardiovascular safety concerns with febuxostat, allopurinol is universally recommended as the first-line xanthine oxidase inhibitor for the treatment of chronic gout.[45] Febuxostat is reserved as a second-line agent for patients who have an inadequate response to allopurinol, are intolerant of it, or have a contraindication (such as being positive for the HLA-B*58:01 allele).[42]
• Use in Renal Impairment: Febuxostat is metabolized primarily by the liver and undergoes less renal clearance than oxipurinol. Consequently, it requires fewer dose adjustments in patients with mild-to-moderate chronic kidney disease, which can be a clinical advantage in this population.[46]

8.2. Allopurinol vs. Probenecid

These two drugs represent fundamentally different strategies for lowering uric acid.

• Mechanism: Their mechanisms are distinct and complementary. Allopurinol is a xanthine oxidase inhibitor that decreases the production of uric acid.[1] Probenecid is a uricosuric agent that increases the renal excretion of uric acid.[24] It works by inhibiting uric acid reabsorption in the proximal tubules of the kidney, primarily by blocking transporters such as URAT1 (urate transporter 1) and OATs (organic anion transporters).[49]
• Efficacy and Patient Suitability: Allopurinol is generally the preferred first-line agent for most patients due to its efficacy across a broad range of individuals. Probenecid's effectiveness is highly dependent on renal function; it is less effective or ineffective in patients with a CrCl below 50 mL/min.[48] Furthermore, because probenecid increases the amount of uric acid in the urine, it is contraindicated or should be used with extreme caution in patients who are "overproducers" of uric acid or who have a history of uric acid kidney stones (nephrolithiasis).[24]
• Adverse Effects: The adverse effect profiles differ significantly. Allopurinol's main serious risk is hypersensitivity/SCARs.[1] Probenecid is commonly associated with gastrointestinal upset and rash, and it carries a significant risk of precipitating uric acid kidney stones, especially if hydration is inadequate.[48]
• Combination Therapy: In patients with refractory gout who fail to reach the target serum urate level on monotherapy, a combination approach can be used. Combining a xanthine oxidase inhibitor like allopurinol with a uricosuric agent like probenecid targets both production and excretion, and can be highly effective.[45]

Table 6: Comparative Profile: Allopurinol, Febuxostat, and Probenecid

Feature	Allopurinol	Febuxostat	Probenecid
Mechanism of Action	Decreases uric acid production (Xanthine Oxidase Inhibitor) 1	Decreases uric acid production (Xanthine Oxidase Inhibitor) 45	Increases uric acid excretion (Uricosuric; URAT1/OAT inhibitor) 50
Place in Therapy	First-line for most patients 45	Second-line; for intolerance or failure of allopurinol 42	Alternative or add-on therapy, primarily for "underexcreters" with good renal function 24
Efficacy	Highly effective; dose titration required 19	Potentially more potent than standard-dose allopurinol 47	Moderately effective; efficacy diminishes with renal impairment 48
Key FDA Warnings	Serious skin reactions (SCARs), HLA-B*58:01 association 21	Black Box Warning: Increased risk of cardiovascular death vs. allopurinol 41	Contraindicated in patients with uric acid kidney stones; risk of hemolytic anemia in G6PD deficiency 51
Major Adverse Effects	Hypersensitivity/SCARs, rash, GI upset, hepatotoxicity 1	Liver function abnormalities, nausea, rash, gout flares, CV events 45	GI upset, rash, precipitation of gout flares, formation of uric acid kidney stones 48
Use in Renal Impairment	Requires significant dose reduction and cautious titration 29	Fewer dose adjustments needed in mild-to-moderate CKD 46	Generally ineffective and not recommended when CrCl < 50 mL/min 48
Cost / Generic Availability	Low cost, widely available as generic 48	Higher cost, available as generic 48	Low cost, available as generic 48

Expert Synthesis and Recommendations for Clinical Practice

Allopurinol has served as the cornerstone of urate-lowering therapy for decades, a status earned through its established efficacy, convenient once-daily administration, and low cost. A sophisticated understanding of its clinical use, however, moves beyond these surface-level benefits to a deep appreciation of its pharmacology. The drug's entire clinical profile—both its strengths and its weaknesses—is fundamentally dictated by the pharmacokinetic behavior of its active metabolite, oxipurinol. The sustained therapeutic effect is a direct result of oxipurinol's long half-life, while the drug's most significant safety risks, namely accumulation in renal disease and the potential for severe hypersensitivity, are also direct consequences of this metabolite's properties and its primary route of elimination. Likewise, its most critical drug interaction with thiopurines is an unavoidable outcome of its core mechanism of action. Therefore, the responsible use of allopurinol is not merely a matter of prescribing but of proactive risk management.

Based on a comprehensive analysis of the available evidence, the following recommendations are provided for clinicians:

1. Patient Selection and First-Line Use: Allopurinol is the appropriate and recommended first-line urate-lowering agent for the vast majority of patients with chronic gout or other conditions requiring long-term management of hyperuricemia.
2. Paramount Importance of Risk Stratification: Prior to prescribing, a multi-factorial risk assessment is mandatory. This must include an evaluation of renal function (via eGFR) and a consideration of the patient's ethnicity. For patients of ancestries with a high prevalence of the HLA-B*58:01 allele (e.g., Han Chinese, Korean, Thai, African), pre-treatment genotyping should be strongly considered, especially if concomitant risk factors like chronic kidney disease are present.
3. Adherence to the "Start Low, Go Slow" Dosing Principle: Therapy should always be initiated at a low dose, typically 100 mg per day in patients with normal renal function, and even lower (e.g., 50 mg per day) in those with significant CKD. The dose should be titrated upwards gradually, every 2 to 5 weeks, guided by serial measurements of serum uric acid, rather than aiming for a standard fixed dose. This methodical approach minimizes the risk of both initial gout flares and the triggering of severe hypersensitivity reactions.
4. Comprehensive Patient Education: Patient counseling is a critical component of safe therapy. Patients must be educated on the importance of strict adherence, the need for adequate hydration to prevent nephrolithiasis, and, most importantly, the absolute necessity of immediately discontinuing the medication and seeking prompt medical evaluation at the first sign of any skin rash, fever, or oral sores.
5. Vigilance for Drug Interactions: A thorough medication reconciliation must be performed before initiation and during treatment. The co-prescription of allopurinol with azathioprine or 6-mercaptopurine is extremely hazardous and requires expert management with drastic dose reductions and intensive monitoring. Clinicians should also be mindful of interactions with diuretics and warfarin.
6. Informed Selection of Alternatives: The choice of an alternative agent should be evidence-based. Febuxostat should be reserved for patients who have a documented intolerance, contraindication (e.g., HLA-B*58:01 positivity), or an inadequate therapeutic response to an appropriately titrated dose of allopurinol. This decision must be made following a shared discussion with the patient regarding the established cardiovascular risks associated with febuxostat. Probenecid may be considered as an alternative or add-on therapy, but only in patients with well-preserved renal function who are confirmed "underexcreters" of uric acid and have no personal or family history of kidney stones.

Commercial Information

Allopurinol is marketed globally under various brand names and is widely available as a generic medication from numerous manufacturers.

Brand Names

Prominent brand names for allopurinol include:

• Zyloprim [5]
• Lopurin [5]
• Uricto [18]
• Aloprim (This brand name is typically associated with the intravenous formulation) [22]

Manufacturers

The original developer of allopurinol was Burroughs-Wellcome, with its introduction in 1966.[4] Today, the market is dominated by generic manufacturers. In the United States, Casper Pharma LLC markets the brand Zyloprim.[54] Dr. Reddy's Laboratories markets the brand Lopurin.[54]

A non-exhaustive list of FDA-approved manufacturers for generic allopurinol tablets includes [54]:

• Accord Healthcare
• Aurobindo Pharma Ltd
• Chartwell
• Endo Operations
• Harman Finochem
• Hetero Labs Ltd
• Indoco
• Mylan
• Northstar Healthcare
• Sun Pharmaceutical Industries
• Teva Pharmaceuticals
• Unichem
• Watson Laboratories
• Zydus Pharmaceuticals

Other global manufacturers and suppliers include AdvaCare Pharma, Camber Pharmaceuticals, and Bristol Laboratories.[53] Additionally, companies like Spectrum Chemical supply USP-grade allopurinol for pharmaceutical manufacturing and research purposes.[58]

Works cited

1. Allopurinol - Wikipedia, accessed July 22, 2025, https://en.wikipedia.org/wiki/Allopurinol
2. Allopurinol (CAS Number: 315-30-0) | Cayman Chemical, accessed July 22, 2025, https://www.caymanchem.com/product/10012597/allopurinol
3. allopurinol (CHEBI:40279) - EMBL-EBI, accessed July 22, 2025, https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:40279
4. Allopurinol CAS#: 315-30-0 - ChemicalBook, accessed July 22, 2025, https://m.chemicalbook.com/ProductChemicalPropertiesCB1181254_EN.htm
5. Allopurinol | CAS 315-30-0 | SCBT - Santa Cruz Biotechnology, accessed July 22, 2025, https://www.scbt.com/p/allopurinol-315-30-0
6. Clinical-Pharmacokinetics-of-Allopurinol.pdf - ResearchGate, accessed July 22, 2025, https://www.researchgate.net/profile/George-Murrell/publication/19626176_Clinical_Pharmacokinetics_of_Allopurinol/links/0deec536c276a9d3b7000000/Clinical-Pharmacokinetics-of-Allopurinol.pdf
7. Allopurinol (UK PID) - InChem.org, accessed July 22, 2025, https://www.inchem.org/documents/ukpids/ukpids/ukpid02.htm
8. Allopurinol for pain relief: more than just crystal clearance? - PMC, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2697767/
9. (PDF) Clinical Pharmacokinetics and Pharmacodynamics of Allopurinol and Oxypurinol, accessed July 22, 2025, https://www.researchgate.net/publication/233578032_Clinical_Pharmacokinetics_and_Pharmacodynamics_of_Allopurinol_and_Oxypurinol
10. Allopurinol - StatPearls - NCBI Bookshelf, accessed July 22, 2025, https://www.ncbi.nlm.nih.gov/books/NBK499942/
11. www.ncbi.nlm.nih.gov, accessed July 22, 2025, https://www.ncbi.nlm.nih.gov/books/NBK499942/#:~:text=Mechanism%20of%20Action,-Allopurinol%20undergoes%20metabolism&text=Allopurinol%20and%20oxypurinol%20both%20inhibit,to%20xanthine%20to%20uric%20acid.
12. Allopurinol (oral route) - Side effects & dosage - Mayo Clinic, accessed July 22, 2025, https://www.mayoclinic.org/drugs-supplements/allopurinol-oral-route/description/drg-20075476
13. Allopurinol: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 22, 2025, https://go.drugbank.com/drugs/DB00437
14. Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2014375/
15. Pharmacology Of Allopurinol ; Pharmacokinetics, Mechanism of Action, Uses, Effects, accessed July 22, 2025, https://www.youtube.com/watch?v=7ELeAWebQpE
16. www.mayoclinic.org, accessed July 22, 2025, https://www.mayoclinic.org/drugs-supplements/allopurinol-oral-route/description/drg-20075476#:~:text=Allopurinol%20is%20used%20to%20prevent,(joint%20pain%20and%20inflammation).
17. Allopurinol oral tablet: Side effects, uses, dosage, and more - Medical News Today, accessed July 22, 2025, https://www.medicalnewstoday.com/articles/drugs-allopurinol-oral-tablet
18. About allopurinol - NHS, accessed July 22, 2025, https://www.nhs.uk/medicines/allopurinol/about-allopurinol/
19. Allopurinol Dosage Guide: Standard Doses for Gout, Kidney Stones - GoodRx, accessed July 22, 2025, https://www.goodrx.com/allopurinol/dosage
20. Allopurinol Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed July 22, 2025, https://www.drugs.com/dosage/allopurinol.html
21. allopurinol tablets - accessdata.fda.gov, accessed July 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/018832s056s058s061,018877s063s065s068lbl.pdf
22. Allopurinol vs Probenecid Comparison - Drugs.com, accessed July 22, 2025, https://www.drugs.com/compare/allopurinol-vs-probenecid
23. The Mechanism and Drug Interaction - Allopurinol and Azathioprine and Risk of Bone Marrow Suppression - EBM Consult, accessed July 22, 2025, https://www.ebmconsult.com/articles/allopurinol-azathioprine-interaction-mechanism-wbc
24. Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients With Gout - JACC, accessed July 22, 2025, https://www.jacc.org/doi/10.1016/j.jacc.2017.12.052
25. Allopurinol in dermatology - PubMed, accessed July 22, 2025, https://pubmed.ncbi.nlm.nih.gov/20509717/
26. Allopurinol Completed Phase Trials for Osteodystrophy / Chronic Kidney Disease (CKD) / Uric Acid Concentration, Serum, Quantitative Trait Locus 7 Treatment - DrugBank, accessed July 22, 2025, https://go.drugbank.com/drugs/DB00437/clinical_trials?conditions=DBCOND0048800%2CDBCOND0016488%2CDBCOND0140850&phase=&purpose=treatment&status=completed
27. How and when to take allopurinol - NHS, accessed July 22, 2025, https://www.nhs.uk/medicines/allopurinol/how-and-when-to-take-allopurinol/
28. Allopurinol | Side Effects, Dosage, Uses & More - Healthline, accessed July 22, 2025, https://www.healthline.com/health/drugs/allopurinol-oral-tablet
29. What is the appropriate dosing for Allopurinol? - Dr.Oracle AI, accessed July 22, 2025, https://www.droracle.ai/articles/12274/allopurinol-dosing
30. Allopurinol - GlobalRPH, accessed July 22, 2025, https://globalrph.com/renal/allopurinol/
31. (PDF) Clinical Pharmacokinetics of Allopurinol - ResearchGate, accessed July 22, 2025, https://www.researchgate.net/publication/19626176_Clinical_Pharmacokinetics_of_Allopurinol
32. pdf.hres.ca, accessed July 22, 2025, https://pdf.hres.ca/dpd_pm/00037852.PDF
33. Allopurinol - Arthritis and Rheumatology Clinics of Kansas, accessed July 22, 2025, https://arck.org/patient-education/medications/allopurinol/
34. ALLOPURINOL-INDUCED SERIOUS CUTANEOUS ADVERSE ..., accessed July 22, 2025, https://www.hsa.gov.sg/docs/default-source/announcements/adverse-drug-reaction-news-bulletin/adr_news_sep2016_vol18_no2.pdf
35. Annotation of FDA Label for allopurinol and HLA-B - PharmGKB, accessed July 22, 2025, https://www.pharmgkb.org/labelAnnotation/PA166234701
36. Allopurinol-induced severe cutaneous adverse reactions: A report of three cases with the HLA-B*58:01 allele who underwent lymphocyte activation test - PMC, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7042004/
37. Allopurinol (intravenous route) - Side effects & uses - Mayo Clinic, accessed July 22, 2025, https://www.mayoclinic.org/drugs-supplements/allopurinol-intravenous-route/description/drg-20067956
38. www.mayoclinic.org, accessed July 22, 2025, https://www.mayoclinic.org/drugs-supplements/allopurinol-oral-route/description/drg-20075476#:~:text=This%20medicine%20may%20cause%20serious,or%20lower%20legs%2C%20or%20weakness.
39. Azathioprine-Allopurinol Interaction: Danger! - Medsafe, accessed July 22, 2025, https://www.medsafe.govt.nz/profs/puarticles/azathioprine.htm
40. Interaction of allopurinol with 6-mercaptopurine and azathioprine - University of Arizona, accessed July 22, 2025, https://experts.arizona.edu/en/publications/interaction-of-allopurinol-with-6-mercaptopurine-and-azathioprine
41. FDA Now Requires Black Box Warning Label For Uloric - Goldwater Law Firm, accessed July 22, 2025, https://goldwaterlawfirm.com/insights/fda-requires-black-box-warning-for-uloric/
42. FDA Adds Boxed Warning to Gout Drug - NEJM Journal Watch, accessed July 22, 2025, https://www.jwatch.org/fw115095/2019/02/25/fda-adds-boxed-warning-gout-drug
43. FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat), accessed July 22, 2025, https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-death-gout-medicine-uloric-febuxostat
44. Allopurinol (Zyloprim): Uses & Side Effects - Cleveland Clinic, accessed July 22, 2025, https://my.clevelandclinic.org/health/drugs/18127-allopurinol-tablets
45. Febuxostat or Allopurinol for Gout Treatment: Which is Better? - GoodRx, accessed July 22, 2025, https://www.goodrx.com/conditions/gout/febuxostat-vs-allopurinol
46. Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis, accessed July 22, 2025, https://www.ser.es/wp-content/uploads/2015/11/Allopurinol.pdf
47. Gout Drugs Compared Side-by-Side - HCPLive, accessed July 22, 2025, https://www.hcplive.com/view/gout-drugs-compared-side-side
48. Uloric vs. Benemid for Gout: Important Differences and Potential Risks., accessed July 22, 2025, https://www.goodrx.com/compare/uloric-vs-benemid
49. Probenecid, a gout remedy, inhibits pannexin 1 channels - PMC, accessed July 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2544448/
50. What is the mechanism of Probenecid? - Patsnap Synapse, accessed July 22, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-probenecid
51. Probenecid: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 22, 2025, https://go.drugbank.com/drugs/DB01032
52. Probenecid | Drug Lookup | Pediatric Care Online - AAP Publications, accessed July 22, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5771/Probenecid
53. Allopurinol - Camber Pharmaceuticals, accessed July 22, 2025, https://www.camberpharma.com/products/allopurinol/
54. Generic Zyloprim Availability - Drugs.com, accessed July 22, 2025, https://www.drugs.com/availability/generic-zyloprim.html
55. Allopurinol Tablets, USP - Teva Pharmaceuticals USA, accessed July 22, 2025, https://www.tevausa.com/our-products/tevagenerics/teva-generics-catalog/vision-product-page/allopurinoltabletsusp
56. Allopurinol Tablets – Manufacturer - AdvaCare Pharma, accessed July 22, 2025, https://www.advacarepharma.com/en/pharmaceuticals/allopurinol-tablets
57. Allopurinol - Bristol Laboratories |, accessed July 22, 2025, https://bristol-labs.co.uk/products/allopurinol/
58. CAS Number 315-30-0 | Allopurinol - Spectrum Chemical, accessed July 22, 2025, https://www.spectrumchemical.com/cas/315-30-0
59. Allopurinol-USP | CAS 315-30-0 | A1577 | Spectrum Chemical, accessed July 22, 2025, https://www.spectrumchemical.com/allopurinol-usp-a1577