Allopurinol

Uses and Indications

Allopurinol Tablets are indicated for the management of adult patients exhibiting signs and symptoms of primary or secondary gout, including acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy. Additionally, Allopurinol is indicated for both adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Furthermore, it is indicated for adult patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in males and 750 mg/day in females, despite lifestyle modifications.

Limitations of use include the recommendation against the treatment of asymptomatic hyperuricemia with Allopurinol Tablets.

Dosage and Administration

For the management of gout, patients with normal kidney function should initiate treatment with an oral dosage of 100 mg daily. The dosage may be increased by 100 mg increments on a weekly basis until the target serum uric acid level of 6 mg/dL or less is achieved, with a maximum allowable dosage of 800 mg daily. For patients with impaired kidney function, the initial dosage is 50 mg orally daily, with titration recommendations to be followed as outlined for renal impairment until the desired serum uric acid level is reached.

In cases of hyperuricemia associated with cancer therapy, adult patients may be prescribed an oral dosage ranging from 300 mg to 800 mg daily. For pediatric patients, the recommended dosage is 100 mg/m² administered orally every 8 to 12 hours, with a maximum daily limit of 800 mg or 10 mg/kg/day.

For the prevention of recurrent calcium oxalate calculi, the recommended initial dosage for patients with normal kidney function is between 200 mg to 300 mg orally daily.

For patients with renal impairment, healthcare professionals should refer to the full prescribing information (FPI) for specific dosage modifications and recommendations tailored to this patient population.

Contraindications

Use of allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or to any of the ingredients of allopurinol tablets. This contraindication is essential to prevent severe allergic reactions that may occur in susceptible individuals.

Warnings and Precautions

Allopurinol is associated with several significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Skin Rash and Hypersensitivity Allopurinol has been linked to serious and potentially fatal dermatological reactions. It is imperative that allopurinol tablets be discontinued immediately upon the first appearance of a skin rash or any other signs indicative of a hypersensitivity reaction.

Gout Flares Patients may experience gout flares during the initiation of allopurinol treatment. To mitigate this risk, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended.

Nephrotoxicity Allopurinol may adversely affect kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol tablets to prevent further renal compromise.

Hepatotoxicity Reversible hepatotoxicity has been reported in patients taking allopurinol. Should any signs or symptoms of hepatotoxicity arise, it is essential to evaluate liver function promptly.

Myelosuppression There have been reports of bone marrow suppression associated with allopurinol use. Monitoring for signs of myelosuppression is advised.

Potential Effect on Driving and Use of Machinery Patients taking allopurinol may experience drowsiness, somnolence, or dizziness. Caution should be exercised when driving or operating machinery until the individual’s response to the medication is known.

Laboratory Tests In the event that signs or symptoms of hepatotoxicity develop, it is crucial to evaluate liver function to ensure patient safety and appropriate management.

Healthcare professionals are encouraged to remain vigilant regarding these warnings and to monitor patients accordingly to mitigate risks associated with allopurinol therapy.

Side Effects

Patients receiving allopurinol may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most commonly reported adverse reactions include nausea, diarrhea, and an increase in liver function tests, with an incidence greater than 1%.

Serious adverse reactions associated with allopurinol include skin rash and hypersensitivity, which can lead to serious and sometimes fatal dermatological reactions. It is crucial to discontinue allopurinol tablets at the first appearance of a skin rash or any other signs of hypersensitivity. Gout flares may also occur during the initiation of treatment; therefore, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended to mitigate this risk.

Nephrotoxicity is another serious concern, as allopurinol may affect kidney function. Patients with decreased kidney function require careful dose adjustments to avoid potential complications. Hepatotoxicity has been reported, with cases of reversible liver damage occurring; thus, it is important to evaluate liver function if any signs or symptoms of hepatotoxicity develop. Additionally, myelosuppression has been noted in some patients, indicating a risk of bone marrow suppression.

Patients should also be aware of the potential effects of allopurinol on driving and the use of machinery, as drowsiness, somnolence, and dizziness have been reported.

It is important to note that allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or any of its ingredients.

Drug Interactions

The concomitant use of certain medications may lead to increased risks of serious skin reactions. Specifically, the following drugs have been identified: bendamustine, thiazide diuretics, ampicillin, and amoxicillin. It is advisable to monitor patients closely for any signs of skin reactions when these agents are used concurrently.

Capecitabine should be avoided in combination with this medication due to potential adverse effects.

For patients receiving mercaptopurine or azathioprine, it is recommended to reduce the dosage of these agents as outlined in their respective prescribing information to mitigate the risk of toxicity.

In the case of pegloticase, it is essential to discontinue and avoid initiating treatment with allopurinol tablets, as this combination may lead to adverse clinical outcomes.

For a comprehensive list of significant drug interactions, refer to the full prescribing information (FPI).

Packaging & NDC

The table below lists all NDC Code configurations of Allopurinol, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of allopurinol for the management of pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing cancer therapy that leads to elevated serum and urinary uric acid levels have been established in approximately 200 pediatric patients. The efficacy and safety profile in this population is comparable to that observed in adults.

However, the safety and effectiveness of allopurinol tablets have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Additionally, allopurinol tablets have not been proven effective for the management of recurrent calcium oxalate calculi in this population. Furthermore, the use of allopurinol has not been established in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may experience significant changes in renal function, which can profoundly affect the elimination of allopurinol tablets. Due to the primary renal excretion of this medication, it is crucial to perform periodic assessments of renal function in geriatric patients, especially those with decreased renal function or concurrent illnesses that may impact renal health.

For elderly patients with renal impairment, it is recommended to initiate treatment with a lower dose of allopurinol tablets. The dosage should be increased gradually, in increments of 50 mg per day, every 2 to 4 weeks. This cautious approach helps to minimize the risk of serious adverse reactions associated with the drug. Close monitoring of kidney function is essential, particularly in gout patients with chronic kidney disease, during the initiation of allopurinol therapy. If there are persistent abnormalities in kidney function, it may be necessary to decrease the dosage or discontinue the medication altogether.

Elderly patients with pre-existing kidney disease, including chronic kidney disease or a history of kidney stones, are at an increased risk for worsening kidney function or acute kidney injury due to the formation of xanthine calculi while receiving allopurinol. Therefore, frequent monitoring of kidney function is advised during the early stages of treatment.

Additionally, allopurinol tablets should be discontinued in patients who exhibit elevated liver enzymes. Geriatric patients should also be advised to avoid operating automobiles or engaging in activities that may be hazardous due to decreased alertness when starting allopurinol or increasing the dosage, until they are aware of how the medication affects them.

Pregnancy

Based on findings in animal studies, allopurinol tablets may cause fetal harm when administered to pregnant women. Adverse developmental outcomes have been observed in exposed animals, and both allopurinol and its metabolite oxypurinol have been shown to cross the placenta following maternal administration.

Limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in the frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in the literature, two infants with major congenital malformations have been reported following maternal exposure to allopurinol. It is important to advise pregnant women of the potential risks to the fetus.

All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Experience with allopurinol during human pregnancy has been limited, as women of reproductive age rarely require treatment with this medication. A case report from 2011 described a full-term pregnancy in a 35-year-old woman with recurrent kidney stones who took allopurinol throughout her pregnancy; the child was born with multiple complex birth defects and died at 8 days of life.

A subsequent report in 2013 provided data on 31 prospectively ascertained pregnancies involving mothers exposed to allopurinol for varying durations during the first trimester. The overall rate of major fetal malformations and spontaneous abortions was reported to be within the normal expected range; however, one child had severe malformations similar to those described in the earlier case report.

Animal studies have shown no evidence of fetotoxicity or teratogenicity in rats or rabbits treated with oral allopurinol during the period of organogenesis at doses up to 200 mg/kg/day and 100 mg/kg/day, respectively, which is approximately 2.4 times the human dose on a mg/m² basis. However, a published report in pregnant mice indicated that single intraperitoneal doses of 50 mg/kg or 100 mg/kg (approximately 0.3 or 0.6 times the human dose on a mg/m² basis) administered on gestation days 10 or 13 resulted in significant increases in fetal deaths and teratogenic effects, including cleft palate, harelip, and digital defects. It remains uncertain whether these findings represent a direct fetal effect or an effect secondary to maternal toxicity.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion of this medication in breast milk or its effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment may experience alterations in kidney function due to allopurinol. It is essential to consider that individuals with decreased kidney function require lower doses of allopurinol tablets to mitigate the risk of adverse effects and ensure therapeutic efficacy. Monitoring of renal function is recommended for these patients to guide appropriate dosing adjustments.

Hepatic Impairment

Patients with hepatic impairment may experience reversible hepatotoxicity. In the event that signs and symptoms of hepatotoxicity develop, it is essential to evaluate liver function promptly. Monitoring of liver function tests should be conducted to assess the extent of any hepatic compromise. Based on the evaluation, appropriate clinical decisions should be made regarding the continuation or modification of therapy in these patients.

Overdosage

In the event of an overdosage of allopurinol tablets, it is important to note that there is no specific antidote available. Healthcare professionals should be aware that both allopurinol and its active metabolite, oxipurinol, are dialyzable. However, the efficacy of hemodialysis or peritoneal dialysis in the management of an allopurinol overdose remains uncertain.

Given the lack of a specific antidote, the primary focus should be on supportive care and symptomatic management. Healthcare providers are advised to monitor the patient closely for any adverse effects and to provide appropriate interventions as necessary. It is essential to assess renal function and consider the potential need for dialysis, keeping in mind the limited information regarding its effectiveness in this context.

In summary, while there are no definitive treatment protocols for allopurinol overdosage, supportive care and careful monitoring are critical components of management.

Nonclinical Toxicology

No evidence of tumorigenicity was observed in male or female mice or rats that received oral allopurinol for the majority of their life spans (greater than 88 weeks) at doses up to 20 mg/kg/day, which corresponds to 0.1 and 0.2 times the maximum recommended human dose (MRHD) on a mg/m² basis in mice and rats, respectively.

Allopurinol tested negative in several genotoxicity assays, including the in vitro Ames assay, the in vitro mouse lymphoma assay, and the in vivo rat bone marrow micronucleus assay. Additionally, allopurinol administered intravenously to rats at a dose of 50 mg/kg was not incorporated into rapidly replicating intestinal DNA. No evidence of clastogenicity was observed in lymphocytes taken from patients treated with allopurinol for a mean duration of 40 months, nor in an in vitro assay with human lymphocytes.

Allopurinol oral doses of 20 mg/kg/day had no effect on male or female fertility in rats or rabbits, which corresponds to approximately 0.2 or 0.5 times the MRHD on a mg/m² basis, respectively.

Postmarketing Experience

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in patients taking allopurinol. These reactions occur in approximately 5 in 10,000 (0.05%) patients. Other serious hypersensitivity reactions include exfoliative, urticarial, and purpuric lesions, generalized vasculitis, and irreversible hepatotoxicity.

The HLA-B58:01 allele has been identified as a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients carrying the HLA-B58:01 allele are at a higher risk for allopurinol hypersensitivity syndrome (AHS); however, hypersensitivity reactions have also been reported in patients who do not carry this allele. Additionally, hypersensitivity reactions may be increased in patients with decreased kidney function who are concurrently receiving thiazide diuretics and allopurinol.

Gout flares have been observed during the initiation of treatment with allopurinol, even when normal or subnormal serum uric acid levels have been achieved, likely due to the mobilization of urates from tissue deposits. These flares typically become shorter and less severe after several months of therapy.

Treatment with allopurinol may lead to acute kidney injury, which can occur due to the formation of xanthine calculi or the precipitation of urates in patients receiving concomitant uricosuric agents. Patients with pre-existing kidney disease, including chronic kidney disease or a history of kidney stones, may be at increased risk for worsening kidney function or acute kidney injury due to xanthine calculi while on allopurinol.

Myelosuppression, manifested by anemia, leukopenia, or thrombocytopenia, has been reported in patients receiving allopurinol, with cytopenias occurring as early as 6 weeks to 6 years after therapy initiation. The most frequent adverse reaction associated with allopurinol is skin rash. Other adverse reactions identified in literature, unpublished clinical trials, or postmarketing reports include gastrointestinal issues (such as diarrhea and nausea), metabolic and nutritional issues (including acute attacks of gout), and various less common reactions across multiple systems.

Patient Counseling

Patients should be advised to take allopurinol tablets after meals to minimize the risk of gastric irritation. In the event that a single dose is forgotten, there is no need to double the dose at the next scheduled time.

It is important to inform patients that allopurinol tablets may increase the risk of serious and potentially fatal dermatologic reactions. Patients should be instructed to discontinue the medication and seek medical attention immediately at the first sign of any skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, swelling of the lips or mouth, or any other signs and symptoms indicative of hypersensitivity reactions.

Patients should also be made aware that gout flares may occur during the initiation of treatment with allopurinol tablets, even if their serum uric acid levels are normal. The concurrent use of additional medications, such as colchicine or other anti-inflammatory agents, can help prevent these gout flares. Patients should be encouraged to continue treatment with both allopurinol tablets and the prophylactic therapy as prescribed, even if gout flares occur. It is essential to reassure patients that achieving control of the flares may take several months, but typically, the flares will become shorter and less severe with continued therapy.

Storage and Handling

The product is supplied in a tight container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F) in a dry place to maintain its integrity and efficacy. Proper storage conditions are essential to ensure the product remains within the specified parameters.

Additional Clinical Information

Prior to initiating treatment with allopurinol tablets in patients with gout, clinicians should assess baseline laboratory tests, including serum uric acid levels, complete blood count, chemistry panel, liver function tests (serum alanine aminotransferase ALT, aspartate aminotransferase AST, alkaline phosphatase, and total bilirubin), and kidney function tests (serum creatinine and estimated glomerular filtration rate eGFR).

Patients should be counseled to take allopurinol tablets after meals to reduce gastric irritation. If a dose is missed, there is no need to double the next dose. It is important to inform patients about the potential risk of serious dermatologic reactions and to seek immediate medical attention if they experience any signs of hypersensitivity, such as skin rash, blisters, fever, or swelling. Additionally, patients may experience gout flares during the initiation of treatment, even with normal serum uric acid levels. The concurrent use of prophylactic medications, such as colchicine or other anti-inflammatory agents, is recommended to manage these flares. Patients should be reassured that while it may take months to achieve control, flares typically become shorter and less severe with continued therapy.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Allopurinol as submitted by Indoco Remedies Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)