Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor. It is chemically identified as 1, 5-dihydro-4H-pyrazolo 3, 4-d pyrimidin-4-one, with a molecular weight of 136.11 g/mol. Allopurinol exhibits a solubility in water of 80.0 mg/dL at 37°C, with increased solubility in alkaline solutions. The formulation is available in white to off-white scored tablets, containing either 100 mg or 300 mg of allopurinol, USP. Inactive ingredients in the tablets include croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone.

Uses and Indications

Allopurinol is 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, it 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.

This drug is also 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 implementation of lifestyle changes.

Allopurinol tablets are not recommended for the treatment of asymptomatic hyperuricemia.

Dosage and Administration

For the management of gout, patients with normal kidney function should initiate treatment with 100 mg orally once daily. The dosage may be increased by 100 mg weekly increments until a 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 once daily, with titration recommendations to be followed as outlined for renal impairment until the target serum uric acid level is reached.

In the case of hyperuricemia associated with cancer therapy, adult patients may be prescribed a dosage range of 300 mg to 800 mg orally daily. For pediatric patients, the recommended dosage is 100 mg/m² orally every 8 to 12 hours, not exceeding a maximum of 800 mg per day (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.

Contraindications

Use of allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or to any of the ingredients of allopurinol tablets. Due to the potential for severe allergic reactions, it is essential to avoid administration in these individuals.

Warnings and Precautions

Allopurinol has been associated with serious and potentially fatal dermatological reactions, including skin rash and hypersensitivity. It is imperative that allopurinol be discontinued immediately at the first appearance of a skin rash or any other signs indicative of a hypersensitivity reaction.

During the initiation of allopurinol treatment, gout flares may occur. To mitigate this risk, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended.

Nephrotoxicity is a concern with allopurinol, as it may adversely affect kidney function. Patients with impaired renal function should receive lower doses of allopurinol to prevent further complications.

Hepatotoxicity has been reported, with cases of reversible liver damage occurring in some patients. If any signs or symptoms of hepatotoxicity develop, it is essential to evaluate liver function promptly.

Myelosuppression has also been documented in patients receiving allopurinol. Regular monitoring of blood counts may be warranted to detect any potential bone marrow suppression.

Additionally, patients taking allopurinol may experience drowsiness, somnolence, and dizziness. Caution is advised when driving or operating machinery until the individual’s response to the medication is known.

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%. These reactions are generally mild but should be monitored.

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 at the first appearance of a skin rash or any other signs of hypersensitivity.

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

Nephrotoxicity is another serious concern, as allopurinol may affect kidney function. Patients with decreased kidney function require careful dose adjustments to avoid further complications. Additionally, cases of reversible hepatotoxicity have been reported; therefore, if signs and symptoms of hepatotoxicity develop, liver function should be evaluated promptly.

Myelosuppression, or bone marrow suppression, has also been reported in patients taking allopurinol.

Furthermore, patients may experience drowsiness, somnolence, and dizziness, which could potentially affect their ability to drive or operate machinery safely.

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

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Additionally, its use has not been validated for the management of recurrent calcium oxalate calculi in this demographic. Furthermore, allopurinol's safety and effectiveness have not been established in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients may require special consideration when being treated with allopurinol, particularly those aged 65 and older or those with renal impairment. In patients with chronic kidney disease, it is essential to monitor kidney function closely upon initiating treatment. The initial dosage of allopurinol for these patients should be 50 mg orally daily, with subsequent dose adjustments made cautiously until the target serum uric acid level is achieved.

For adult patients with gout and impaired kidney function, the recommended initial dosages are as follows: for those with an estimated glomerular filtration rate (eGFR) greater than 60 mL/minute, no dosage modification is necessary. For patients with an eGFR between 30 to 60 mL/minute, the initial dose should be 50 mg daily. In cases where the eGFR is between 15 to 30 mL/minute, the dosage should be adjusted to 50 mg every other day. For patients with an eGFR of 5 to 15 mL/minute, the recommended dose is 50 mg twice weekly, and for those with an eGFR less than 5 mL/minute, the dosage should be reduced to 50 mg once weekly.

It is important to note that allopurinol may adversely affect kidney function; therefore, lower doses are warranted for patients with decreased renal function. Additionally, the use of allopurinol is not recommended in patients who are HLA-B*58:01 positive unless the potential benefits clearly outweigh the risks, as these patients are at an increased risk for allopurinol hypersensitivity syndrome.

Elderly patients should be advised to increase their fluid intake during therapy to help prevent the formation of kidney stones and to be vigilant for any signs of nephrotoxicity. Furthermore, drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol, and elderly patients may exhibit heightened sensitivity to these effects. Therefore, careful monitoring and appropriate dose adjustments are crucial in this population to ensure safety and efficacy.

Pregnancy

Based on findings in animal studies, allopurinol 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. Healthcare professionals should advise pregnant women of the potential risks to the fetus.

It is important to note that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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, partly because women of reproductive age rarely require treatment with this medication. A case report published in 2011 described the outcome of a full-term pregnancy in a 35-year-old woman with a history of 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 lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with allopurinol. It is essential to consider that individuals with reduced kidney function require lower doses of allopurinol to mitigate the risk of adverse effects. Careful monitoring of renal function is recommended in this population to ensure appropriate dosing and to prevent potential complications.

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 dosage adjustments or treatment modifications may be necessary to ensure patient safety and therapeutic efficacy.

Overdosage

In the event of an allopurinol overdosage, it is important to note that there is no specific antidote available. Management of such cases should focus on supportive care and symptomatic treatment.

Both allopurinol and its active metabolite, oxipurinol, are known to be dialyzable. However, the efficacy of hemodialysis or peritoneal dialysis in the context of allopurinol overdose remains uncertain. Healthcare professionals should consider these factors when determining the appropriate course of action for patients presenting with an overdose.

Monitoring of the patient’s clinical status is essential, and supportive measures should be implemented as necessary. It is advisable to consult with a poison control center or a medical toxicologist for guidance on the management of specific symptoms and complications that may arise from an overdose of allopurinol.

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

Postmarketing experience has identified several important safety considerations associated with allopurinol. Serious and sometimes fatal dermatologic reactions have been reported, necessitating immediate discontinuation of the medication and medical attention at the first sign of a skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, swelling of the lips or mouth, or other hypersensitivity symptoms.

Gout flares may occur during the initiation of allopurinol treatment, even in patients with normal serum uric acid levels. Additionally, allopurinol may impact kidney function; therefore, it is recommended that patients increase fluid intake during therapy to help prevent kidney stones.

There is a noted risk of hepatotoxicity, and patients are advised to report any signs of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia. Myelosuppression has also been observed, with patients encouraged to report symptoms such as infection, fever, bleeding, shortness of breath, or significant fatigue.

Drowsiness, somnolence, and dizziness have been reported among patients taking allopurinol. The central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. Furthermore, there are risks of adverse effects when allopurinol is used in conjunction with certain medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics.

Patient Counseling

Healthcare providers should advise patients to take allopurinol after meals to minimize gastric irritation. In the event that a single dose of allopurinol is occasionally forgotten, patients should be informed that there is no need to double the dose at the next scheduled time.

Patients must be informed that allopurinol may increase the risk of serious and potentially fatal dermatologic reactions. They should be instructed to discontinue allopurinol and seek medical attention immediately at the first sign of a 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 of hypersensitivity reactions.

It is important to inform patients that gout flares may occur during the initiation of treatment with allopurinol, even when their serum uric acid levels are normal. Healthcare providers should recommend the concurrent use of additional medications such as colchicine or other anti-inflammatory agents to prevent gout flares. Patients should be advised to continue treatment with both allopurinol and the prophylactic therapy as prescribed, even if gout flares occur. Reassurance should be provided that it may take months to achieve control of the flares, but they typically become shorter and less severe after several months of therapy.

Patients should be informed that allopurinol may affect kidney function. They should be advised to increase their fluid intake during therapy, aiming for at least 2 liters of liquids per day, to stay well hydrated and help prevent kidney stones.

Healthcare providers should inform patients of the risk of hepatotoxicity associated with allopurinol. Patients should be instructed to report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

Patients must also be made aware of the risk of myelosuppression. They should report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider.

Drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol. Patients should be informed that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. Healthcare providers should advise patients to avoid operating automobiles or other dangerous machinery and engaging in activities that may be hazardous due to decreased alertness when starting allopurinol or increasing the dose, until they understand how the drug affects them.

Patients should be informed of the risks of adverse effects when allopurinol is used with certain medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics. They should be advised to disclose all medications they are currently using and to follow their physician's instructions.

Pregnant women should be advised of the potential risk to a fetus and should notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with allopurinol. Additionally, women should be advised not to breastfeed during treatment with allopurinol and for one week after the last dose.

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.

Additional Clinical Information

Patients should be screened for HLA-B5801 prior to initiating treatment with allopurinol, particularly in populations with a high prevalence of this allele. Screening is not recommended for patients from populations with low prevalence or for current allopurinol users, as the risk of serious skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) is primarily associated with the initial months of therapy, independent of HLA-B5801 status.

Clinicians should counsel patients to discontinue allopurinol and seek immediate medical attention if a rash develops. Patients are advised to continue allopurinol and any prophylactic treatments during gout flares, as it may take time to achieve effective control. Adequate fluid intake is essential to maintain a urinary output of at least 2 liters per day, which helps prevent xanthine calculi formation and renal precipitation of urates, especially in those receiving uricosuric agents. Additionally, patients should be informed that allopurinol may enhance the effects of alcohol and other central nervous system depressants, and they should avoid operating heavy machinery or engaging in hazardous activities until they are aware of how the medication affects their alertness.

FDA Insert (PDF)

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

View full prescribing information (PDF)