Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1, 5-dihydro-4H-pyrazolo3, 4-dpyrimidin-4-one, with a molecular weight of 136.11 g/mol. The compound exhibits a solubility of 80.0 mg/dL in water at 37°C, with increased solubility in alkaline solutions. Allopurinol is administered orally.

The formulation includes scored white, flat cylindrical tablets containing 100 mg of allopurinol, along with inactive ingredients such as corn starch, lactose monohydrate, magnesium stearate, povidone, and purified water. Additionally, there are scored peach, flat cylindrical tablets that contain 300 mg of allopurinol, incorporating inactive ingredients including corn starch, FD&C Yellow No. 6 Aluminium Lake, lactose monohydrate, magnesium stearate, povidone, and purified water.

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, this medication is indicated for both adult and pediatric patients diagnosed with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Allopurinol 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 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 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 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 excipients present in allopurinol tablets. This contraindication is essential to prevent potential allergic reactions that could lead to serious adverse effects.

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 other anti-inflammatory agents is recommended.

Nephrotoxicity Allopurinol can impact 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 and 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 minimize 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%. 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 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 further 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, indicating potential bone marrow suppression in some patients.

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 in conjunction.

Capecitabine should be avoided in combination with the drug in question 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 overview of significant drug interactions, please 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 have been established in approximately 200 pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing cancer therapy that leads to elevated serum and urinary uric acid levels. The efficacy and safety profile in this population is comparable to that observed in adults.

However, the use of allopurinol tablets for the treatment of signs and symptoms of primary or secondary gout in pediatric patients has not been established. Additionally, its safety and effectiveness have not been determined for managing recurrent calcium oxalate calculi or 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 with renal impairment. For patients aged 65 and older, the initial dosage of allopurinol should be adjusted based on renal function to ensure safety and efficacy.

In patients with an estimated glomerular filtration rate (eGFR) greater than 60 mL/minute, no dosage modification is necessary. However, for those with eGFR between 30 to 60 mL/minute, the recommended initial dosage is 50 mg daily. For patients with eGFR ranging from 15 to 30 mL/minute, the dosage should be reduced to 50 mg every other day, while those with eGFR between 5 to 15 mL/minute should receive 50 mg twice weekly. In cases where eGFR is less than 5 mL/minute, the dosage should be further reduced to 50 mg once weekly.

It is crucial to monitor kidney function frequently during the early stages of allopurinol administration, especially in geriatric patients with chronic kidney disease. If persistent abnormalities in kidney function are observed, the dosage should be decreased or the medication withdrawn.

Elderly patients are also advised to remain well-hydrated to prevent the formation of kidney stones and to be vigilant for signs of hypersensitivity reactions, such as skin rash, which may be more severe in this population. 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 this genetic marker is associated with an increased risk of hypersensitivity reactions.

Pregnancy

Based on findings in animal studies, allopurinol tablets may pose a risk of fetal harm when administered to pregnant patients. Adverse developmental outcomes have been observed in animal models following exposure to allopurinol. The drug and its metabolite, oxypurinol, are known to cross the placenta after maternal administration.

Limited published data on allopurinol use in pregnant women do not indicate a clear pattern or an increased frequency of adverse developmental outcomes. Among approximately 50 pregnancies documented in the literature, two infants with major congenital malformations were reported following maternal exposure to allopurinol. Healthcare professionals should advise pregnant women of the potential risks to the fetus associated with allopurinol use.

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 in the general U.S. population is estimated to be 2% to 4% and 15% to 20%, respectively. The specific background risk for the population indicated for allopurinol is currently unknown.

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 a history of recurrent kidney stones who was treated with 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 detailed 31 prospectively ascertained pregnancies involving mothers exposed to allopurinol during the first trimester. The overall rate of major fetal malformations and spontaneous abortions was reported to be within the expected normal range; however, one child exhibited severe malformations similar to those noted 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 organogenesis period 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 study 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 were due to direct fetal effects or 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 altered 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 in this patient population 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 management of overdosage should focus on supportive care and symptomatic treatment. Monitoring of the patient’s clinical status is essential, and appropriate interventions should be implemented based on the symptoms presented. Healthcare providers are advised to consider the potential need for dialysis, although the benefits in this context are not well established.

In summary, while there is no antidote for allopurinol overdose, the possibility of dialysis should be evaluated on a case-by-case basis, keeping in mind the unknown effectiveness of such interventions.

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 serious and, in some cases, fatal dermatologic reactions associated with allopurinol tablets. Reports of hypersensitivity reactions have included skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, and swelling of the lips or mouth. Additionally, cases of nephrotoxicity have been reported, suggesting potential effects on kidney function.

Instances of hepatotoxicity have also been documented, with signs and symptoms of liver failure such as jaundice, pruritus, bleeding, bruising, or anorexia being noted. Myelosuppression has been observed, with reports indicating signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue.

Furthermore, drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol tablets, indicating potential central nervous system effects. Adverse effects have also been reported when allopurinol tablets are used in conjunction with other medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics.

Patient Counseling

Patients should be advised to take allopurinol tablets after meals to minimize gastric irritation. In the event that a single dose is occasionally 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 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.

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 flares. Patients should be advised to continue treatment with both allopurinol tablets and the prophylactic therapy as prescribed, even if gout flares occur. It is important to reassure them that it may take several months to achieve control of the flares, but typically, the flares become shorter and less severe over time.

Additionally, patients should be informed that allopurinol tablets 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.

Patients should be made aware of the risk of hepatotoxicity associated with allopurinol. They should report any signs and symptoms of liver failure, such as jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

There is also a risk of myelosuppression with allopurinol. Patients should be advised to report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider.

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

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

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

Patients starting treatment with allopurinol tablets should be screened for the HLA-B5801 allele, 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 tablets immediately if a skin rash develops and to seek medical attention promptly. Patients are advised to continue allopurinol tablets and any prophylactic treatment during gout flares, as it may take time to achieve control. Adequate fluid intake is essential to maintain a urinary output of at least 2 liters per day to prevent xanthine calculi formation and renal precipitation of urates, especially in those receiving uricosuric agents. Additionally, patients should be informed of the potential additive central nervous system depressant effects of allopurinol with alcohol and other CNS depressants, and they should avoid operating vehicles or engaging in hazardous activities until they understand how the medication affects them.

FDA Insert (PDF)

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

View full prescribing information (PDF)