Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor, chemically designated as 1, 5-dihydro-4 H-pyrazolo 3, 4-d pyrimidin-4-one, with a molecular weight of 136.11 g/mol. It exhibits a solubility of 80.0 mg/dL in water at 37°C, with increased solubility in alkaline solutions. Allopurinol is administered orally in tablet form.

Allopurinol Tablets USP are available in two strengths: 100 mg and 300 mg. The tablets contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized corn starch, and sodium lauryl sulfate. The 300 mg formulation additionally includes FD&C Yellow No. 6.

Uses and Indications

Allopurinol Tablets 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. Allopurinol Tablets 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 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 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 once 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 are advised to take between 300 mg and 800 mg orally each day. For pediatric patients, the recommended dosage is 100 mg/m² administered orally every 8 to 12 hours, with a maximum daily limit of 10 mg/kg or 800 mg.

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

For patients with renal impairment, healthcare professionals should refer to the full prescribing information (FPI) for specific dosage modifications tailored to the degree of renal dysfunction.

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 and ensure patient safety.

Warnings and Precautions

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

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

Allopurinol may have nephrotoxic effects, particularly in patients with pre-existing kidney impairment. It is essential to monitor kidney function closely, and patients with decreased renal function should receive lower doses of Allopurinol Tablets to avoid exacerbating renal issues.

Hepatotoxicity has been reported in some cases, with instances of reversible liver damage. Should any signs or symptoms of hepatotoxicity arise, it is crucial to evaluate liver function promptly to ensure patient safety.

Additionally, myelosuppression has been documented in patients receiving allopurinol. Regular monitoring of blood counts may be warranted to detect any potential bone marrow suppression early.

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 fully understood.

Side Effects

Patients receiving Allopurinol may experience a range of adverse reactions. The most common adverse reactions reported 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.

Nephrotoxicity is another serious concern, as Allopurinol may affect kidney function. Patients with decreased kidney function require lower doses of Allopurinol Tablets to mitigate this risk. Additionally, cases of reversible hepatotoxicity have been reported; if signs and symptoms of hepatotoxicity develop, liver function should be evaluated promptly. Myelosuppression, or bone marrow suppression, has also been documented in patients taking Allopurinol.

Furthermore, patients may experience drowsiness, somnolence, and dizziness, which could potentially affect their ability to drive or operate machinery. It is important to note that individuals with known hypersensitivity to allopurinol or any of its ingredients should not use Allopurinol Tablets.

Drug Interactions

The concomitant use of certain medications may increase the risk of serious skin reactions. Specifically, the following drugs have been identified: bendamustine, thiazide diuretics, ampicillin, and amoxicillin. Caution is advised when these agents are used together.

For patients receiving capecitabine, it is recommended to avoid concomitant use due to potential interactions that may exacerbate adverse effects.

When administering mercaptopurine or azathioprine, it is essential to reduce the dose of mercaptopurine or azathioprine as outlined in the respective prescribing information to mitigate the risk of toxicity.

In the case of pegloticase, it is critical 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, 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 for managing 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 were found to be similar 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, there is insufficient evidence to support the use of Allopurinol Tablets for managing recurrent calcium oxalate calculi in this population. The use of allopurinol has also not been established in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients may experience altered pharmacokinetics due to age-related changes in renal function, which can significantly impact the elimination of Allopurinol and its primary active metabolite, oxipurinol. Given that both compounds are primarily excreted by the kidneys, it is crucial to monitor renal function closely in this population.

For geriatric patients, particularly those aged 65 and older, it is recommended to perform periodic assessments of renal function. In cases where renal impairment is present or if the patient has concurrent illnesses that may further compromise renal function, healthcare providers should reassess the dosage of Allopurinol Tablets. Adjustments to the dosage may be necessary to ensure safety and efficacy, minimizing the risk of adverse effects associated with elevated drug exposure.

Pregnancy

Based on findings in animal studies, Allopurinol Tablets may pose a risk of fetal harm when administered to pregnant women. Adverse developmental outcomes have been observed in animal models exposed to allopurinol. 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 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.

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 population indicated for allopurinol is not well defined. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively.

Experience with Allopurinol Tablets 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 included data from 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 normal expected 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 nephrotoxicity associated with Allopurinol. It is essential to consider that these patients require lower doses of Allopurinol Tablets due to their reduced kidney function. Careful monitoring of renal function is recommended to ensure appropriate dosing and to mitigate potential adverse effects.

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 overdose remains uncertain.

Given the lack of a specific antidote, the primary focus should be on supportive care and symptomatic management. Monitoring of vital signs and laboratory parameters is recommended to assess the patient's condition and guide further treatment. In cases of suspected overdose, healthcare providers should consider consulting a poison control center for additional guidance on management strategies.

It is essential to remain vigilant for any potential symptoms that may arise from an overdose, although specific symptoms have not been detailed in the available data. Prompt recognition and appropriate management are crucial in mitigating the effects of an overdose of Allopurinol Tablets.

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 have included skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, swelling of the lips or mouth, and other signs and symptoms indicative of hypersensitivity reactions.

Additionally, there have been reports of gout flares occurring during the initiation of treatment with Allopurinol Tablets, even in patients with normal serum uric acid levels. Nephrotoxicity has also been noted, with effects on kidney function documented in postmarketing reports.

Hepatotoxicity has been reported, with signs and symptoms of liver failure such as jaundice, pruritus, bleeding, bruising, or anorexia. Myelosuppression has been observed, with associated signs and symptoms including infection, fever, bleeding, shortness of breath, or significant fatigue.

Furthermore, drowsiness, somnolence, and dizziness have been reported in patients taking Allopurinol Tablets, with potential central nervous system depressant effects that may be additive to those of alcohol and other CNS depressants. Adverse effects have also been reported when Allopurinol Tablets are used in conjunction with medications such as 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 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 any prophylactic therapy as prescribed, even if gout flares occur. It is essential 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 must be made aware of the risk of hepatotoxicity associated with Allopurinol Tablets. 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 Tablets. Patients should be instructed 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 Tablets 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, light-resistant container equipped with a child-resistant closure. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to maintain its integrity and efficacy.

Additional Clinical Information

Clinicians should consider screening for HLA-B5801 before initiating treatment with Allopurinol Tablets in patients from 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.

Patients should be counseled to discontinue Allopurinol Tablets immediately if a skin rash develops and to seek medical attention promptly. They should continue taking Allopurinol Tablets and any prophylactic treatment even during gout flares, as it may take time to achieve control. It is important to maintain adequate fluid intake to ensure 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 about the potential additive central nervous system depressant effects of Allopurinol Tablets with alcohol and other CNS depressants, advising caution with activities requiring alertness when starting or adjusting the dosage of the medication.

FDA Insert (PDF)

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

View full prescribing information (PDF)