Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1,5-dihydro-4H-pyrazolo 3,4-d pyrimidin-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 and is available in tablet form, with each tablet containing either 100 mg, 200 mg, or 300 mg of allopurinol, USP. The tablets also include inactive ingredients such as croscarmellose sodium, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, povidone, and FD&C Yellow No. 6 aluminum Lake, which is present only in the 300 mg formulation.

Uses and Indications

Allopurinol tablet 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 medication 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 aimed at reducing uric acid levels.

Allopurinol tablet is 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 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 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 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 and 300 mg orally once daily. For patients with renal impairment, healthcare professionals should refer to the full prescribing information for specific dosage modifications.

Contraindications

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

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 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. Additionally, cases of reversible hepatotoxicity have been reported; if patients exhibit signs and symptoms of hepatotoxicity, 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 safely.

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 increase the risk of serious skin reactions. Specifically, the following drugs have been identified: bendamustine, thiazide diuretics, ampicillin, and amoxicillin.

In the case of capecitabine, it is advised to avoid its use alongside the medication in question due to potential interactions.

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

Additionally, when considering treatment with pegloticase, it is crucial to discontinue and avoid initiating allopurinol therapy, as this combination may lead to significant complications.

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 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 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 managing 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, particularly those aged 65 and older, may exhibit altered pharmacokinetics and pharmacodynamics, necessitating careful consideration when prescribing allopurinol. In patients with renal impairment, the initial dosage should be set at 50 mg orally daily, with subsequent dose adjustments made cautiously until the target serum uric acid level is achieved. This approach is especially critical for geriatric patients, who often present with diminished kidney function.

Frequent monitoring of kidney function is essential during the initial stages of allopurinol therapy in elderly patients, as they are at an increased risk for deterioration of renal function or acute kidney injury. Dosage modifications should be based on the patient's renal function, which is frequently compromised in this population.

It is advisable to instruct elderly patients to maintain adequate fluid intake to mitigate the risk of kidney stones and to support overall kidney function during treatment with allopurinol. Additionally, there is an elevated risk of serious and potentially fatal dermatologic reactions, including hypersensitivity, in elderly patients, particularly those with impaired renal function.

Furthermore, geriatric patients may demonstrate heightened sensitivity to side effects such as drowsiness, somnolence, and dizziness. These effects can significantly impact their ability to perform tasks requiring alertness, including driving or operating machinery. Therefore, careful monitoring and patient education regarding these risks are paramount in the management of elderly patients receiving allopurinol.

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. Therefore, 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 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 nursing mothers or its effects on lactation. Consequently, healthcare professionals should exercise caution when considering this medication for lactating mothers. The potential risks and benefits should be carefully evaluated, and alternative treatments may be considered if necessary. Breastfed infants should be monitored for any adverse effects if the mother is using this medication.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with allopurinol. It is essential to consider that individuals with decreased 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 clinical decisions should be made regarding the continuation or modification of therapy in these patients.

Overdosage

In the event of an allopurinol overdosage, 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 focus of management should be on supportive care and symptomatic treatment. Monitoring of renal function and electrolytes is recommended, as well as the assessment of any potential complications arising from the overdose. Healthcare providers should remain vigilant for any adverse effects that may manifest and manage them accordingly.

In summary, while dialysis may be considered due to the dialyzability of the drug, the overall benefit in cases of allopurinol overdosage is not well established, necessitating a careful and individualized approach to patient 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, with a mean duration of treatment of 40 months, nor in an in vitro assay with human lymphocytes.

Oral doses of allopurinol at 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. Patients are advised to discontinue the medication and seek immediate 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 signs and symptoms indicative of hypersensitivity reactions.

Additionally, there is a risk of hepatotoxicity with allopurinol tablets. Patients should report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider. Myelosuppression has also been reported; patients are encouraged to inform their healthcare provider of any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue.

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

Patient Counseling

Advise patients to take allopurinol tablets after meals to minimize gastric irritation. Instruct patients that if they occasionally forget a single dose of allopurinol, there is no need to double the dose at the next scheduled time.

Inform patients that allopurinol tablets may increase the risk of serious and sometimes 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 other signs and symptoms of hypersensitivity reactions.

Patients should be made aware that gout flares may occur during the initiation of treatment with allopurinol, even when their serum uric acid levels are normal. Concurrent use of additional medications such as colchicine or other anti-inflammatory agents can help prevent gout flares. Advise patients to continue treatment with both allopurinol and the prophylactic therapy as prescribed, even if gout flares occur. Reassure them that it may take months to achieve control of the flares, but typically, the flares become shorter and less severe after several months of therapy.

Inform patients that allopurinol tablets may affect kidney function. Advise them to increase their fluid intake during therapy, recommending at least 2 liters of liquids per day for adults, to stay well hydrated and prevent kidney stones.

Patients should be informed of the risk of hepatotoxicity and instructed to report any signs and symptoms of liver failure to their healthcare provider, including jaundice, pruritus, bleeding, bruising, or anorexia.

Advise patients of the risk of myelosuppression and instruct them to report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider.

Inform patients that drowsiness, somnolence, and dizziness have been reported in individuals taking allopurinol tablets. Additionally, the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. 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.

Finally, inform patients 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. Advise patients 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 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 on uricosuric agents. Additionally, patients should be informed about 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 their alertness.

FDA Insert (PDF)

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

View full prescribing information (PDF)