Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor. It is chemically known as 1, 5-dihydro-4H-pyrazolo 3, 4-d pyrimidin-4-one, with a molecular formula of C5H4N4O and a molecular weight of 136.11 g/mol. Allopurinol exhibits slight solubility in sodium hydroxide and potassium hydroxide solutions, very slight solubility in water and alcohol, and is practically insoluble in chloroform and ether. Each functionally scored white to off-white round tablet contains either 100 mg or 300 mg of allopurinol USP. The inactive ingredients include crospovidone, lactose monohydrate, magnesium stearate, corn starch, and povidone.

Uses and Indications

Allopurinol tablets are a xanthine oxidase inhibitor indicated for the management of various conditions associated with elevated uric acid levels. This medication is indicated for 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 diagnosed with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy that results in increased 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 implementing lifestyle modifications.

Limitations of use: Allopurinol 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 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 cases 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 once 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 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 be discontinued immediately at the first sign of a skin rash or any other indication 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 can impact kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol to prevent further renal compromise.

Hepatotoxicity Reversible hepatotoxicity has been reported in patients taking allopurinol. If any signs or symptoms indicative 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 of blood counts may be warranted in patients receiving this medication.

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 patient's response to the medication is known.

Laboratory Tests Healthcare professionals should evaluate liver function if any signs or symptoms of hepatotoxicity develop during treatment with allopurinol. Regular monitoring of renal function may also be necessary, particularly in patients with pre-existing kidney issues.

In summary, careful monitoring and prompt action in response to adverse reactions are crucial for the safe administration of allopurinol.

Side Effects

Patients receiving allopurinol may experience a range of adverse reactions, which can be categorized into common and serious events.

The most common adverse reactions reported include nausea, diarrhea, and an increase in liver function tests. These reactions are typically mild and may resolve with continued treatment or dose adjustment.

Serious adverse reactions associated with allopurinol include skin rash and hypersensitivity, which can lead to severe 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 adversely affect kidney function. Patients with decreased kidney function require careful dose adjustments to avoid further complications. Additionally, cases of reversible hepatotoxicity have been reported; thus, if signs and symptoms of hepatotoxicity develop, liver function should be evaluated promptly.

Myelosuppression has been noted in some patients, indicating a potential risk for bone marrow suppression. Furthermore, patients may experience drowsiness, somnolence, and dizziness, which could 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 components. Monitoring for these adverse reactions is essential to ensure patient safety and effective management during treatment.

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. It is advisable to monitor patients closely for any signs of skin reactions when these agents are used together.

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

When administering mercaptopurine or azathioprine, dosage adjustments may be necessary. It is important to refer to the respective prescribing information for guidance on reducing the dose of these medications.

In the case of pegloticase, it is crucial to discontinue and avoid initiating treatment with allopurinol, as this combination may lead to significant complications.

For a comprehensive overview of significant drug interactions, please refer to the full prescribing information (FPI). No additional drug interactions or laboratory test interactions have been reported.

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, allopurinol has not been proven effective for the management of recurrent calcium oxalate calculi in this population. Furthermore, its 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 with renal impairment. For patients aged 65 and older, the initial dosage of allopurinol should be 50 mg orally daily, with careful titration of the dose until the target serum uric acid level is achieved. In patients with chronic kidney disease, it is essential to monitor kidney function closely upon initiating treatment. If persistent abnormalities in kidney function are observed, the dosage should be decreased or the medication withdrawn.

The recommended initial dosages for adult patients with gout and impaired kidney function are stratified by estimated glomerular filtration rate (eGFR) as follows: for eGFR greater than 60 mL/minute, no dosage modification is necessary; for eGFR between 30 to 60 mL/minute, the recommended dose is 50 mg daily; for eGFR between 15 to 30 mL/minute, the dose should be adjusted to 50 mg every other day; for eGFR between 5 to 15 mL/minute, the dosage should be 50 mg twice weekly; and for eGFR less than 5 mL/minute, the dose should be reduced to 50 mg once weekly. It is critical to note that patients with decreased kidney function require lower doses of allopurinol to mitigate the risk of adverse effects.

Elderly patients who are HLA-B*58:01 positive should not be prescribed allopurinol unless the potential benefits clearly outweigh the risks, as they are at an increased risk for allopurinol hypersensitivity syndrome. Additionally, hypersensitivity reactions may be exacerbated in patients with decreased kidney function who are concurrently taking thiazide diuretics.

Healthcare providers should advise elderly patients to maintain adequate hydration to prevent the formation of kidney stones and to monitor for signs of nephrotoxicity, hepatotoxicity, and myelosuppression. Furthermore, drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol; therefore, elderly patients should be cautioned regarding the potential effects on their ability to drive or operate machinery safely.

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. 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. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, 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 the outcome of a full-term pregnancy in a 35-year-old woman with recurrent kidney stones who took allopurinol throughout her pregnancy; the child had 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. Additionally, no data are provided concerning the excretion of this medication in breast milk or its potential 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 individuals with decreased kidney function require lower doses of allopurinol to mitigate the risk of adverse effects. Monitoring of renal function is recommended in this patient 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 treatment of allopurinol overdose remains uncertain.

Management of an overdose should focus on supportive care and symptomatic treatment. Continuous monitoring of the patient’s clinical status is essential, and appropriate interventions should be implemented based on the symptoms presented. Given the lack of a specific antidote, healthcare providers should remain vigilant and prepared to address any complications that may arise during the course of treatment.

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 indicated that allopurinol tablets may increase the risk of serious and sometimes fatal dermatologic reactions. 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 consistent with hypersensitivity reactions.

Additionally, there is a risk of hepatotoxicity associated with allopurinol tablets, with reports of liver failure symptoms such as jaundice, pruritus, bleeding, bruising, and anorexia. Myelosuppression has also been reported, with associated signs and symptoms including infection, fever, bleeding, shortness of breath, and significant fatigue.

Furthermore, drowsiness, somnolence, and dizziness have been noted in patients taking allopurinol tablets. The central nervous system depressant effects of allopurinol tablets may be additive to those of alcohol and other CNS depressants.

Patient Counseling

Healthcare providers should advise patients to take allopurinol tablets after meals to minimize gastric irritation. In the event that a single dose is occasionally forgotten, patients should be informed that 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 gout flares. Patients should be advised to continue treatment with both allopurinol tablets and any prophylactic therapy as prescribed, even if gout flares occur. Reassurance should be provided that it may take several months to achieve control of the flares, but they typically 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 tablets. They should report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

The risk of myelosuppression should also be communicated to patients, along with the importance of reporting 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. They should be cautioned that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. 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.

Healthcare providers should inform patients 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.

Pregnant women should be advised of the potential risks to a fetus and should notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with allopurinol tablets. Furthermore, women should be advised not to breastfeed during treatment with allopurinol tablets 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, in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should consider screening for HLA-B5801 before initiating allopurinol treatment in patients from populations with a high prevalence of this allele. However, 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.

Patient counseling should emphasize the importance of discontinuing allopurinol and seeking immediate medical attention if a rash develops. Patients are advised to continue allopurinol and any prophylactic treatments during gout flares, as achieving control may take several months. It is also crucial 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 taking 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)