Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor, chemically designated 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. The compound 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. Allopurinol is administered orally and is available in functionally scored round tablets, which are white to off-white in color, containing either 100 mg or 300 mg of allopurinol USP. The tablets also include inactive ingredients such as crospovidone, lactose monohydrate, magnesium stearate, corn starch, and povidone.

Uses and Indications

Allopurinol tablets are indicated for the management of various conditions associated with elevated uric acid levels. This medication is specifically indicated for adult patients exhibiting signs and symptoms of primary or secondary gout, which may include 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 implementation of lifestyle modifications.

Limitations of use include the recommendation against the treatment of asymptomatic hyperuricemia with Allopurinol. There are no teratogenic or nonteratogenic effects associated with this medication.

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. In 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.

For hyperuricemia associated with cancer therapy, adults may be prescribed a dosage range of 300 mg to 800 mg orally daily. Pediatric patients should receive 100 mg/m² orally every 8 to 12 hours, with a maximum daily dosage of 800 mg or 10 mg/kg/day.

In the case 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.

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 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. Patients with impaired renal function may require dosage adjustments to avoid potential nephrotoxic effects.

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 or symptoms of hepatotoxicity develop, it is crucial to evaluate liver function to ensure patient safety and appropriate management.

Healthcare professionals should remain vigilant regarding these warnings and take appropriate action to monitor and manage any adverse effects 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. These reactions are generally mild but should be monitored during treatment.

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; if patients exhibit signs and symptoms of liver dysfunction, liver function should be evaluated promptly.

Myelosuppression, or bone marrow suppression, has been documented in patients taking allopurinol, necessitating monitoring of blood counts. Furthermore, patients may experience drowsiness, somnolence, and dizziness, which could impact 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.

Drug Interactions

The concomitant use of certain medications may lead to an increased 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.

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 mercaptopurine or azathioprine as outlined in their respective prescribing information to mitigate the risk of interactions.

In the case of pegloticase, it is essential 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).

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 or in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, may require specific considerations when prescribed allopurinol for the management of gout. For elderly patients with normal kidney function, the initial recommended dosage is 100 mg orally daily, with the possibility of increasing the dose by 100 mg weekly until a target serum uric acid level of 6 mg/dL or less is achieved, not exceeding a maximum daily dose of 800 mg.

In contrast, for elderly patients with impaired kidney function, the initial dosage should be reduced to 50 mg orally daily, with careful monitoring and lower increments in dosage until the desired serum uric acid level is reached. It is essential to note that patients with decreased kidney function require lower doses of allopurinol to mitigate the risk of adverse effects.

Frequent monitoring of kidney function is crucial during the early stages of allopurinol administration, particularly in elderly patients with chronic kidney disease. If persistent abnormalities in kidney function are observed, it may be necessary to decrease the dosage or withdraw the medication altogether.

Additionally, the presence of the HLA-B*58:01 allele, a genetic marker associated with severe skin reactions indicative of hypersensitivity to allopurinol, should be considered. Screening for this allele is advisable in elderly patients from populations with a known high prevalence.

Elderly patients should be advised to maintain adequate fluid intake to prevent the formation of kidney stones and to remain vigilant for signs of nephrotoxicity, hepatotoxicity, and myelosuppression. Furthermore, it is important to inform elderly patients about the potential side effects of allopurinol, including drowsiness, somnolence, and dizziness, which may impair 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. Therefore, healthcare professionals should 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. 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 reduced kidney function require lower doses of allopurinol to mitigate the risk of adverse effects on kidney function. Dosing adjustments should be made based on the degree of renal impairment to ensure safe and effective use of the medication. Regular monitoring of renal function is recommended for these patients to assess the need for further dose modifications.

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 are encouraged to consult with a poison control center or a medical toxicologist for guidance on the best management practices in cases of allopurinol overdosage.

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. 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.

There is a recognized risk of hepatotoxicity; patients should report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider. Additionally, myelosuppression has been reported, and 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 among patients taking allopurinol tablets, which may have additive effects when combined with alcohol and other central nervous system depressants. Furthermore, risks of adverse effects have been noted when allopurinol tablets are used concurrently with medications such as 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. If a single dose of allopurinol tablets is occasionally forgotten, 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. Instruct patients to discontinue allopurinol tablets 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 tablets, 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 tablets 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 the flares typically become shorter and less severe after several months of therapy.

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

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

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 patients taking allopurinol tablets. Additionally, the central nervous system depressant effects of allopurinol tablets 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 made hazardous by decreased alertness when starting allopurinol tablets or increasing the dose, until they know how the drug affects them.

Finally, inform patients of the risks of adverse effects when allopurinol tablets are used with certain drugs, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics. Advise patients to disclose all medications they are using and to follow the instructions of their physician.

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

Patients starting treatment with allopurinol should be screened for the HLA-B*5801 allele, particularly in populations with a high prevalence of this genetic marker. Clinicians are advised to monitor kidney function closely during the initial stages of allopurinol therapy, especially in patients being treated for gout or recurrent calcium oxalate calculi, and to conduct daily assessments in those receiving treatment for tumor lysis syndrome. Additionally, periodic monitoring of liver enzymes is recommended for patients with pre-existing liver conditions.

Patients should be counseled to discontinue allopurinol and seek immediate medical attention if a rash develops. It is important to inform patients that they should continue taking allopurinol and any prophylactic treatments even if gout flares occur, as achieving control may take several months. Patients should also be made aware that allopurinol may enhance the effects of alcohol and other central nervous system 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 Camber Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)