Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1, 5-dihydro-4 H-pyrazolo 3, 4-dpyrimidin-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 and is available in three tablet formulations:

• Each scored white hexagon-shaped tablet contains 100 mg of allopurinol, along with inactive ingredients including lactose monohydrate, magnesium stearate, potato starch, and povidone.

• Each scored white round tablet contains 200 mg of allopurinol, with inactive ingredients comprising lactose monohydrate, magnesium stearate, corn starch, and povidone.

• Each scored peach tablet contains 300 mg of allopurinol, incorporating inactive ingredients such as corn starch, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, and povidone.

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. It is also indicated for 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. Additionally, this medication is indicated for adult patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients, despite implementation of lifestyle changes.

Limitations of use include the recommendation against the use of allopurinol tablet 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 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 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 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. Patients with impaired renal function may require dosage adjustments to avoid potential nephrotoxic effects. Regular monitoring of renal function is advised for these patients.

Hepatotoxicity Instances of reversible hepatotoxicity have been reported in patients taking allopurinol. Should any signs or symptoms of hepatotoxicity arise, it is essential to evaluate liver function promptly.

Myelosuppression Bone marrow suppression has been documented in patients receiving allopurinol. Healthcare providers should monitor blood counts regularly to detect any signs of myelosuppression.

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.

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 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 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 signs and symptoms of hepatotoxicity develop, liver function should be evaluated promptly. Myelosuppression, or bone marrow suppression, has also been noted 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. 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 in conjunction.

Capecitabine should be avoided in patients receiving treatment, as its concomitant use is contraindicated.

For patients taking mercaptopurine or azathioprine, it is recommended to reduce the dosage of mercaptopurine or azathioprine in accordance with the guidelines provided in the respective prescribing information to mitigate potential interactions.

In the case of pegloticase, it is essential to discontinue and avoid initiating treatment with allopurinol tablets, as this combination may lead to adverse effects.

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 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 managing recurrent calcium oxalate calculi in this demographic. Furthermore, allopurinol's safety and effectiveness remain unestablished in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, may require special consideration when prescribed allopurinol. For elderly patients with normal kidney function, the recommended initial 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, with a maximum allowable dose of 800 mg daily.

In contrast, for elderly patients with impaired kidney function, the initial dosage should be reduced to 50 mg orally daily, with titration based on renal function until the desired serum uric acid level is reached. It is important to note that patients with decreased kidney function necessitate lower doses of allopurinol tablets.

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

Elderly patients are at an increased risk for serious and potentially fatal dermatologic reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome, particularly if they have decreased kidney function. Therefore, it is crucial to advise these patients to maintain adequate hydration to help prevent kidney stones and to monitor for signs of nephrotoxicity.

Additionally, elderly patients may exhibit increased sensitivity to side effects, which underscores the need for careful monitoring and potential dosage adjustments to ensure safety and efficacy in this population.

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. 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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) of allopurinol 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, the potential for excretion in breast milk and the impact on breastfed infants remain undetermined. Healthcare professionals should exercise caution and consider the benefits and risks when prescribing this medication to lactating mothers.

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 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 management of an overdose.

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.

Gout flares may occur during the initiation of treatment with allopurinol tablets, even in patients with normal serum uric acid levels. Additionally, cases of nephrotoxicity have been reported, suggesting that allopurinol tablets may impact kidney function. Hepatotoxicity has also been documented, with signs and symptoms of liver failure including jaundice, pruritus, bleeding, bruising, or anorexia.

Instances of myelosuppression have been noted, prompting patients to be vigilant for 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, with potential additive effects observed when combined with alcohol and other central nervous system depressants.

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 taking both allopurinol tablets and the 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 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 must 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 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 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

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, regardless of HLA-B5801 status.

Frequent monitoring of kidney function is essential during the early stages of allopurinol administration for patients managing gout or recurrent calcium oxalate calculi, and daily monitoring is required for those undergoing treatment for tumor lysis syndrome. Liver enzymes should be evaluated if patients experience symptoms such as anorexia, weight loss, or pruritus, and periodic monitoring is advised for those with pre-existing liver conditions. Blood counts should be monitored more closely when allopurinol is used in conjunction with cytotoxic drugs.

Patients should be counseled to discontinue allopurinol tablets and seek immediate medical attention if a rash develops. They should continue taking allopurinol and any prophylactic treatments even during gout flares, as achieving control may take several months. Additionally, patients should be informed about the potential additive central nervous system depressant effects of allopurinol and substances like alcohol, advising them to 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 Rising Pharma Holdings, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)