Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1,5-Dihydro-4H-pyrazolo3,4-dpyrimidin-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 scored, white, round tablets containing either 100 mg or 300 mg of allopurinol, USP. The formulation includes inactive ingredients such as colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium lauryl sulfate, and sodium starch glycolate (potato).

Uses and Indications

Allopurinol tablets are 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, these tablets are indicated for both adult and pediatric patients diagnosed with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Allopurinol 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 implementation of lifestyle modifications.

Limitations of use include the recommendation against the use of allopurinol tablets 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. 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 excipients present in allopurinol tablets. 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 tablets 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 therapy, patients may experience gout flares. To mitigate this risk, concurrent prophylactic treatment with colchicine or other anti-inflammatory agents is recommended.

Nephrotoxicity is a concern with allopurinol, as it may adversely affect kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol tablets to prevent further renal compromise.

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

Additionally, myelosuppression has been documented in patients receiving allopurinol, necessitating careful monitoring of blood counts.

Patients taking allopurinol may experience drowsiness, somnolence, and dizziness. Caution is advised when driving or operating machinery until the individual response to the medication is established.

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 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 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. Monitoring for these adverse reactions is essential to ensure patient safety and effective management during treatment.

Drug Interactions

The following drug interactions have been identified, categorized by their potential clinical effects and necessary management strategies.

Pharmacodynamic Interactions

Certain medications may increase the risk of serious skin reactions when used concurrently. These include:

• Bendamustine

• Thiazide diuretics

• Ampicillin

• Amoxicillin

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

Pharmacokinetic Interactions

• Capecitabine: Concomitant use with capecitabine is contraindicated.

• Mercaptopurine and Azathioprine: When these agents are used, it is recommended to reduce the dose of mercaptopurine or azathioprine as specified in their respective prescribing information to mitigate potential adverse effects.

• Pegloticase: Allopurinol tablets should be discontinued, and initiation of treatment with allopurinol should be avoided in patients receiving pegloticase.

For a comprehensive list of significant drug interactions, 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 have been established in approximately 200 pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing cancer therapy that results in elevated serum and urinary uric acid levels. The efficacy and safety profile in this population is comparable to that observed in adults.

However, the use of allopurinol tablets for the treatment of signs and symptoms of primary or secondary gout in pediatric patients has not been established. Additionally, its safety and effectiveness have not been determined for managing 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 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 essential to note that patients with decreased kidney function necessitate lower doses of allopurinol tablets to mitigate the risk of adverse effects.

Close monitoring of kidney function is crucial in elderly patients, particularly those with chronic kidney disease, during the initial stages of allopurinol therapy. This vigilance is necessary to prevent potential complications associated with renal impairment.

Elderly patients may also face an increased risk of serious and potentially fatal dermatologic reactions, including hypersensitivity, especially if they have decreased kidney function. Therefore, healthcare providers should exercise caution and consider the patient's overall health status when prescribing allopurinol.

Additionally, it is advisable to encourage elderly patients to maintain adequate fluid intake to help prevent the formation of kidney stones and to remain vigilant for signs of nephrotoxicity.

Lastly, it is important to inform elderly patients about the potential side effects of allopurinol, such as drowsiness, somnolence, and dizziness. These effects may impair their ability to drive or operate machinery safely, and appropriate precautions should be taken.

Pregnancy

Based on findings in animal studies, allopurinol tablets 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 remains 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 tablets 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 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 (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

Allopurinol and its active metabolite, oxypurinol, are excreted in human milk. A single case report indicated that a lactating mother receiving 300 mg of allopurinol daily at 5 weeks postpartum had detectable levels of both compounds in her breast milk. The estimated relative infant doses were 0.14 mg/kg for allopurinol and between 7.2 mg/kg to 8 mg/kg for oxypurinol daily.

There have been no reported effects of allopurinol on breastfed infants or on milk production. However, due to the potential for serious adverse reactions in a breastfed child, it is advised that lactating mothers refrain from breastfeeding during treatment with allopurinol tablets and for one week after the last dose.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with allopurinol, which can adversely affect kidney function. It is recommended that patients with decreased kidney function receive lower doses of allopurinol tablets to mitigate the risk of further renal compromise. Careful monitoring of renal function is advised in this population to ensure appropriate dosing and to prevent 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 allopurinol 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 significant overdose, healthcare providers may consider the potential role of dialysis, although the clinical benefits in this context have not been established.

It is essential for healthcare professionals to remain vigilant for any symptoms that may arise from an overdose, although specific symptoms were not detailed in the provided information. Prompt recognition and management of any adverse effects are crucial in ensuring patient safety and optimizing outcomes.

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 consistent with hypersensitivity reactions.

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 such as jaundice, pruritus, bleeding, bruising, or anorexia noted in some patients.

Instances of myelosuppression have been observed, with patients presenting signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue. Furthermore, drowsiness, somnolence, and dizziness have been reported among patients taking allopurinol tablets, with potential additive effects when used in conjunction 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 occasionally 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 should 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. They should be made aware that 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 accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. It is essential to protect the product from moisture to maintain its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)