Allopurinol

Description

Allopurinol, USP 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 37ºC, with increased solubility in alkaline solutions. Allopurinol is administered orally and is available in scored tablets containing either 100 mg or 300 mg of allopurinol, USP. The tablets also include the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and sodium starch glycolate.

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, this medication is 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 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 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. 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 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 its ingredients. 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 therapy. 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 further complications. Regular monitoring of renal function is advised.

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. Clinicians should monitor patients for signs of myelosuppression and take appropriate action if necessary.

Potential Effect on Driving and Use of Machinery Patients may experience drowsiness, somnolence, or dizziness while on allopurinol. Caution should be exercised when driving or operating machinery until the patient's response to the medication is known.

Laboratory Tests Healthcare providers should evaluate liver function if any signs or symptoms of hepatotoxicity develop during treatment with allopurinol. Regular monitoring of renal function is also recommended for patients with decreased kidney function.

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

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%. These reactions are generally mild but should be monitored.

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 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.

Drug Interactions

The concomitant use of certain medications may lead to increased risks 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 this treatment due to potential interactions that may exacerbate adverse effects.

For patients taking mercaptopurine or azathioprine, it is recommended to reduce the dosage of these agents as outlined in their respective prescribing information to mitigate the risk of toxicity.

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

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 remain unestablished in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, are recommended to initiate treatment for the management of gout with an initial dosage of 100 mg of allopurinol orally daily. Dosage may be increased by 100 mg weekly until a target serum uric acid level of 6 mg/dL or less is achieved. In cases where renal impairment is present, the initial dosage should be reduced to 50 mg orally daily, with subsequent dose increments adjusted accordingly to reach the desired serum uric acid level.

It is critical to note that elderly patients with decreased kidney function require lower doses of allopurinol. Frequent monitoring of kidney function is essential during the early stages of allopurinol administration in this population. If persistent abnormalities in kidney function are observed, it may be necessary to decrease the dosage or discontinue the medication altogether.

To mitigate the risk of drug-induced serious adverse reactions, the dosage of allopurinol should be adjusted gradually in elderly patients. Additionally, it is advisable for these patients to maintain adequate fluid intake to prevent the formation of kidney stones and to be vigilant for signs of nephrotoxicity.

Elderly patients may exhibit increased sensitivity to certain side effects associated with allopurinol, including drowsiness, somnolence, and dizziness. Therefore, careful monitoring for these effects is warranted. Furthermore, allopurinol is contraindicated in patients with a history of hypersensitivity reactions to the drug or its components.

Pregnancy

Based on findings in animal studies, allopurinol may cause fetal harm when administered to pregnant patients. 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. 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. 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, partly because 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, 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

No specific information is available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion in breast milk or its effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers on 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 any symptoms that arise should be addressed promptly. Given the lack of a specific antidote, healthcare providers should remain vigilant for potential complications and manage them according to standard medical protocols.

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.

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.

Additionally, gout flares may occur during the initiation of treatment with allopurinol tablets, even when serum uric acid levels are within the normal range. There have also been reports of nephrotoxicity linked to the use of allopurinol tablets.

Hepatotoxicity has been documented, with signs and symptoms of liver failure such as jaundice, pruritus, bleeding, bruising, or anorexia. Myelosuppression has been reported, presenting with signs and symptoms including infection, fever, bleeding, shortness of breath, or significant fatigue. Furthermore, drowsiness, somnolence, and dizziness have been noted in patients receiving allopurinol tablets.

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 the prophylactic therapy as prescribed, even if gout flares occur. It is important 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 advised 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 a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP guidelines for Controlled Room Temperature. Care must be taken to protect the product from moisture and light to ensure its integrity and efficacy.

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 is essential; patients should be instructed to discontinue allopurinol and seek immediate medical attention if a rash develops. They should continue allopurinol and any prophylactic treatments during gout flares, as it may take time to achieve effective control. Patients are advised 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 when taking uricosuric agents. Additionally, patients should be informed that allopurinol may have additive central nervous system depressant effects 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 Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)