Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor. It is chemically identified as 1, 5-dihydro-4H-pyrazolo [3, 4-d]pyrimidin-4-one, with a molecular weight of 136.11 g/mol. Allopurinol exhibits a solubility in water of 80.0 mg/dL at 37°C, with increased solubility in alkaline solutions. The drug is available in scored white to off-white tablets, containing either 100 mg or 300 mg of allopurinol. Inactive ingredients in the formulation include croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

Uses and Indications

Allopurinol is indicated for the management of adult patients with 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, Allopurinol 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 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. 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 the case of hyperuricemia associated with cancer therapy, adult patients may be prescribed a dosage range of 300 mg to 800 mg orally once 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 for specific dosage modifications.

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 potential 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 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 remain vigilant for signs of myelosuppression 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 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 are encouraged to monitor patients closely for these potential adverse effects and to provide appropriate guidance regarding the use 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 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; thus, 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 impair 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 following drug interactions have been identified, categorized by their potential clinical effects and necessary precautions.

Skin Reactions Concomitant use of the following agents may increase the risk of serious skin reactions:

• Bendamustine

• Thiazide diuretics

• Ampicillin

• Amoxicillin

Antimetabolites For patients receiving mercaptopurine or azathioprine, it is recommended to reduce the dose of mercaptopurine or azathioprine as specified in the respective prescribing information to mitigate potential interactions.

Allopurinol The use of allopurinol tablets is contraindicated with pegloticase. It is advised to discontinue allopurinol and avoid initiating treatment with it while on pegloticase therapy.

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

However, the safety and effectiveness of allopurinol tablets have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Additionally, allopurinol has not been shown to be safe or effective for managing recurrent calcium oxalate calculi in this population. Furthermore, its use has not been established in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may require special consideration when initiating treatment with allopurinol, especially in the presence of renal impairment. For these patients, the initial dosage should be set at 50 mg orally daily, with subsequent dose increases made cautiously in increments of 50 mg per day every 2 to 4 weeks until the target serum uric acid level is achieved. This gradual titration is essential to minimize the risk of serious adverse reactions associated with the medication.

Close monitoring of kidney function is critical for geriatric patients with chronic kidney disease when starting allopurinol therapy. If there are any persistent abnormalities in kidney function, it may be necessary to decrease the dosage or discontinue the medication altogether. While the maximum dosage for patients with varying levels of renal impairment has not been established based on estimated glomerular filtration rate (eGFR), caution is advised.

Elderly patients with a history of kidney disease, including chronic kidney disease or previous episodes of kidney stones, may be at an elevated risk for further deterioration of kidney function or acute kidney injury due to the formation of xanthine calculi during allopurinol treatment. Therefore, frequent monitoring of kidney function is recommended during the initial stages of therapy, particularly for those being treated for gout or recurrent calcium oxalate calculi.

Additionally, it is advisable for elderly patients to increase their fluid intake during treatment, aiming for at least 2 liters of liquids per day, to maintain hydration and help prevent the formation of kidney stones.

Finally, healthcare providers should be aware that the presence of the HLA-B*58:01 allele in patients is associated with a higher risk of severe skin reactions and hypersensitivity to allopurinol. Genetic testing for this allele may be warranted in certain cases to identify patients at increased risk for allopurinol hypersensitivity syndrome (AHS).

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 an increased 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 associated with allopurinol use. It is important to note that 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 approximately 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 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 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. However, a published report in pregnant mice indicated that single intraperitoneal doses of 50 mg/kg or 100 mg/kg 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

Allopurinol and its active metabolite, oxypurinol, are excreted in human milk. A single case report indicated that both compounds were detected in the milk of a lactating mother receiving a daily dose of 300 mg of allopurinol at 5 weeks postpartum. 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 following the last dose.

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 tablets to mitigate the risk of adverse effects. Monitoring of renal function is recommended 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. Both allopurinol and its active metabolite, oxipurinol, are known to be dialyzable. However, the efficacy of hemodialysis or peritoneal dialysis in the treatment of an allopurinol overdose remains uncertain.

Healthcare professionals should monitor the patient closely for any potential symptoms associated with overdosage, although specific symptoms were not detailed in the available information. Supportive care and symptomatic management should be the primary focus in such cases.

Given the lack of a definitive antidote and the ambiguity surrounding the effectiveness of dialysis, it is recommended that healthcare providers consider consulting a poison control center or a medical toxicologist for further guidance on managing an allopurinol 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. When administered intravenously to rats at a dose of 50 mg/kg, allopurinol was not incorporated into rapidly replicating intestinal DNA. Additionally, no evidence of clastogenicity was observed in lymphocytes taken from patients treated with allopurinol over a mean duration of 40 months, nor in an in vitro assay with human lymphocytes.

Oral doses of allopurinol at 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

Reports from postmarketing surveillance indicate that allopurinol tablets may be associated with an increased risk of serious and potentially fatal dermatologic reactions. Adverse events reported include skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, and swelling of the lips or mouth, which may be indicative of hypersensitivity reactions.

Additionally, gout flares have been observed during the initiation of treatment with allopurinol tablets, even in patients with normal serum uric acid levels. There is evidence suggesting that allopurinol tablets may impact kidney function and carry a risk of hepatotoxicity. Myelosuppression has also been reported in patients receiving allopurinol.

Patients taking allopurinol tablets have experienced drowsiness, somnolence, and dizziness. Furthermore, there are potential risks of adverse effects when allopurinol is used in conjunction with certain medications, including 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 is 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 activities made hazardous by decreased alertness when starting allopurinol tablets or increasing the dose, until they know how the drug affects them.

Patients should be informed 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 in use and to follow the instructions of their physician.

Advise pregnant women of the potential risk to a fetus and instruct them to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with allopurinol tablets. Additionally, advise women 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 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 generally 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.

Patients should be counseled to discontinue allopurinol tablets immediately if a skin rash develops and to seek medical attention promptly. They should continue taking allopurinol tablets and any prophylactic treatment even during gout flares, as it may take time to achieve control. It is important 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 receiving uricosuric agents. Additionally, patients should be informed that the central nervous system depressant effects of allopurinol may be enhanced by alcohol and other CNS depressants, and they should 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 Chartwell RX, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)