Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor. It is chemically identified as 1, 5-dihydro-4H-pyrazolo 3, 4-dpyrimidin-4-one, with a molecular weight of 136.1 g/mol. Allopurinol exhibits solubility in solutions of potassium and sodium hydroxides, is very slightly soluble in water and alcohol, and is practically insoluble in chloroform and ether.

The formulation includes scored white round-shaped tablets containing 100 mg of allopurinol, along with inactive ingredients such as colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Additionally, there are scored orange round-shaped tablets that contain 300 mg of allopurinol, with inactive ingredients including colloidal silicon dioxide, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, 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 males and 750 mg/day in females, despite implementation of lifestyle modifications.

Limitations of Use: Allopurinol tablets are not recommended 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. 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 desired 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 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 population.

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 dermatological reactions, including skin rash and hypersensitivity. It is imperative that allopurinol tablets be discontinued at the first appearance of any skin rash or other signs indicative of a hypersensitivity reaction to prevent potentially fatal outcomes.

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. Patients with impaired renal function should receive lower doses of allopurinol tablets to avoid exacerbating renal issues.

Hepatotoxicity has been reported in some cases, with instances of reversible liver damage occurring during treatment. 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 monitoring of blood counts as part of patient management.

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

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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. Caution is advised when considering allopurinol for these indications in the pediatric population.

Geriatric Use

Elderly patients may require special consideration when being treated with allopurinol tablets. The use of allopurinol is not recommended for the treatment of asymptomatic hyperuricemia. In geriatric patients with renal impairment, the initial dosage should be 50 mg orally daily, with careful titration of the dose until the target serum uric acid level is achieved.

For elderly patients with chronic kidney disease, it is essential to monitor kidney function closely upon initiating treatment with allopurinol. If persistent abnormalities in kidney function occur, the dosage should be decreased or the medication withdrawn. The recommended initial dosages for adult patients with gout and impaired kidney function are as follows:

• For patients with an estimated glomerular filtration rate (eGFR) greater than 60 mL/minute, no dosage modification is necessary.

• For those with an eGFR between 30 to 60 mL/minute, the recommended dose is 50 mg daily.

• For patients with an eGFR between 15 to 30 mL/minute, the dosage should be adjusted to 50 mg every other day.

• In cases where the eGFR is between 5 to 15 mL/minute, the dosage should be 50 mg twice weekly.

• For patients with an eGFR less than 5 mL/minute, the recommended dosage is 50 mg once weekly.

Elderly patients with decreased kidney function will require lower doses of allopurinol. Additionally, the use of allopurinol is not recommended in patients who are HLA-B*58:01 positive unless the potential benefits clearly outweigh the risks.

It is important to note that hypersensitivity reactions to allopurinol may be more frequent in patients with decreased kidney function who are also receiving thiazide diuretics concurrently. Therefore, frequent monitoring of kidney function is advised during the early stages of allopurinol administration, particularly in those with pre-existing kidney disease.

Elderly patients should also be advised to increase their fluid intake during therapy to help prevent kidney stones and ensure adequate hydration.

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. 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 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

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Consequently, healthcare professionals should exercise caution when considering this medication for lactating mothers. The potential risks and benefits should be carefully evaluated, and alternative treatments may be considered if necessary. Breastfed infants should be monitored for any adverse effects if the mother is using this medication.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with allopurinol, which can affect kidney function. It is recommended that patients with decreased kidney function receive lower doses of allopurinol tablets to mitigate the risk of adverse effects. Careful monitoring of renal function is advised in this population 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 overdosage of allopurinol tablets, it is important to note that there is no specific antidote available. Management of such cases should focus on supportive care and symptomatic treatment.

Dialyzability of Allopurinol and Oxipurinol 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. Healthcare professionals should consider the potential benefits of dialysis on a case-by-case basis, taking into account the patient's clinical status and the timing of the overdose.

Recommended Actions In cases of suspected overdosage, immediate medical attention is warranted. Supportive measures should be initiated, and symptomatic treatment should be provided as necessary. Continuous monitoring of the patient’s vital signs and renal function is essential to manage any complications that may arise from the overdose.

Healthcare professionals are advised to consult local poison control centers or toxicology experts for further guidance on the management of 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. 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 with allopurinol tablets has identified several important safety considerations. Serious and sometimes fatal dermatologic reactions have been reported, necessitating immediate discontinuation of the medication and medical attention at the first sign of skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, swelling of the lips or mouth, or other hypersensitivity symptoms.

Gout flares may occur during the initiation of treatment with allopurinol tablets, even in patients with normal serum uric acid levels. Additionally, allopurinol tablets may impact kidney function; therefore, it is recommended that patients increase fluid intake during therapy to help prevent kidney stones.

There is a noted risk of hepatotoxicity associated with allopurinol tablets. Patients are advised to report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia. Myelosuppression has also been reported, and patients should be vigilant for signs of infection, fever, bleeding, shortness of breath, or significant fatigue.

Drowsiness, somnolence, and dizziness have been observed in patients taking allopurinol tablets. The central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants.

Furthermore, there are risks of adverse effects when allopurinol tablets are co-administered 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 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 to their healthcare provider, including jaundice, pruritus, bleeding, bruising, or anorexia.

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.

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 they are using 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, regardless 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 Par Health USA, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)