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 136.11 g/mol. Allopurinol exhibits a solubility in water of 80.0 mg/dL at 37°C, with increased solubility in alkaline solutions. The formulation is available in white to off-white scored tablets, containing either 100 mg or 300 mg of allopurinol, USP. Inactive ingredients in the tablets include croscarmellose sodium, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone.

Uses and Indications

Allopurinol 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, 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 until the target serum uric acid level is reached.

In the case of hyperuricemia associated with cancer therapy, adults are advised to take a dosage ranging from 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.

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 has been associated with serious and potentially fatal dermatological reactions, including skin rash and hypersensitivity. It is imperative that allopurinol 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 treatment, gout flares may occur. To mitigate this risk, concurrent prophylactic treatment with colchicine or 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 to prevent further complications.

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

Myelosuppression has also been documented in patients receiving allopurinol. Regular monitoring of blood counts may be warranted to detect any potential bone marrow suppression.

Additionally, patients taking allopurinol may experience drowsiness, somnolence, and dizziness. Caution is advised when driving or operating machinery until the individual’s response to the medication is fully understood.

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. Monitoring and appropriate management of these adverse reactions are essential for patient safety.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding 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 for the management of 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 the management of 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, 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 careful and gradual increases in dosage by 50 mg/day increments every 2 to 4 weeks until the target serum uric acid level is achieved. This approach is crucial to minimize the risk of serious adverse reactions associated with the medication.

Close monitoring of kidney function is essential for geriatric patients with chronic kidney disease who are 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. It is important to note that the maximum dosage for patients with varying degrees of renal impairment has not been established based on different estimated glomerular filtration rate (eGFR) levels.

Elderly patients with a history of kidney disease, including chronic kidney disease or 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 while on allopurinol. Therefore, frequent monitoring of kidney function during the initial stages of treatment is recommended.

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

The presence of the HLA-B5801 allele, a genetic marker associated with severe skin reactions and hypersensitivity to allopurinol, should also be considered. The use of allopurinol is not recommended in patients who test positive for HLA-B58:01 unless the potential benefits clearly outweigh the associated risks.

Furthermore, geriatric patients receiving thiazide diuretics concurrently with allopurinol may experience an increased risk of hypersensitivity reactions, necessitating careful monitoring and consideration of alternative therapies.

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, 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, healthcare professionals should advise pregnant women of the potential risks to the fetus.

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 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 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 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 exhibited 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

There is no specific information available regarding the use of this medication in nursing mothers or any lactation considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to lactating mothers, as the effects on breastfed infants are not established. It is advisable to weigh the potential benefits against any unknown risks when considering treatment options for lactating patients.

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 to mitigate the risk of adverse effects. Careful monitoring of renal function is recommended 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 impairment and to guide further management. Adjustments to dosing or treatment may be necessary based on the results of these evaluations.

Overdosage

In the event of an allopurinol overdosage, it is important to note that there is no specific antidote available. Management of such cases should focus on supportive care and symptomatic treatment.

Both allopurinol and its active metabolite, oxipurinol, are known to be dialyzable. However, the efficacy of hemodialysis or peritoneal dialysis in the context of allopurinol overdose remains uncertain. Healthcare professionals should consider these factors when determining the appropriate course of action for patients presenting with an overdose.

Monitoring of the patient’s clinical status is essential, and supportive measures should be implemented as necessary. It is advisable to consult with a poison control center or a medical toxicologist for guidance on the management of specific symptoms and complications that may arise from an overdose of allopurinol.

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 several important safety considerations associated with allopurinol. Patients are advised that allopurinol may increase the risk of serious and potentially fatal dermatologic reactions. It is recommended that patients discontinue allopurinol and seek immediate medical attention 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 indicative of hypersensitivity reactions.

Additionally, patients may experience gout flares during the initiation of allopurinol treatment, even if their serum uric acid levels are normal. There is also a risk of nephrotoxicity; therefore, patients are encouraged to increase fluid intake during therapy to help prevent kidney stones. Hepatotoxicity has been reported, and patients should be vigilant for signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia.

Myelosuppression is another potential risk, and patients are advised to report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider. Furthermore, drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol. Patients should avoid operating automobiles or engaging in activities that may be hazardous due to decreased alertness when starting allopurinol or increasing the dose, until they are aware of how the medication affects them.

Finally, there are 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

Healthcare providers should advise patients to take allopurinol after meals to minimize gastric irritation. In the event that a single dose of allopurinol is occasionally forgotten, patients should be informed that there is no need to double the dose at the next scheduled time.

It is important to inform patients that allopurinol may increase the risk of serious and potentially fatal dermatologic reactions. Patients should be instructed to discontinue allopurinol 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 be made aware that gout flares may occur during the initiation of treatment with allopurinol, even when their serum uric acid levels are normal. The concurrent use of additional medications such as colchicine or other anti-inflammatory agents can help prevent gout flares. Patients should be advised to continue treatment with both allopurinol and the prophylactic therapy as prescribed, even if gout flares occur. They should be reassured that it may take several months to achieve control of the flares, but typically, the flares become shorter and less severe over time.

Inform patients that allopurinol 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 also be informed of the risk of hepatotoxicity associated with allopurinol. They should report any signs and symptoms of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

Additionally, patients should be made aware of the risk of myelosuppression. They should report any signs and symptoms of infection, fever, bleeding, shortness of breath, or significant fatigue to their healthcare provider.

Drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol. Patients should be informed that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. They 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 or increasing the dose, until they understand how the drug affects them.

Patients should be informed of the risks of adverse effects when allopurinol is used with certain medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics. They should be advised to disclose all medications they are currently using and to follow their physician's instructions.

Pregnant women should be advised of the potential risk to a fetus and should notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with allopurinol. Furthermore, women should be advised not to breastfeed during treatment with allopurinol 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 allopurinol treatment in patients from populations with a high prevalence of this allele. However, screening is generally 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 even during gout flares, as it may take time to achieve effective control. Maintaining adequate fluid intake to ensure a urinary output of at least 2 liters per day is crucial to prevent xanthine calculi formation and renal precipitation of urates, especially in those receiving uricosuric agents. Additionally, patients should be made aware that allopurinol may have additive central nervous system depressant effects when combined with alcohol or 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 Unichem Pharmaceuticals (USA) , Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)