Allopurinol

Description

Allopurinol is known chemically as 1,5-dihydro-4H-pyrazolo 3,4-dpyrimidin-4-one. It is administered orally and is available in strengths of 100 mg and 300 mg. The inactive ingredients include lactose, magnesium stearate, starch, and povidone. Allopurinol has a solubility in water at 37°C of 800 mg/mL, which increases in alkaline solutions.

Uses and Indications

Allopurinol Tablets 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. Additionally, it 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 Tablets 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 treatment of asymptomatic hyperuricemia with Allopurinol Tablets.

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 tailored to this patient population.

Contraindications

Use of Allopurinol Tablets is contraindicated in patients with known hypersensitivity to allopurinol or to any of the ingredients contained in the formulation. This contraindication is essential to prevent potential allergic reactions that may pose significant health risks.

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 at the first appearance of any skin rash or other signs indicative of a hypersensitivity reaction.

During the initiation of treatment, patients may experience gout flares. 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. Therefore, patients with impaired renal function should receive lower doses of Allopurinol Tablets to prevent further renal compromise.

Hepatotoxicity has been reported, with cases of reversible liver damage occurring in some patients. 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 Tablets 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 Tablets may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

The most common adverse reactions reported include nausea, diarrhea, and an increase in liver function tests. These reactions are generally 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. Additionally, gout flares may 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 monitoring and may need lower doses of Allopurinol Tablets. Hepatotoxicity has also been reported, with cases of reversible liver damage occurring; thus, it is important to evaluate liver function if signs and symptoms of hepatotoxicity develop.

Myelosuppression, or bone marrow suppression, has 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 patients with known hypersensitivity to allopurinol or any of the ingredients in Allopurinol Tablets should not use this medication.

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 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 Tablets have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Additionally, there is insufficient evidence to support the use of Allopurinol Tablets for managing recurrent calcium oxalate calculi in this population. The use of allopurinol has also not been established in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients may exhibit altered pharmacokinetics and pharmacodynamics, necessitating careful consideration when prescribing Allopurinol Tablets. In patients aged 65 and older, particularly those with renal impairment, the initial dosage should be 50 mg orally daily, with subsequent dose adjustments made cautiously to achieve the target serum uric acid level. This approach is critical, as geriatric patients often present with compromised kidney function.

Frequent monitoring of kidney function is essential during the initial stages of Allopurinol administration in elderly patients, who are at an increased risk for worsening renal function or acute kidney injury. Dosage adjustments must be made based on renal function to mitigate potential adverse effects.

Elderly patients should be advised to maintain adequate fluid intake to prevent the formation of kidney stones and to remain vigilant for any signs of nephrotoxicity. Additionally, this population may demonstrate heightened sensitivity to side effects such as drowsiness, somnolence, and dizziness, which could impair their ability to operate machinery or drive safely.

There is an increased risk of serious and potentially fatal dermatologic reactions, including hypersensitivity, in elderly patients, especially those with renal impairment. Allopurinol Tablets should be discontinued at the first sign of a skin rash or other indications of hypersensitivity. Furthermore, it is advisable to consider screening for the HLA-B*58:01 allele in elderly patients, as they may be at a greater risk for severe skin reactions associated with Allopurinol.

Pregnancy

Based on findings in animal studies, Allopurinol Tablets may pose a risk of fetal harm when administered to pregnant women. Adverse developmental outcomes have been observed in animal models, indicating potential risks associated with maternal exposure. Allopurinol and its metabolite, oxypurinol, have been shown to cross the placenta following maternal administration.

Limited published data on the use of allopurinol in pregnant women do not demonstrate a clear pattern or an increased frequency of adverse developmental outcomes. Among approximately 50 pregnancies documented in the literature, two infants with major congenital malformations were 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 population using allopurinol is not well defined. 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 is limited, as women of reproductive age rarely require treatment with this medication. A case report from 2011 described a full-term pregnancy in a 35-year-old woman with a history of recurrent kidney stones who was treated with 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 included data from 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 expected range; however, one child exhibited severe malformations similar to those noted 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 organogenesis period 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 study 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 were due to direct fetal effects or secondary to maternal toxicity.

Lactation

There is no specific information available regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about 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 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 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 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 overdosage, healthcare providers should consider the potential need for renal support, although the role of dialysis in this context is not well 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 available 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 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 prompt 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 hypersensitivity symptoms.

Gout flares may occur during the initiation of treatment, even in patients with normal serum uric acid levels. Patients are advised to continue both Allopurinol Tablets and any prescribed prophylactic therapy, as flares typically become shorter and less severe after several months of treatment, although achieving control may take time.

Allopurinol Tablets may also impact kidney function; therefore, patients should be instructed to increase fluid intake to at least 2 liters per day to prevent kidney stones. Additionally, there is a risk of hepatotoxicity, and patients should report any signs of liver failure, such as jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

Myelosuppression has been noted, and patients should be vigilant for signs of infection, fever, bleeding, shortness of breath, or significant fatigue. Reports of drowsiness, somnolence, and dizziness have also been associated with Allopurinol Tablets, with potential additive central nervous system depressant effects when combined with alcohol or other CNS depressants. Patients are advised to avoid operating automobiles or engaging in hazardous activities until they understand how the medication affects their alertness.

Furthermore, there are 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.

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 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 various package configurations, with specific NDC numbers available upon request. It is essential to store the product at a temperature range of 15° to 30°C (59° to 86°F) and to protect it from moisture to maintain its integrity and efficacy. Proper handling and storage conditions are crucial to ensure the product remains effective throughout its shelf life.

Additional Clinical Information

Clinicians should consider screening for the HLA-B*5801 allele in patients from populations with a high prevalence of this allele before initiating treatment with Allopurinol Tablets. Screening is not recommended for patients from populations with low prevalence or for current users of allopurinol.

Patient counseling is essential when prescribing Allopurinol Tablets. Patients should be instructed to discontinue the medication immediately and seek medical attention if a skin rash develops. 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 the formation of xanthine calculi and renal precipitation of urates, especially in those receiving concomitant uricosuric agents. Additionally, patients should be made aware that the central nervous system depressant effects of Allopurinol Tablets 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 their alertness.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Allopurinol as submitted by Dr. Reddy's Laboratories Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)