Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1,5-Dihydro-4H-pyrazolo3,4-dpyrimidin-4-one, with a molecular weight of 136.11 g/mol. It exhibits a solubility of 80.0 mg/dL in water at 37°C, which increases in alkaline solutions. Allopurinol is administered orally and is available in scored, white, round tablets containing either 100 mg or 300 mg of allopurinol, USP. The formulation includes inactive ingredients such as colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium lauryl sulfate, and sodium starch glycolate (potato).

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 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 administered orally every 8 to 12 hours, with a maximum daily limit of 800 mg or 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 (FPI) for specific dosage modifications and recommendations tailored to this patient 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 potential allergic reactions that could lead to serious adverse effects.

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

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 patient'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 advised to remain vigilant regarding these warnings and to educate patients on the importance of reporting any adverse reactions promptly.

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 imperative to discontinue allopurinol tablets at the first appearance of a skin rash or any other signs of hypersensitivity.

Gout flares may occur during the initiation of treatment with allopurinol. To mitigate this risk, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended.

Nephrotoxicity is another serious concern, as allopurinol may affect kidney function. Patients with decreased kidney function require lower doses of allopurinol tablets to avoid potential complications.

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

Additionally, myelosuppression has been noted in patients taking allopurinol, indicating a risk of bone marrow suppression.

Patients should also be aware of the potential effects on driving and the use of machinery, as drowsiness, somnolence, and dizziness have been reported.

Lastly, allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or any of the ingredients in allopurinol tablets. Monitoring for these adverse reactions is crucial to ensure patient safety and effective management of treatment.

Drug Interactions

The concomitant use of certain medications may increase the risk of serious skin reactions. Specifically, the following drugs have been identified: bendamustine, thiazide diuretics, ampicillin, and amoxicillin. Caution is advised when these agents are used together.

Capecitabine should be avoided in combination with this medication due to potential adverse effects.

For patients receiving mercaptopurine or azathioprine, it is recommended to reduce the dosage of mercaptopurine or azathioprine as outlined in the 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 tablets, as this combination may lead to significant complications.

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 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 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, defined as those aged 65 and older, may require careful consideration when prescribed allopurinol for the management of gout. The initial recommended dosage for these patients with normal kidney function is 100 mg orally daily, with the possibility of increasing the dose by 100 mg weekly until a target serum uric acid level of 6 mg/dL or less is achieved, not exceeding a maximum of 800 mg daily.

For elderly patients with impaired kidney function, a lower initial dosage of 50 mg orally daily is advised, with more cautious increments to reach the desired serum uric acid level. It is essential to note that allopurinol tablets should be administered at reduced doses in patients exhibiting decreased kidney function.

Frequent monitoring of kidney function is crucial during the early stages of allopurinol therapy, particularly in geriatric patients. If persistent abnormalities in kidney function are observed, it may be necessary to decrease the dosage or discontinue the medication altogether.

Elderly patients should also be advised to maintain adequate fluid intake to ensure a urinary output of at least 2 liters per day. This practice is important to prevent the formation of kidney stones and to mitigate the risk of potential nephrotoxicity associated with allopurinol.

Additionally, it is important to inform elderly patients about the potential side effects of allopurinol, including drowsiness, somnolence, and dizziness. These effects may impair their ability to drive or operate machinery safely.

Finally, the use of allopurinol is contraindicated in patients with a history of hypersensitivity reactions to the drug or its components, a consideration that is particularly relevant for elderly patients who may have multiple comorbidities.

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, 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 indicate 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. 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 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 during human pregnancy has been 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 for varying durations during the first trimester. The overall rate of major fetal malformations and spontaneous abortions was reported to be within the expected normal 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

Allopurinol and its active metabolite, oxypurinol, are excreted in human milk. A single case report indicated that a lactating mother receiving 300 mg of allopurinol daily at 5 weeks postpartum had detectable levels of both compounds in her breast milk. 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 after 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 dosage adjustments or treatment modifications may be necessary to ensure patient safety and therapeutic efficacy.

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 allopurinol 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 overdose, healthcare providers may consider the potential role of dialysis, although the clinical benefits in this context have not been 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 provided 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 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 gout flares. Patients should be advised to continue treatment with both allopurinol tablets and any prophylactic therapy as prescribed, even if gout flares occur. It is essential 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 must 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 instructed 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 that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, the product must be protected from moisture to ensure its integrity and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Allopurinol as submitted by REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)