Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1, 5-dihydro-4 H-pyrazolo 3, 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, with increased solubility in alkaline solutions. Allopurinol is administered orally.

The formulation includes scored white to off-white round tablets containing 100 mg of allopurinol, along with inactive ingredients such as crospovidone, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone. Additionally, scored peach round tablets are available, each containing 300 mg of allopurinol, with inactive ingredients including crospovidone, colloidal silicon dioxide, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone.

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, these tablets are 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 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 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 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 may adversely affect kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol tablets to prevent further renal compromise.

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. Monitoring of blood counts may be warranted 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.

In summary, healthcare professionals should remain vigilant regarding these warnings and take appropriate actions to monitor and manage potential adverse effects associated with allopurinol therapy.

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%.

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 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 affect kidney function. Patients with decreased kidney function require careful dose adjustments to avoid potential complications. Hepatotoxicity has been reported, with cases of reversible liver damage occurring; thus, it is important to evaluate liver function if signs and symptoms of hepatotoxicity develop. Additionally, myelosuppression has been noted, indicating a risk of bone marrow suppression in some patients.

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

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 mechanisms.

Pharmacodynamic Interactions

Certain medications may increase the risk of serious skin reactions when used concomitantly. These include:

• Bendamustine

• Thiazide diuretics

• Ampicillin

• Amoxicillin

Healthcare professionals should monitor patients closely for any signs of skin reactions when these drugs are used together.

Pharmacokinetic Interactions

• Capecitabine: Concomitant use is contraindicated. It is advised to avoid the use of capecitabine alongside this medication.

• Mercaptopurine or Azathioprine: It is recommended to reduce the dosage of mercaptopurine or azathioprine as specified in their respective prescribing information to mitigate potential interactions.

• Pegloticase: Patients should discontinue the use of allopurinol tablets and avoid initiating treatment with them while on pegloticase therapy.

For a comprehensive list of significant drug interactions, 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 may exhibit altered pharmacokinetics and pharmacodynamics, necessitating careful consideration when prescribing allopurinol. For patients aged 65 and older, particularly those with renal impairment, the initial dosage should be 50 mg orally daily. Subsequent dose increases should be made cautiously and only after monitoring serum uric acid levels to reach the target level, as elderly patients often present with decreased kidney function.

Frequent monitoring of kidney function is essential during the early stages of allopurinol administration, especially in those with chronic kidney disease, which is prevalent among geriatric patients. The dosage required to achieve control of gout may vary based on disease severity; therefore, it is advisable to initiate treatment with lower dosages in elderly patients and to titrate slowly. This approach helps mitigate the risk of gout flares and serious adverse reactions associated with the medication.

Elderly patients with diminished kidney function will require lower doses of allopurinol, underscoring the importance of individualized dosing in this population. Additionally, it is recommended that these patients maintain adequate fluid intake to prevent the formation of kidney stones and to remain vigilant for any signs of deteriorating kidney function.

Healthcare providers should also be aware of the potential for increased sensitivity to side effects in elderly patients, particularly concerning the risks of myelosuppression and hepatotoxicity. Furthermore, the use of allopurinol is contraindicated in patients with a history of hypersensitivity reactions, a condition that may be more common in older adults.

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. 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. 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. The background risk of major birth defects and miscarriage for the population indicated for allopurinol is currently unknown.

Experience with allopurinol tablets 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 normal 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

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

Allopurinol tablets and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore, changes in renal function significantly impact drug exposure. In patients with decreased renal function or those with concurrent illnesses that may affect renal function, it is essential to perform periodic laboratory assessments of renal parameters and reassess the dosage of allopurinol tablets accordingly. Additionally, patients with reduced kidney function require lower doses of allopurinol tablets to mitigate the risk of adverse effects on kidney function.

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 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 overdosage, 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 administered at 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

Patients using allopurinol tablets have been advised of several important considerations based on postmarketing experience. Serious and potentially fatal dermatologic reactions have been reported, necessitating immediate discontinuation of the medication and prompt medical attention at the first sign of skin rash, blisters, fever, painful urination, blood in urine, eye irritation, or swelling of the lips or mouth.

Gout flares may occur during the initiation of allopurinol therapy, even with normal serum uric acid levels. The concurrent use of medications such as colchicine or other anti-inflammatory agents is recommended to prevent these flares. Patients are encouraged to continue both allopurinol and any prophylactic therapy as prescribed, understanding that it may take several months to achieve control over the flares, which typically become shorter and less severe over time.

Allopurinol tablets may also impact kidney function; therefore, patients are advised to increase fluid intake to at least 2 liters per day to stay well-hydrated and prevent kidney stones. Additionally, there is a risk of hepatotoxicity associated with allopurinol, and patients should report any signs of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

Myelosuppression has been noted as a potential risk, and patients should be vigilant for signs of infection, fever, bleeding, shortness of breath, or significant fatigue, reporting these symptoms to their healthcare provider.

Drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol. The central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. Patients are advised to avoid operating vehicles or engaging in hazardous activities 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. Patients should disclose all medications they are taking and adhere to their physician's instructions.

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 a tight, light-resistant container as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), classified as USP Controlled Room Temperature. Additionally, it is essential to keep the product in a dry place and protect it from light to maintain its integrity and efficacy.

Additional Clinical Information

Patients should be counseled to take allopurinol tablets after meals to reduce gastric irritation. If a dose is missed, there is no need to double the next dose. It is important to inform patients about the potential for serious dermatologic reactions, advising them to discontinue the medication and seek immediate medical attention if they experience any signs of hypersensitivity, such as skin rash, blisters, or swelling.

During the initiation of allopurinol therapy, patients may experience gout flares, even with normal serum uric acid levels. The concurrent use of prophylactic medications like colchicine can help manage these flares. Patients should be encouraged to maintain hydration, consuming at least 2 liters of fluids daily, to mitigate the risk of kidney stones and monitor for signs of hepatotoxicity and myelosuppression. Additionally, patients should be made aware of possible central nervous system effects, including drowsiness and dizziness, and should avoid operating machinery until they understand how the medication affects them. They should also disclose all medications they are taking, as there are known interactions with several drugs. Pregnant women should be informed of potential risks to the fetus and advised against breastfeeding during treatment and for one week after the last dose.

FDA Insert (PDF)

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

View full prescribing information (PDF)