Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor, chemically designated as 1, 5-dihydro-4 H-pyrazolo 3, 4-dpyrimidin-4-one, with a molecular weight of 136.1 g/mol. The compound is soluble in potassium and sodium hydroxide solutions, very slightly soluble in water and alcohol, and practically insoluble in chloroform and ether. Allopurinol is administered orally.

The formulation includes two tablet strengths: each scored white round-shaped tablet contains 100 mg of allopurinol, along with inactive ingredients such as colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Each scored orange round-shaped tablet contains 300 mg of allopurinol, with the same inactive ingredients, in addition to FD&C Yellow No. 6 Lake.

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 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 per the guidelines 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 tailored to the patient's renal function.

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 for signs of myelosuppression is advised.

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.

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 encouraged 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 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 require immediate attention. Notably, skin rash and hypersensitivity reactions can occur, which may be serious and sometimes fatal. It is imperative to discontinue allopurinol tablets at the first appearance of a skin rash or any signs of hypersensitivity.

Gout flares may also 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 should receive lower doses of allopurinol tablets to minimize the risk of adverse effects. Additionally, cases of reversible hepatotoxicity have been reported; therefore, 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 also 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

The following drug interactions have been identified, categorized by their potential clinical effects and necessary management strategies.

Increased Risk of Serious Skin Reactions Concomitant use of the following agents may elevate the risk of serious skin reactions:

• Bendamustine

• Thiazide diuretics

• Ampicillin

• Amoxicillin

Pharmacokinetic Interactions

• Capecitabine: Concomitant use is contraindicated.

• Mercaptopurine or Azathioprine: It is recommended to reduce the dose of mercaptopurine or azathioprine as specified in the respective prescribing information.

• Pegloticase: Allopurinol tablets should be discontinued, and initiation of treatment with allopurinol should be avoided.

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 this medication. Clinical studies have indicated that patients aged 65 years and older may experience an increased risk of adverse reactions. Therefore, it is recommended that healthcare providers closely monitor these patients for any signs of intolerance or side effects.

Dosage adjustments may be necessary for geriatric patients, particularly those with renal impairment or other comorbid conditions that could affect drug metabolism and clearance. It is advisable to initiate treatment at the lower end of the dosing range and titrate cautiously based on the patient's response and tolerability.

In clinical trials, the safety and efficacy of this medication in geriatric patients were consistent with those observed in younger populations; however, the potential for increased sensitivity to the drug's effects in elderly patients should be taken into account. Regular assessment of renal function and other relevant health parameters is recommended to ensure optimal therapeutic outcomes while minimizing risks.

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 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 tablets 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. Additionally, there is no data on the potential for excretion of this medication in breast milk or its effects on breastfed infants. Healthcare professionals should consider the lack of information 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 allopurinol overdose remains uncertain.

Monitoring of the patient is essential, and supportive care should be provided as needed. Symptoms of overdosage may vary, and healthcare providers should remain vigilant for any signs of toxicity. Given the lack of a specific antidote, the focus should be on symptomatic treatment and supportive measures.

In cases of suspected overdose, it is advisable to consult a poison control center or a medical toxicologist for further guidance on management strategies tailored to the individual patient's needs.

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

Postmarketing experience has identified serious and sometimes fatal dermatologic reactions associated with allopurinol tablets. Reports include 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 consistent with hypersensitivity reactions.

Additionally, there have been reports of gout flares occurring during the initiation of treatment with allopurinol tablets, even in patients with normal serum uric acid levels. Cases of nephrotoxicity have been documented, indicating potential effects on kidney function. Instances of hepatotoxicity have also been reported, with signs and symptoms of liver failure such as jaundice, pruritus, bleeding, bruising, or anorexia.

Myelosuppression has been noted, with associated signs and symptoms including infection, fever, bleeding, shortness of breath, or significant fatigue. Furthermore, drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol tablets, with central nervous system depressant effects potentially additive to those of alcohol and other CNS depressants.

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.

Finally, inform patients 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.

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

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Allopurinol as submitted by Cardinal Health 107, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)