Allopurinol

Description

Allopurinol is known chemically as 1,5-Dihydro-4H-pyrazolo3,4-dpyrimidin-4-one, with a molecular weight of 136.11 g/mol. It exhibits a solubility in water at 37°C of 80.0 mg/dL, which increases in alkaline solutions. The drug is available in scored, white, round tablets containing either 100 mg or 300 mg of allopurinol, USP. Inactive ingredients in the formulation include 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. In 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.

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 daily.

For patients with renal impairment, healthcare professionals should refer to the full prescribing information for specific dosage modifications tailored to the degree of renal dysfunction.

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 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 to prevent potentially fatal outcomes.

During the initiation of allopurinol therapy, patients may experience gout flares. To mitigate this risk, concurrent prophylactic treatment with colchicine or other 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 tablets to avoid exacerbating renal issues.

Hepatotoxicity has been reported in some cases, with instances of reversible liver damage occurring during treatment. 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 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 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 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 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 adversely affect kidney function. Patients with decreased kidney function require careful monitoring and may need lower doses of allopurinol tablets. Additionally, cases of reversible hepatotoxicity have been reported; if patients exhibit signs and symptoms of hepatotoxicity, liver function should be evaluated promptly.

Myelosuppression, characterized by bone marrow suppression, has also 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 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 necessary management strategies.

Pharmacodynamic Interactions

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

• Bendamustine

• Thiazide Diuretics

• Ampicillin

• Amoxicillin

Pharmacokinetic Interactions

• Capecitabine: Concomitant use is contraindicated and should be avoided to prevent adverse effects.

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

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

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 results in 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 not require specific dosage adjustments based solely on age; however, caution is advised when prescribing to this population. It is important to consider that elderly patients often have reduced renal function, which may necessitate lower doses of allopurinol. For patients with impaired kidney function, the recommended initial dosage is 50 mg orally daily, with careful titration based on renal function.

Close monitoring of kidney function is essential in elderly patients, particularly during the early stages of treatment, to mitigate the risk of potential nephrotoxicity. Additionally, elderly patients may exhibit increased sensitivity to side effects, including a heightened risk of skin rash and hypersensitivity reactions.

Furthermore, it is important to recognize that elderly patients are more likely to be on multiple concurrent medications, which can increase the risk of drug interactions and adverse effects. Therefore, healthcare providers should exercise caution and conduct thorough medication reviews when treating geriatric patients.

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. 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 is unknown; however, 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 had 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 (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 (about 0.3 or 0.6 times the human dose on a mg/m² basis) of allopurinol 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

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 following 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 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 management of overdosage primarily involves supportive care and symptomatic treatment. Healthcare providers should monitor the patient closely for any adverse effects and provide appropriate interventions as necessary. It is advisable to assess renal function and consider the potential need for dialysis based on the clinical scenario and the patient's overall condition.

In summary, while both allopurinol and oxipurinol can be removed from the body through dialysis, the clinical benefits of such interventions in cases of overdose are not well established. Therefore, a careful evaluation of the patient's status and supportive management are critical in addressing allopurinol overdosage.

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 indicated that allopurinol tablets may increase the risk of serious and sometimes fatal dermatologic reactions. 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 consistent with hypersensitivity reactions.

Additionally, there is a risk of hepatotoxicity associated with allopurinol tablets, with reports of liver failure symptoms such as jaundice, pruritus, bleeding, bruising, and anorexia. Myelosuppression has also been reported, with associated signs and symptoms including infection, fever, bleeding, shortness of breath, and significant fatigue.

Furthermore, drowsiness, somnolence, and dizziness have been noted in patients taking allopurinol tablets, with central nervous system depressant effects potentially additive to those of alcohol and other CNS depressants.

Patient Counseling

Healthcare providers should advise patients to take allopurinol tablets after meals to minimize gastric irritation. In the event that a single dose 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 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.

Inform patients 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. Additionally, patients should be informed of the risk of hepatotoxicity and instructed to report any signs and symptoms of liver failure, such as jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

Patients should also be made aware of the risk of myelosuppression and 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 tablets. 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 tablets or increasing the dose, until they understand how the drug affects them.

Patients should be informed of the risks of adverse effects when allopurinol tablets are 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 tablets. Furthermore, women should be advised 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 for identification. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from moisture to ensure its integrity and efficacy. Proper handling and storage conditions must be maintained to preserve the quality of the product.

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)