Allopurinol

Description

Allopurinol, USP is a xanthine oxidase inhibitor. It is chemically identified as 1, 5-dihydro-4H-pyrazolo 3, 4-dpyrimidin-4-one, with a molecular weight of 136.1 g/mol. Allopurinol exhibits solubility in solutions of potassium and sodium hydroxides, is very slightly soluble in water and alcohol, and is practically insoluble in chloroform and ether.

The formulation includes scored white round-shaped tablets, each containing 100 mg of allopurinol, along with inactive ingredients such as colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Additionally, there are scored orange round-shaped tablets that contain 300 mg of allopurinol, with inactive ingredients including colloidal silicon dioxide, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

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 male patients and 750 mg/day in female patients, despite implementation of lifestyle changes.

Limitations of use include the recommendation against the use of allopurinol tablets for the treatment of asymptomatic hyperuricemia. There are no teratogenic or nonteratogenic effects associated with this medication.

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, not exceeding a maximum of 800 mg per day (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 (FPI) 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 immediately at the first appearance of a skin rash or any other signs indicative of a hypersensitivity reaction.

During the initiation of allopurinol therapy, patients may experience gout flares. To mitigate this risk, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended.

Nephrotoxicity is a potential concern with allopurinol, as it may adversely affect kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol tablets to avoid exacerbating their condition.

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 should also be advised of the potential effects of allopurinol on their ability to drive or operate machinery. Reports of drowsiness, somnolence, and dizziness have been noted, and caution is advised when engaging in such activities.

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 lower doses of allopurinol tablets 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.

Lastly, 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.

Skin Reactions Concomitant use of the following agents may increase the risk of serious skin reactions:

• Bendamustine

• Thiazide diuretics

• Ampicillin

• Amoxicillin

Antimetabolite Interactions For patients receiving mercaptopurine or azathioprine, it is recommended to reduce the dose of mercaptopurine or azathioprine as specified in the respective prescribing information to mitigate potential adverse effects.

Allopurinol Interaction Patients should discontinue the use of allopurinol tablets and avoid initiating treatment with pegloticase, as this combination may lead to significant adverse reactions.

For a comprehensive list of significant drug interactions, refer to the full prescribing information (FPI). No additional drug interactions or laboratory test interactions have been reported.

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.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may require special consideration when prescribed allopurinol, especially in the context of renal impairment. For these patients, the initial dosage should be set at 50 mg orally daily, with careful and gradual increases to achieve the target serum uric acid level. It is recommended to increase the dose in increments of 50 mg per day every 2 to 4 weeks. This cautious approach is essential to minimize the risk of serious adverse reactions associated with the medication.

Close monitoring of kidney function is critical for geriatric patients with chronic kidney disease who are initiating treatment with allopurinol. If there are any signs of increased abnormalities in kidney function, the dosage should be decreased or the medication withdrawn entirely. It is important to note that patients with decreased kidney function will require lower doses of allopurinol, although the maximum dosage for various levels of renal impairment has not been clearly defined based on estimated glomerular filtration rate (eGFR).

Additionally, elderly patients may be at an increased risk for hypersensitivity reactions when allopurinol is used concurrently with thiazide diuretics. Therefore, healthcare providers should exercise caution and monitor for any adverse effects in this population.

Patients taking allopurinol may experience drowsiness, somnolence, and dizziness. It is advisable to counsel elderly patients to avoid operating automobiles or engaging in other potentially hazardous activities until they are aware of how the medication affects them.

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 a full-term pregnancy in a 35-year-old woman with recurrent kidney stones who took allopurinol throughout her pregnancy; the child had 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 (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, which can affect kidney function. It is recommended that patients with decreased kidney function receive lower doses of allopurinol tablets to mitigate the risk of adverse effects. Careful monitoring of renal function is advised in this population 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 treatment of allopurinol overdose remains uncertain.

Given the lack of a specific antidote, management of an overdose should focus on supportive care and symptomatic treatment. Monitoring of renal function and electrolytes is recommended, as well as providing appropriate interventions based on the clinical presentation of the patient.

Healthcare providers are advised to remain vigilant for potential symptoms associated with allopurinol overdosage, although specific symptoms were not detailed in the provided information. Prompt recognition and management of any adverse effects are crucial in mitigating the risks associated with overdose.

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

Adverse reactions associated with the use of allopurinol tablets have been identified through literature, unpublished clinical trials, and postmarketing reports. Due to the voluntary nature of these reports from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequently reported adverse reaction is skin rash.

Serious dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been documented in patients taking allopurinol. These reactions occur in approximately 5 in 10,000 (0.05%) patients. Other serious hypersensitivity reactions reported include exfoliative, urticarial, and purpuric lesions, generalized vasculitis, and irreversible hepatotoxicity. It is recommended to discontinue allopurinol tablets permanently at the first appearance of a skin rash or other signs indicative of a hypersensitivity reaction.

Gout flares have been reported during the initiation of treatment with allopurinol tablets, even when normal or subnormal serum uric acid levels have been achieved, due to the mobilization of urates from tissue deposits. Despite adequate therapy, it may take several months to sufficiently deplete the uric acid pool to control the flares, which typically become shorter and less severe over time.

Treatment with allopurinol tablets may lead to acute kidney injury, potentially due to the formation of xanthine calculi or precipitation of urates in patients receiving concomitant uricosuric agents. Patients with pre-existing kidney disease, including chronic kidney disease or a history of kidney stones, may be at increased risk for worsening kidney function or acute kidney injury.

Reversible clinical hepatotoxicity has been reported in patients taking allopurinol tablets, with some experiencing asymptomatic rises in serum alkaline phosphatase or serum transaminase levels. If symptoms such as anorexia, weight loss, or pruritus develop, liver enzymes should be evaluated. In patients with pre-existing liver disease, periodic monitoring of liver enzymes is advised, and allopurinol tablets should be discontinued in cases of elevated liver enzymes.

Myelosuppression, characterized by anemia, leukopenia, or thrombocytopenia, has been observed in patients receiving allopurinol tablets. These cytopenias may occur as early as 6 weeks to 6 years after initiating therapy. The concomitant use of allopurinol tablets with cytotoxic drugs associated with myelosuppression may increase the risk of these effects, necessitating more frequent monitoring of blood counts.

Drowsiness, somnolence, and dizziness have also 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.

Patient Counseling

Healthcare providers should assess baseline tests prior to initiating treatment with allopurinol tablets in patients with gout. These tests should include serum uric acid level, complete blood count, chemistry panel, liver function tests (including serum alanine aminotransferase ALT, aspartate aminotransferase AST, alkaline phosphatase, and total bilirubin), as well as kidney function tests (serum creatinine and estimated glomerular filtration rate eGFR).

Patients should be informed that gout flares may occur after the initiation of allopurinol tablets due to changes in serum uric acid levels, which can lead to the mobilization of urate from tissue deposits. It is recommended that flare prophylaxis with colchicine or an anti-inflammatory agent be initiated according to practice guidelines upon starting allopurinol tablets. While adjusting the dosage of allopurinol tablets in patients receiving colchicine and/or anti-inflammatory agents, it is important to continue flare prophylaxis until serum uric acid levels have normalized and the patient has been free of gout flares for several months. If a gout flare occurs during treatment with allopurinol tablets, the medication should not be discontinued; instead, the flare should be managed appropriately for the individual patient.

Patients should be advised of the possibility of gout flares and instructed to remain on allopurinol tablets if such flares occur. They should also be encouraged to increase fluid intake during therapy to help prevent kidney stones.

Instruct patients to discontinue allopurinol tablets immediately if they develop a skin rash. They should seek medical attention promptly if a rash occurs.

Additionally, healthcare providers should advise patients 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.

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

Prior to initiating treatment with allopurinol tablets in patients with gout, clinicians should assess baseline laboratory tests, including serum uric acid levels, complete blood count, chemistry panel, liver function tests (serum alanine aminotransferase ALT, aspartate aminotransferase AST, alkaline phosphatase, and total bilirubin), as well as kidney function tests (serum creatinine and estimated glomerular filtration rate eGFR).

Patients should be informed about the potential for gout flares and advised to continue taking allopurinol tablets if such flares occur. It is also recommended that patients increase their fluid intake during therapy to help prevent kidney stones. Additionally, patients should be cautioned against operating automobiles or engaging in hazardous activities that require alertness when starting allopurinol tablets or adjusting the dose, until they are aware of how the medication affects them.

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)