Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1,5-dihydro-4H-pyrazolo 3,4-d pyrimidin-4-one, with a molecular weight of 136.11 g/mol. The compound exhibits a solubility of 80.0 mg/dL in water at 37°C, with increased solubility in alkaline solutions. Allopurinol is administered orally and is available in tablet form, containing either 100 mg, 200 mg, or 300 mg of allopurinol, USP. The tablets include inactive ingredients such as croscarmellose sodium, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, povidone, and FD&C Yellow No. 6 aluminum Lake, which is present only in the 300 mg formulation.

Uses and Indications

Allopurinol tablet is indicated for the management of adult patients with signs and symptoms of primary or secondary gout, including acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy. It is also indicated for adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Additionally, Allopurinol is 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 lifestyle modifications.

Limitations of use: Allopurinol tablet is not recommended 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 per the guidelines for renal impairment until the target serum uric acid level is reached.

In the case 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 prescribing information for specific dosage modifications tailored to the patient's renal status.

Contraindications

Use of allopurinol is contraindicated in patients with known hypersensitivity to allopurinol or to any of its ingredients. This contraindication is essential to prevent severe allergic reactions that may occur in susceptible individuals.

Warnings and Precautions

Allopurinol has been associated with serious and potentially fatal dermatological reactions, including skin rash and hypersensitivity. It is imperative that allopurinol 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 treatment, patients may experience gout flares. To mitigate this risk, concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended.

Nephrotoxicity is a concern with allopurinol, as it may adversely affect kidney function. Therefore, patients with impaired renal function should receive lower doses of allopurinol to prevent further complications.

Hepatotoxicity has been reported in some cases, with instances of reversible liver damage. 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 by seriousness and frequency.

The most common adverse reactions observed in clinical trials 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 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 adversely affect kidney function. Patients with decreased kidney function require careful dose adjustments to avoid further complications. Additionally, cases of reversible hepatotoxicity have been reported; if patients exhibit signs and symptoms of hepatotoxicity, liver function should be evaluated promptly. Myelosuppression, or 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 effects and necessary precautions.

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

• Bendamustine

• Thiazide diuretics

• Ampicillin

• Amoxicillin

Capecitabine Concomitant use of capecitabine is contraindicated.

Mercaptopurine and Azathioprine When used together, it is recommended to reduce the dosage of mercaptopurine or azathioprine as specified in their respective prescribing information.

Pegloticase Allopurinol should be discontinued, and initiation of treatment with allopurinol is not advised during pegloticase therapy.

For a comprehensive list 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 for the management of pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing cancer therapy that leads to elevated serum and urinary uric acid levels have been established in approximately 200 pediatric patients. The efficacy and safety profile in this population were found to be similar to that observed in adults.

However, the safety and effectiveness of allopurinol have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Additionally, its use has not been validated for the management of recurrent calcium oxalate calculi in this demographic. Furthermore, allopurinol's safety and effectiveness have not been established in pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients may exhibit altered pharmacokinetics and pharmacodynamics, necessitating careful consideration when prescribing allopurinol. In 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 until the target serum uric acid level is achieved, as geriatric patients often have compromised renal function.

Close monitoring of kidney function is essential during the early stages of allopurinol administration in elderly patients. If persistent abnormalities in kidney function are observed, it may be necessary to decrease the dosage or discontinue the medication. The dosage of allopurinol must be adjusted based on renal function, which is frequently diminished in this population.

Elderly patients are at an increased risk for adverse reactions due to potential decreased renal function and heightened sensitivity to side effects. It is advisable to encourage adequate hydration in these patients to help prevent kidney stones and to monitor for signs of nephrotoxicity, such as changes in urine output or alterations in kidney function.

Furthermore, the use of allopurinol is not recommended in patients with severe renal impairment (eGFR <20 mL/min) without a thorough evaluation of the associated risks and benefits, particularly in the elderly population.

Pregnancy

Based on findings in animal studies, allopurinol may cause fetal harm when administered to pregnant patients. 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, healthcare professionals should 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 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 published in 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, 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 or its effects on lactation. Consequently, the potential for excretion in breast milk and the impact on breastfed infants remain undetermined. Healthcare professionals should exercise caution and consider the benefits and risks when prescribing this medication to lactating mothers.

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 to mitigate the risk of adverse effects. Monitoring of renal function is recommended in this patient 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 allopurinol overdosage, 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.

Management of an overdose should focus on supportive care and symptomatic treatment. Continuous monitoring of the patient’s clinical status is essential, and appropriate interventions should be implemented based on the symptoms presented. Given the lack of a specific antidote, healthcare providers should remain vigilant for any potential complications arising from the overdose and manage them accordingly.

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, with a mean duration of treatment of 40 months, nor in an in vitro assay with human lymphocytes.

Oral doses of allopurinol at 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 consistent with hypersensitivity reactions.

Additionally, there have been reports of gout flares occurring during the initiation of treatment with allopurinol, even in patients with normal serum uric acid levels. Cases of nephrotoxicity have also been documented, suggesting a potential impact on kidney function.

Hepatotoxicity has been reported, with manifestations of liver failure such as jaundice, pruritus, bleeding, bruising, or anorexia. Instances of myelosuppression have been noted, presenting with symptoms including infection, fever, bleeding, shortness of breath, or significant fatigue.

Furthermore, drowsiness, somnolence, and dizziness have been reported among patients taking allopurinol tablets, with the possibility of additive effects when used in conjunction with alcohol and other central nervous system depressants.

Patient Counseling

Patients should be advised to take allopurinol tablets after meals to minimize gastric irritation. In the event that a single dose is 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 if they experience any signs of a skin rash, blisters, fever, painful urination, blood in the urine, irritation of the eyes, swelling of the lips or mouth, or other symptoms indicative of hypersensitivity reactions.

Patients should also be made aware that gout flares may occur during the initiation of treatment with allopurinol, 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 these flares. Patients should be encouraged to continue taking both allopurinol 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 over the flares, but they typically become shorter and less severe with continued therapy.

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.

The risk of myelosuppression should also be communicated to patients, along with the importance of reporting 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 cautioned that the central nervous system depressant effects of allopurinol may be additive to those of alcohol and other CNS depressants. Therefore, patients should avoid operating automobiles or engaging in other activities that may be hazardous due to decreased alertness when starting allopurinol or increasing the dose, until they understand how the medication affects them.

Finally, patients should be informed of the potential for 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 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 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

Clinicians should consider screening for HLA-B*5801 before initiating treatment with allopurinol in patients from populations with a high prevalence of this allele. Screening is not generally recommended for patients from populations with low prevalence or for current allopurinol users.

Patient counseling is essential. Patients should be instructed to discontinue allopurinol immediately and seek medical attention if a rash develops. They should continue allopurinol and any prophylactic treatment even during gout flares, as it may take months to achieve effective control. It is important to maintain adequate fluid intake to ensure a urinary output of at least 2 liters per day, which helps prevent xanthine calculi formation and renal precipitation of urates, especially in those receiving concomitant uricosuric agents. Additionally, patients should be made aware that allopurinol may have additive central nervous system depressant effects when combined with alcohol or other CNS depressants, and they should avoid operating vehicles or engaging in hazardous activities until they understand how the medication affects them.

FDA Insert (PDF)

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

View full prescribing information (PDF)