Allopurinol

Description

Allopurinol is known chemically as 1, 5-Dihydro-4H-pyrazolo 3, 4-dpyrimidin-4-one, with a molecular weight of 136.11 g/mol. It exhibits a solubility in water of 80.0 mg/dL at 37°C, which increases in alkaline solutions. Allopurinol is available in two tablet forms: each scored white round tablet contains 100 mg of allopurinol, USP, along with inactive ingredients including corn starch, croscarmellose sodium, lactose, magnesium stearate, and povidone; each scored orange round tablet contains 300 mg of allopurinol, USP, with the same inactive ingredients as the white tablet, plus FD&C yellow #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, 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 the 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 desired 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 excipients present in 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. If 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 and symptoms of hepatotoxicity develop, it is crucial to evaluate liver function to ensure patient safety and appropriate management.

Healthcare professionals are advised to remain vigilant regarding these warnings and to educate patients on the importance of reporting any adverse reactions or symptoms promptly.

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%. These reactions are generally mild but should be monitored.

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 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.

Additionally, cases of reversible hepatotoxicity have been reported. If patients develop signs and symptoms indicative of hepatotoxicity, liver function should be evaluated promptly.

Myelosuppression has also been noted in patients taking allopurinol, indicating a risk of bone marrow suppression.

Patients should 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 the drug or any of its ingredients. Monitoring and appropriate management of these adverse reactions are essential for patient safety.

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 The use of allopurinol tablets is contraindicated with pegloticase. It is advised to discontinue allopurinol prior to initiating treatment with pegloticase to avoid serious complications.

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 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 safety and effectiveness of allopurinol tablets have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Additionally, allopurinol has not been proven safe or effective for managing recurrent calcium oxalate calculi in this population, nor has it been established for pediatric patients with rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may exhibit altered pharmacokinetics and pharmacodynamics, necessitating careful consideration when prescribing allopurinol. For patients with impaired kidney function, the initial dosage should be 50 mg orally daily, with subsequent dose increases made cautiously until the target serum uric acid level is achieved. It is essential to recognize that patients with decreased kidney function require lower doses of allopurinol tablets to mitigate the risk of adverse effects.

Frequent monitoring of kidney function is critical during the early stages of allopurinol administration, especially in geriatric patients with chronic kidney disease. Although the maximum dosage for patients with varying levels of renal impairment has not been defined based on estimated glomerular filtration rate (eGFR), it is advisable to initiate treatment with a lower dose in this population. Dose increments should be made gradually, typically in 50 mg/day increments every 2 to 4 weeks, to minimize the risk of serious drug-induced adverse reactions.

Additionally, it is recommended that elderly patients increase their fluid intake during therapy to help prevent the formation of kidney stones. The presence of the HLA-B *5801 allele, a genetic marker linked to an increased risk of allopurinol-related hypersensitivity syndrome, should be considered, and screening for this allele is advised in populations with a known high prevalence. Furthermore, caution is warranted when allopurinol is prescribed to patients with decreased kidney function who are concurrently receiving thiazide diuretics, as this combination may heighten the risk of hypersensitivity reactions.

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, healthcare professionals should advise pregnant women of the potential risks to the fetus.

It is important to note that 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 approximately 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. However, a published report indicated that in pregnant mice, single intraperitoneal doses of 50 mg/kg or 100 mg/kg 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 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 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 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 revealed 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 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 also been documented, indicating a potential impact on kidney function.

Hepatotoxicity has been reported, with signs and symptoms 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 in patients taking allopurinol tablets, with potential additive effects when combined with alcohol and other central nervous system 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, including jaundice, pruritus, bleeding, bruising, or anorexia, to their healthcare provider.

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 engaging in 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 to ensure its integrity and efficacy. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the quality of the product throughout its shelf life.

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 Sun Pharmaceutical Industries, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)