Allopurinol

Description

Allopurinol is a xanthine oxidase inhibitor, chemically designated as 1,5-dihydro-4H-pyrazolo3,4-dpyrimidin-4-one, with a molecular weight of 136.11 g/mol. It exhibits a solubility of 80.0 mg/dL in water at 37°C, which increases in alkaline solutions. Allopurinol is administered orally.

The formulation includes scored tablets in three strengths: each white to off-white round tablet contains 100 mg or 200 mg of allopurinol, with inactive ingredients comprising crospovidone, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone. Additionally, each scored peach round tablet contains 300 mg of allopurinol, along with crospovidone, colloidal silicon dioxide, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone.

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 changes.

Allopurinol tablets are 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 an oral dosage of 100 mg 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 reduced to 50 mg orally daily, with titration recommendations provided in the prescribing information to reach the desired serum uric acid level.

For hyperuricemia associated with cancer therapy, adults may be prescribed an oral dosage ranging from 300 mg to 800 mg 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 and 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 excipients present in 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 and potentially fatal 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 (5.1).

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 (5.2).

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 (5.3).

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 (5.4).

Additionally, myelosuppression has been documented in patients receiving allopurinol, necessitating careful monitoring of blood counts (5.5).

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 (5.6).

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.

Hepatotoxicity has also been reported, with cases of reversible liver damage occurring in some patients. If signs and symptoms of hepatotoxicity develop, it is essential to evaluate liver function promptly.

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

Patients should also be aware of the potential effects 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 the ingredients in allopurinol tablets. 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 mechanisms.

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.

• Mercaptopurine and Azathioprine: It is recommended to reduce the dosage of mercaptopurine or azathioprine as specified in their 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, 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 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 careful consideration when initiating treatment with allopurinol. For elderly patients with normal kidney function, the recommended initial dosage is 100 mg orally daily, with weekly increments of 100 mg until a target serum uric acid level of 6 mg/dL or less is achieved, not exceeding a maximum dosage of 800 mg daily.

In contrast, for elderly patients with impaired kidney function, the initial dosage should be reduced to 50 mg orally daily, with titration based on renal function until the desired serum uric acid level is reached. It is essential to monitor kidney function closely in this population, particularly in those with chronic kidney disease, during the early stages of allopurinol administration. Should persistent abnormalities in kidney function occur, it is advisable to decrease the dosage or withdraw the medication.

Elderly patients may exhibit increased sensitivity to side effects associated with allopurinol, which underscores the necessity for careful monitoring and potential dosage adjustments. The use of allopurinol in geriatric patients should be approached with caution, especially in those with renal impairment or those concurrently taking medications that may adversely affect kidney function.

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 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

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 after the last dose.

Renal Impairment

Allopurinol tablets and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore, changes in renal function significantly impact drug exposure. In patients with decreased renal function or those with concurrent illnesses that may affect renal function, it is essential to perform periodic laboratory assessments of renal parameters and reassess the dosage of allopurinol tablets accordingly. Additionally, patients with reduced kidney function require lower doses of allopurinol tablets to mitigate the risk of adverse effects on kidney function.

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 primary focus should be on supportive care and symptomatic management. Healthcare providers are advised to monitor the patient closely for any adverse effects and to provide appropriate interventions as necessary. It is essential 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 there is no antidote for allopurinol overdose, the potential for dialysis should be evaluated, keeping in mind the limited evidence regarding its effectiveness in this context.

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 identified several important safety considerations associated with the use of allopurinol tablets. Reports indicate an increased risk of serious and potentially fatal dermatologic reactions. Patients are advised to discontinue allopurinol tablets and seek immediate medical attention 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 symptoms indicative of hypersensitivity reactions.

Additionally, it has been noted that gout flares may occur during the initiation of treatment with allopurinol tablets, even when serum uric acid levels are normal. Patients are encouraged to continue both allopurinol tablets and any prescribed prophylactic therapy, despite the occurrence of gout flares. It is important to reassure patients that while it may take several months to achieve control of these flares, they typically become shorter and less severe over time.

There is also a risk of impaired kidney function associated with allopurinol tablets. Patients are advised to increase their fluid intake to at least 2 liters per day to stay well-hydrated and help prevent kidney stones. Furthermore, hepatotoxicity has been reported, and patients should be vigilant for signs of liver failure, including jaundice, pruritus, bleeding, bruising, or anorexia, and report these to their healthcare provider.

Myelosuppression is another potential risk, with patients advised to report any signs of infection, fever, bleeding, shortness of breath, or significant fatigue. Reports have also indicated that drowsiness, somnolence, and dizziness may occur in patients taking allopurinol tablets.

Finally, there are known risks of adverse effects when allopurinol tablets are used in conjunction with certain medications, including dicumarol, warfarin, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, pegloticase, theophylline, and thiazide diuretics.

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.

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 as defined by the United States Pharmacopeia (USP). It should be stored at a temperature range of 20° to 25°C (68° to 77°F), classified as USP Controlled Room Temperature. Additionally, it is essential to keep the product in a dry place and protect it from light to maintain its integrity and efficacy.

Additional Clinical Information

Patients should be counseled to take allopurinol tablets after meals to reduce gastric irritation. If a dose is missed, there is no need to double the next dose. It is important to inform patients about the potential for serious dermatologic reactions, advising them to discontinue the medication and seek immediate medical attention if they experience any signs of hypersensitivity, such as skin rash, blisters, or fever. Gout flares may occur during the initiation of treatment, even with normal serum uric acid levels; therefore, concurrent use of prophylactic medications like colchicine is recommended. Patients should be reassured that while it may take months to control flares, they typically become shorter and less severe over time.

Clinicians should advise patients to maintain adequate hydration to prevent kidney stones, as allopurinol can affect kidney function. Patients should also be informed of the risks of hepatotoxicity and myelosuppression, prompting them to report any concerning symptoms such as jaundice or signs of infection. Drowsiness and dizziness have been reported, so patients should be cautioned against operating heavy machinery until they understand how the medication affects them. Additionally, patients should disclose all medications they are taking, as there are known interactions with drugs such as warfarin and thiazide diuretics. Pregnant women should be made aware of potential risks to the fetus and are advised to notify their healthcare provider if they become pregnant. Breastfeeding is not recommended during treatment and for one week after the last dose.

FDA Insert (PDF)

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

View full prescribing information (PDF)