Allopurinol

Uses and Indications

Allopurinol tablets are 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.

• Adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer therapy that causes elevations of serum and urinary uric acid levels. Treatment with allopurinol should be discontinued when the potential for overproduction of uric acid is no longer present.

• 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 changes. Therapy in such patients should be carefully assessed initially and reassessed periodically to determine that treatment is beneficial and that the benefits outweigh the risks.

Limitations of Use

Allopurinol tablets are not recommended for the treatment of asymptomatic hyperuricemia.

Dosage and Administration

The recommended dosage of Allopurinol varies based on the condition being treated and the patient's renal function.

Gout:For patients with normal kidney function, the initial dosage is 100 mg orally daily. This dosage may be increased by 100 mg weekly increments until a serum uric acid level of 6 mg/dL or less is achieved, with a maximum dosage of 800 mg daily. For patients with impaired kidney function, the initial dosage is 50 mg orally daily, with titration based on renal function and serum uric acid levels.

Hyperuricemia Associated with Cancer Therapy:In adults, the dosage ranges from 300 mg to 800 mg orally daily. For pediatric patients, the recommended dosage is 100 mg/m² orally every 8 to 12 hours, with a maximum of 800 mg per day.

Recurrent Calcium Oxalate Calculi:The recommended initial dosage for patients with normal kidney function is between 200 mg to 300 mg orally daily.

Dosage in Patients with Renal Impairment:For patients with renal impairment, specific dosage modifications are necessary. Refer to the full prescribing information (FPI) for detailed recommendations based on the degree of renal impairment.

Administration Notes:Allopurinol is generally better tolerated when taken after meals. Adequate hydration is advised to maintain a daily urinary output of at least 2 liters and to help maintain a neutral or slightly alkaline urine.

Contraindications

Known hypersensitivity to allopurinol or to any of the ingredients of allopurinol tablets is a contraindication for use. Additionally, patients who have developed a severe reaction to allopurinol should not be restarted on the drug.

Warnings and Precautions

Allopurinol has been associated with serious and sometimes fatal dermatological reactions. Discontinue allopurinol tablets at the first appearance of skin rash or other signs of hypersensitivity reaction. In some instances, a skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome and/or generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death.

Gout Flares

Gout flares may occur during the initiation of treatment. Concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended.

Nephrotoxicity

Allopurinol may affect kidney function. Patients with decreased kidney function require lower doses of allopurinol tablets. Patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration. Renal failure in association with allopurinol administration has been observed among patients with hyperuricemia secondary to neoplastic diseases. Patients with impaired renal function should be carefully observed during the early stages of administration, and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

Hepatotoxicity

Cases of reversible hepatotoxicity have occurred. If signs and symptoms of hepatotoxicity develop, evaluate liver function. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy. If anorexia, weight loss, or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup.

Myelosuppression

Bone marrow suppression has been reported with allopurinol.

Potential Effect on Driving and Use of Machinery

Drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol tablets. Patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.

General Precautions

An increase in acute attacks of gout has been reported during the early stages of administration, even when normal or subnormal serum uric acid levels have been attained. Accordingly, maintenance doses of colchicine generally should be given prophylactically when allopurinol is begun.

Laboratory Tests

Evaluate liver function if signs and symptoms of hepatotoxicity develop. The correct dosage and schedule for maintaining the serum uric acid within the normal range is best determined by using the serum uric acid level as an index. In patients with decreased renal function or who have concurrent illnesses which can affect renal function, periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed and the patient’s dosage of allopurinol reassessed.

Stop Taking and Call Your Doctor

Discontinue allopurinol tablets at the first appearance of skin rash or other signs of hypersensitivity reaction.

Side Effects

Most common adverse reactions associated with allopurinol include:

• Nausea

• Diarrhea

• Increase in liver function tests (incidence > 1%)

Serious adverse reactions include:

• Skin Rash and Hypersensitivity: Allopurinol has been associated with serious and sometimes fatal dermatological reactions. It is crucial to discontinue allopurinol tablets at the first appearance of skin rash or other signs of hypersensitivity reaction.

• Gout Flares: Gout flares may occur during the initiation of treatment. Concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended to mitigate this risk.

• Nephrotoxicity: Allopurinol may affect kidney function. Patients with decreased kidney function require lower doses of allopurinol tablets to avoid potential complications.

• Hepatotoxicity: Cases of reversible hepatotoxicity have been reported. If signs and symptoms of hepatotoxicity develop, liver function should be evaluated promptly.

• Myelosuppression: Bone marrow suppression has been reported in patients taking allopurinol.

• Potential Effect on Driving and Use of Machinery: Drowsiness, somnolence, and dizziness have been reported in patients taking allopurinol tablets, which may impair the ability to drive or operate machinery safely.

Additional adverse reactions or important notes include:

• Known hypersensitivity to allopurinol or to any of the ingredients of allopurinol tablets should be considered before initiating treatment.

• Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome or drug hypersensitivity syndrome (DHS) has been reported in association with allopurinol use. This syndrome can be life-threatening and may present with fever, severe skin rash, elevated leukocyte counts, and multi-organ involvement. Symptoms may develop approximately one week after initiating therapy, but longer latency periods have also been observed.

Drug Interactions

The concomitant use of allopurinol with certain medications may lead to significant interactions, particularly concerning the risk of serious skin reactions and the need for dosage adjustments.

Pharmacodynamic Interactions

• Skin Reactions: The following drugs have been associated with an increased risk of serious skin reactions when used with allopurinol: bendamustine, thiazide diuretics, ampicillin, and amoxicillin.

• Capecitabine: It is advised to avoid the concomitant use of capecitabine with allopurinol due to potential adverse effects.

• Mercaptopurine and Azathioprine: When allopurinol is administered to patients receiving mercaptopurine or azathioprine, the dose of these medications should be reduced to approximately one-third to one-fourth of the usual dose, as per the respective prescribing information.

Pharmacokinetic Interactions

• Dicumarol: Allopurinol prolongs the half-life of dicumarol, an anticoagulant. Although the clinical significance of this interaction is not fully established, caution is warranted when administering allopurinol to patients already on dicumarol therapy.

• Uricosuric Agents: The use of uricosuric agents alongside allopurinol may decrease the excretion of oxypurines (hypoxanthine and xanthine) and increase urinary uric acid excretion compared to allopurinol alone.

• Thiazide Diuretics: The combination of allopurinol and thiazide diuretics may enhance allopurinol toxicity. Renal function should be monitored in patients receiving both treatments, and dosage adjustments should be made if renal impairment is detected.

• Chlorpropamide: Allopurinol may prolong the plasma half-life of chlorpropamide, increasing the risk of hypoglycemia, particularly in patients with renal insufficiency.

• Cyclosporine: There are rare reports indicating that cyclosporine levels may be increased when used concurrently with allopurinol. Monitoring of cyclosporine levels and potential dosage adjustments should be considered.

Monitoring Recommendations

• Patients receiving allopurinol in combination with thiazide diuretics should have their renal function closely monitored, and dosage levels should be conservatively adjusted if diminished renal function is detected.

• For those on mercaptopurine or azathioprine, careful monitoring of therapeutic response and potential toxic effects is essential following dosage adjustments.

For a complete list of significant drug interactions, refer to the full prescribing information.

Pediatric Use

The safety and effectiveness of allopurinol for the management of pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer therapy that causes elevations of serum and urinary uric acid levels have been established in approximately 200 pediatric patients. The efficacy and safety profile observed in this patient population were similar to that observed in adults.

However, the safety and effectiveness of allopurinol have not been established for the following indications in pediatric patients:

• Treatment of signs and symptoms of primary or secondary gout.

• Management of recurrent calcium oxalate calculi.

• Treatment of rare inborn errors of purine metabolism.

Allopurinol is rarely indicated for use in children, except for those with hyperuricemia secondary to malignancy or certain rare inborn errors of purine metabolism.

Geriatric Use

Elderly patients may have reduced renal function, necessitating careful dosage adjustments and monitoring when prescribing allopurinol. The initial recommended dosage for patients with impaired kidney function is 50 mg orally daily, with gradual increases based on renal function and serum uric acid levels. It is crucial to monitor kidney function closely during the early stages of treatment, particularly in elderly patients with chronic kidney disease, to prevent nephrotoxicity and acute kidney injury.

Elderly patients may exhibit increased sensitivity to side effects, including drowsiness, somnolence, dizziness, and the risk of serious dermatologic reactions such as hypersensitivity. The presence of comorbid conditions and polypharmacy in this population may further heighten the risk of adverse effects and drug interactions, particularly with thiazide diuretics, which can increase the likelihood of skin reactions when used concurrently with allopurinol.

To mitigate the risk of kidney stones, it is advised that elderly patients maintain adequate hydration, aiming for a urinary output of at least 2 liters per day. Additionally, screening for the HLA-B*58:01 allele is recommended in populations with a known high prevalence, as carriers are at a higher risk for severe hypersensitivity reactions associated with allopurinol. Overall, a cautious approach to dosing and vigilant monitoring is essential for the safe use of allopurinol in geriatric patients.

Pregnancy

Based on findings in animals, allopurinol may cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been described in exposed animals, and 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 allopurinol exposure. It is advised that pregnant women be informed of the potential risk to the fetus.

All pregnancies have 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. 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, partly because 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 who had recurrent kidney stones since age 18 and took allopurinol throughout the pregnancy. The child had multiple complex birth defects and died at 8 days of life. A second 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.

There was no evidence of fetotoxicity or teratogenicity in rats or rabbits treated during the period of organogenesis with oral allopurinol at doses up to 200 mg/kg/day and up to 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) on gestation days 10 or 13 produced significant increases in fetal deaths and teratogenic effects, including cleft palate, harelip, and digital defects. It remains uncertain whether these findings represented a fetal effect or an effect secondary to maternal toxicity.

Due to the potential risks, allopurinol should be used during pregnancy only if clearly needed.

Lactation

Allopurinol and its active metabolite, oxypurinol, are excreted in human milk. A 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 approximately 0.14 mg/kg for allopurinol and between 7.2 mg/kg to 8 mg/kg for oxypurinol daily.

Despite the presence of these substances in breast milk, there have been no reported adverse effects on breastfed infants or on milk production. However, due to the potential for serious adverse reactions in breastfed children, it is recommended that lactating mothers refrain from breastfeeding during treatment with allopurinol and for at least one week after the last dose. Caution should be exercised when considering the use of allopurinol in nursing women, as the effects on nursing infants remain unknown.

Renal Impairment

Patients with renal impairment require careful consideration when prescribed allopurinol, as both the drug and its primary active metabolite, oxipurinol, are eliminated by the kidneys. Consequently, alterations in renal function can significantly impact drug exposure.

For patients with decreased kidney function, it is essential to administer lower doses of allopurinol tablets to mitigate the risk of nephrotoxicity. Regular monitoring of renal function through laboratory parameters is recommended, particularly for those with concurrent illnesses that may further affect renal performance. Dosing adjustments should be made based on these assessments to ensure patient safety and therapeutic efficacy.

Additionally, the risk of hypersensitivity reactions may be heightened in patients with reduced renal function, especially when allopurinol is used concurrently with thiazide diuretics. In such cases, these combinations should be approached with caution, and patients should be closely observed for any adverse reactions.

Hepatic Impairment

In patients with hepatic impairment, allopurinol has been associated with cases of reversible hepatotoxicity. If signs and symptoms of hepatotoxicity develop, it is essential to evaluate liver function.

A few cases of reversible clinical hepatotoxicity have been noted, with some patients experiencing asymptomatic rises in serum alkaline phosphatase or serum transaminase levels. In patients presenting with anorexia, weight loss, or pruritus while on allopurinol, liver function evaluation should be included in their diagnostic workup.

For patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy to monitor for potential hepatotoxic effects.

Overdosage

In the event of an overdose of allopurinol, there is no specific antidote available for treatment. Both allopurinol and its active metabolite, oxipurinol, are dialyzable; however, the effectiveness of hemodialysis or peritoneal dialysis in managing an overdose of allopurinol remains uncertain.

Massive overdosing or acute poisoning with allopurinol has not been reported in clinical settings. Animal studies indicate that the 50% lethal dose (LD50) for allopurinol is approximately 160 mg/kg when administered intraperitoneally in mice, with deaths potentially delayed up to five days. When given orally, the LD50 is around 700 mg/kg, which is approximately 140 times the usual human dose, with delayed fatalities up to three days. In rats, the acute LD50 is reported as 750 mg/kg intraperitoneally and 6000 mg/kg orally, equating to about 1200 times the human dose.

Due to the lack of clinical experience with patients who have ingested massive amounts of allopurinol, monitoring and supportive care are essential. Healthcare providers should be prepared to manage symptoms as they arise and consider the potential need for dialysis, despite the unknown efficacy in this context.

Nonclinical Toxicology

Teratogenic Effects

No information is provided regarding teratogenic effects associated with allopurinol.

Non-Teratogenic Effects

No information is provided regarding non-teratogenic effects associated with allopurinol.

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 approximately 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 (mean duration of treatment 40 months) or 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.

Storage and Handling

Allopurinol is supplied in tablet form.

Tablets should be stored at 20°C to 25°C (68°F to 77°F), which is consistent with USP Controlled Room Temperature, in a dry place. It is essential to protect the tablets from moisture and light.

Dispensing should occur in a tight, light-resistant container as defined in the USP, and in some cases, a child-resistant closure is recommended to ensure safety.