Allopurinol

Description

Allopurinol is chemically defined as 1,5-dihydro-4H-pyrazolo3,4-dpyrimidin-4-one, with a structural formula that supports its function as a xanthine oxidase inhibitor. This medication is administered orally and is available in two tablet formulations. Each scored white to off-white tablet contains 100 mg of allopurinol, along with inactive ingredients including corn starch, lactose monohydrate, magnesium stearate, povidone, and purified water. The scored peach tablet formulation contains 300 mg of allopurinol, with the same inactive ingredients, except for the addition of FD&C Yellow No. 6 Aluminum Lake as a colorant. Allopurinol exhibits a solubility of 80.0 mg/dL in water at 37°C, with increased solubility in alkaline solutions.

Uses and Indications

Allopurinol tablets are indicated for the reduction of serum and urinary uric acid concentrations. This medication is specifically indicated for:

1. The management of patients exhibiting signs and symptoms of primary or secondary gout, including acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy.

2. The management of patients with leukemia, lymphoma, and other malignancies undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Treatment with allopurinol tablets should be discontinued when the risk of overproduction of uric acid is no longer present.

3. The management of 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. In these cases, therapy should be carefully assessed initially and periodically reassessed to ensure that the benefits of treatment outweigh the associated risks.

No specific teratogenic or nonteratogenic effects have been identified for allopurinol.

Dosage and Administration

The dosage of allopurinol tablets is determined by the severity of the condition being treated. For mild gout, the average dosage is 200 to 300 mg per day. In cases of moderately severe tophaceous gout, the average dosage increases to 400 to 600 mg per day. The minimal effective dosage is 100 to 200 mg daily, while the maximal recommended dosage should not exceed 800 mg daily.

Dosage may be administered either in divided doses or as a single equivalent dose using the 300-mg tablet. For patients requiring dosages greater than 300 mg, it is recommended that these be given in divided doses. To minimize the risk of acute gouty flare-ups, treatment should commence with a low dose of allopurinol (100 mg daily), which can be increased by 100 mg at weekly intervals until a target serum uric acid level of 6 mg/dL or lower is achieved, without surpassing the maximal recommended dosage. Normal serum urate levels are typically reached within 1 to 3 weeks.

In patients with renal impairment, dosage adjustments are necessary. For those with a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg is appropriate. For patients with a creatinine clearance of less than 10 mL/min, the daily dosage should not exceed 100 mg. In cases of extreme renal impairment (creatinine clearance less than 3 mL/min), the interval between doses may need to be extended.

For the prevention of uric acid nephropathy during intensive therapy for neoplastic disease, a dosage of 600 to 800 mg daily for 2 to 3 days is recommended, accompanied by increased fluid intake. In managing recurrent calcium oxalate stones in hyperuricosuric patients, the recommended dosage is 200 to 300 mg per day, which can be given in divided doses or as a single equivalent dose, and should be adjusted based on 24-hour urinary urate determinations.

For pediatric patients, those aged 6 to 10 years with secondary hyperuricemia related to malignancies may receive 300 mg daily, while children under 6 years may be administered 150 mg daily. The response to treatment should be evaluated approximately 48 hours after initiation for potential dosage adjustments.

Contraindications

Patients who have experienced a severe reaction to allopurinol tablets should not be reinitiated on the medication.

Warnings and Precautions

Allopurinol tablets should be discontinued at the first appearance of a skin rash or any other signs indicative of an allergic reaction. Such reactions may escalate to more severe hypersensitivity events, including exfoliative dermatitis, urticarial lesions, purpura, Stevens-Johnson syndrome (erythema multiforme exudativum), generalized vasculitis, irreversible hepatotoxicity, and, in rare cases, death.

Reversible clinical hepatotoxicity has been observed in some patients taking allopurinol tablets, with asymptomatic elevations in serum alkaline phosphatase or serum transaminases noted. If patients experience anorexia, weight loss, or pruritus, a thorough evaluation of liver function should be included in their diagnostic workup. For patients with pre-existing liver disease, it is advisable to conduct periodic liver function tests during the initial stages of therapy.

Due to the potential for drowsiness, patients should be cautioned to take necessary precautions when engaging in activities that require full alertness. The risk of hypersensitivity reactions may be heightened in patients with decreased renal function who are concurrently receiving thiazides and allopurinol tablets. Therefore, such combinations should be administered with caution, and patients should be closely monitored.

An increase in acute gout attacks has been reported during the early administration of allopurinol tablets, even when serum uric acid levels are normal or subnormal. Consequently, prophylactic maintenance doses of colchicine are generally recommended when initiating allopurinol therapy.

Patients with pre-existing renal disease or poor urate clearance may experience an increase in blood urea nitrogen (BUN) levels during treatment with allopurinol tablets. Close observation is warranted for these patients during the early stages of therapy, and dosage adjustments or discontinuation of the drug may be necessary if renal function abnormalities arise and persist.

Renal failure associated with allopurinol administration has been documented in patients with hyperuricemia secondary to neoplastic diseases, particularly in those with concurrent conditions such as multiple myeloma and congestive heart failure. Patients with decreased renal function require lower doses of allopurinol tablets compared to those with normal renal function. It is essential to initiate therapy with lower than recommended doses in patients with impaired renal function and to monitor them closely during the early stages of treatment.

Bone marrow depression has been reported in patients receiving allopurinol tablets, particularly among those taking concomitant medications that may contribute to this adverse effect.

To ensure the correct dosage and schedule for maintaining serum uric acid levels within the normal range, serum uric acid should be used as a monitoring index. For patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy. In patients with decreased renal function or concurrent illnesses affecting renal function, such as hypertension and diabetes mellitus, regular assessments of renal function parameters, particularly BUN and serum creatinine or creatinine clearance, should be performed, and the dosage of allopurinol tablets should be reassessed accordingly. Additionally, the prothrombin time should be periodically evaluated in patients receiving dicumarol who are also prescribed allopurinol tablets.

Side Effects

Patients receiving allopurinol may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most common reactions that are probably causally related include gastrointestinal symptoms such as diarrhea, nausea, and increases in alkaline phosphatase and SGOT/SGPT levels. Metabolic and nutritional adverse reactions may manifest as acute attacks of gout. Skin reactions commonly observed include rash and maculopapular rash.

Less common adverse reactions, occurring in less than 1% of patients and probably causally related, encompass a variety of systems. Body-wide reactions may include ecchymosis, fever, and headache. Cardiovascular issues such as necrotizing angiitis and vasculitis have also been reported. Gastrointestinal adverse reactions may include serious conditions like hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, and dyspepsia. Hematological reactions may involve thrombocytopenia, eosinophilia, leukocytosis, and leukopenia. Musculoskeletal symptoms can include myopathy and arthralgias. Neurological effects may manifest as peripheral neuropathy, neuritis, paresthesia, and somnolence. Respiratory reactions such as epistaxis have also been noted. Skin and appendage reactions can be severe, including erythema multiforme exudativum (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), hypersensitivity vasculitis, purpura, vesicular bullous dermatitis, exfoliative dermatitis, eczematoid dermatitis, pruritus, urticaria, alopecia, onycholysis, and lichen planus. Special senses may be affected, with reports of taste loss or perversion. Urogenital adverse reactions may include renal failure and uremia.

Additionally, there are reactions with an incidence of less than 1% where the causal relationship is unknown. These include malaise, cardiovascular issues such as pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, and vasodilation. Endocrine reactions may involve male infertility, hypercalcemia, and gynecomastia. Gastrointestinal issues may include hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, and anorexia. Hematological concerns may involve aplastic anemia, agranulocytosis, eosinophilic fibrohistiocytic lesions of the bone marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, and lymphocytosis. Musculoskeletal symptoms may include myalgia. Neurological effects can include optic neuritis, confusion, dizziness, vertigo, foot drop, decreased libido, depression, amnesia, tinnitus, asthenia, and insomnia. Respiratory reactions may include bronchospasm, asthma, pharyngitis, and rhinitis. Skin and appendage reactions may include furunculosis, facial edema, sweating, and skin edema. Special senses may be affected by cataracts, macular retinitis, iritis, conjunctivitis, and amblyopia. Urogenital issues may include nephritis, impotence, primary hematuria, and albuminuria.

It is critical to note that allopurinol tablets should be discontinued at the first appearance of a skin rash or other signs indicative of an allergic reaction. In some cases, a skin rash may precede more severe hypersensitivity reactions, including exfoliative, urticarial, and purpuric lesions, as well as Stevens-Johnson syndrome, generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death.

Furthermore, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome or drug hypersensitivity syndrome (DHS) has been reported in association with allopurinol use. This syndrome is potentially life-threatening and may include severe reactions such as fever, profuse skin rash, elevated leukocyte and eosinophil counts, lymphadenopathy, and multi-organ pathologies. Symptoms may develop approximately one week after initiating allopurinol therapy, although longer latency periods have also been documented.

Drug Interactions

In patients receiving PURINETHOL (mercaptopurine) or IMURAN (azathioprine), the concomitant administration of allopurinol tablets at doses ranging from 300 to 600 mg per day necessitates a reduction in the dose of mercaptopurine or azathioprine to approximately one third to one fourth of the usual dosage. This adjustment is critical to mitigate the risk of toxicity.

Allopurinol tablets have been observed to prolong the half-life of the anticoagulant dicumarol; however, the clinical implications of this interaction remain unclear. Caution is advised when administering allopurinol to patients already on dicumarol therapy.

Uricosuric agents, which enhance urate excretion, may reduce the effectiveness of allopurinol by increasing the excretion of oxipurinol, thereby diminishing the inhibition of xanthine oxidase.

The concomitant use of allopurinol tablets and thiazide diuretics may lead to increased allopurinol toxicity in certain patients. It is recommended that renal function be closely monitored in patients taking both medications, with dosage adjustments made conservatively if renal impairment is detected.

Increased frequency of skin rash has been reported in patients receiving ampicillin or amoxicillin alongside allopurinol tablets compared to those not receiving both medications.

Enhanced bone marrow suppression has been noted in patients with neoplastic diseases (excluding leukemia) when treated with cyclophosphamide and other cytotoxic agents in conjunction with allopurinol tablets.

The conversion of tolbutamide to inactive metabolites is catalyzed by xanthine oxidase; however, the clinical significance of this interaction is not well established. Additionally, chlorpropamide's plasma half-life may be prolonged by allopurinol, which could increase the risk of hypoglycemia, particularly in patients with renal insufficiency.

Rare instances have been reported where cyclosporine levels may be elevated during concurrent treatment with allopurinol tablets. Therefore, monitoring of cyclosporine levels is advisable, and dosage adjustments may be necessary based on the observed levels.

Allopurinol tablets are not known to affect the accuracy of laboratory tests.

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

Allopurinol tablets are rarely indicated for use in pediatric patients, with specific exceptions. The medication may be considered for children with hyperuricemia secondary to malignancy or certain rare inborn errors of purine metabolism. Healthcare professionals should exercise caution when prescribing allopurinol to this population, ensuring that the benefits outweigh the risks.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may require careful consideration when prescribed allopurinol tablets, especially in the context of renal function. Patients with decreased renal function necessitate lower doses than those with normal renal function. It is recommended that lower than the standard initial doses be utilized for any patient with compromised renal function, with close observation during the early stages of therapy.

In cases of severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in plasma is significantly prolonged. Therefore, a reduced dosage of 100 mg per day or 300 mg twice a week, or potentially less, may be adequate to achieve sufficient xanthine oxidase inhibition to lower serum urate levels effectively.

Elderly patients with pre-existing renal disease or poor urate clearance have been noted to experience an increase in blood urea nitrogen (BUN) levels during allopurinol therapy. Although the underlying mechanism remains unclear, it is crucial for healthcare providers to monitor these patients closely during the initial treatment phase. If persistent abnormalities in renal function arise, it may be necessary to decrease the dosage or discontinue the medication.

Additionally, renal failure associated with allopurinol administration has been documented in elderly patients with hyperuricemia secondary to neoplastic diseases, particularly in those with concurrent conditions such as multiple myeloma and congestive myocardial disease.

The risk of hypersensitivity reactions to allopurinol may be heightened in patients with decreased renal function, particularly when thiazides are co-administered. Therefore, caution is advised when prescribing these combinations, and patients should be monitored closely for any adverse effects.

Lastly, due to the potential for drowsiness associated with allopurinol, elderly patients should be advised to exercise caution when engaging in activities that require full alertness.

Pregnancy

Reproductive studies conducted in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day) have shown no impaired fertility or harm to the fetus due to allopurinol. However, a study involving pregnant mice administered 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13 revealed increased numbers of dead fetuses in dams receiving the higher dose of 100 mg/kg, while no such effects were observed in those given 50 mg/kg. Additionally, both doses resulted in increased external malformations on gestation day 10 and skeletal malformations on gestation day 13. It remains unclear whether these findings represent direct fetal effects or are secondary to maternal toxicity.

There are no adequate or well-controlled studies in pregnant women, and due to the limitations of animal reproduction studies in predicting human response, allopurinol should be used during pregnancy only if clearly needed. Experience with allopurinol during human pregnancy is limited, as women of reproductive age rarely require treatment with this medication.

A literature case report from 2011 described 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 reviewed 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 noted in the earlier case report.

Given these findings, healthcare professionals should carefully weigh the potential risks and benefits of allopurinol use in pregnant patients.

Lactation

Allopurinol and its metabolite, oxipurinol, have been detected in the breast milk of a lactating mother receiving allopurinol tablets. The effects of allopurinol on breastfed infants are not well understood. Therefore, caution is advised when administering allopurinol tablets to nursing mothers.

Renal Impairment

Patients with renal impairment may experience an increased occurrence of hypersensitivity reactions when allopurinol tablets are administered concurrently with thiazides. Due to this heightened risk, caution is advised when prescribing this combination to individuals with reduced kidney function. Close observation of these patients is recommended to monitor for any adverse reactions.

Hepatic Impairment

Patients with hepatic impairment may experience reversible clinical hepatotoxicity while taking allopurinol tablets. Asymptomatic elevations in serum alkaline phosphatase or serum transaminase levels have been observed in some individuals.

In cases where patients develop symptoms such as anorexia, weight loss, or pruritus, an evaluation of liver function should be included in their diagnostic workup. For patients with pre-existing liver disease, it is recommended that periodic liver function tests be conducted during the early stages of therapy to monitor for any potential adverse effects related to liver function.

Overdosage

In cases of overdosage with allopurinol tablets, it is important to note that massive overdosing or acute poisoning has not been reported in clinical settings. However, animal studies provide some insight into the potential toxicity of allopurinol.

Toxicity Data In murine models, the 50% lethal dose (LD50) for allopurinol administered intraperitoneally (IP) is 160 mg/kg, with mortality occurring up to 5 days post-administration. When given orally (PO), the LD50 is 700 mg/kg, which is approximately 140 times the typical human dose, with deaths occurring within 3 days. In rat models, the acute LD50 is significantly higher, at 750 mg/kg IP and 6000 mg/kg PO, equating to approximately 1200 times the human dose.

Management of Overdosage Currently, there is no specific antidote available for allopurinol overdose. Due to the lack of clinical experience with patients who have ingested massive amounts of allopurinol, management strategies remain largely undefined.

Both allopurinol and its active metabolite, oxipurinol, are known to be dialyzable. However, the efficacy of hemodialysis or peritoneal dialysis in the context of allopurinol overdose has not been established. Therefore, healthcare professionals should exercise caution and consider supportive care and symptomatic treatment as the primary management approach in suspected cases of overdosage.

Nonclinical Toxicology

Reproductive studies conducted in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day) indicated no impaired fertility or harm to the fetus associated with allopurinol. However, a published report detailing a study in pregnant mice administered 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13 revealed increased numbers of dead fetuses in dams receiving 100 mg/kg, while those receiving 50 mg/kg did not exhibit this effect. Additionally, there were increased instances of external malformations in fetuses at both doses on gestation day 10, as well as increased skeletal malformations at both doses on gestation day 13. It remains unclear whether these findings represent a direct fetal effect or are secondary to maternal toxicity.

There are no adequate or well-controlled studies in pregnant women, and since animal reproduction studies do not always predict human response, allopurinol should be used during pregnancy only if clearly needed. Experience with allopurinol tablets during human pregnancy has been limited, as women of reproductive age rarely require treatment with this medication. Notably, a literature 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.

Postmarketing Experience

Data derived from literature, unpublished clinical trials, and voluntary reports since the marketing of allopurinol tablets indicate various adverse reactions associated with its use.

Historically, the most frequent event following the initiation of allopurinol treatment was an increase in acute gout attacks, with an average incidence of 6% reported in early studies. However, current analysis suggests that this incidence has decreased to less than 1%, potentially due to a more gradual initiation of therapy, although the reason for this decline remains undetermined.

The most commonly reported adverse reaction to allopurinol tablets is skin rash, which can be severe and occasionally fatal. It is recommended that treatment be discontinued immediately if a rash develops. Among a cohort of 55 patients with gout treated with allopurinol for a duration of 3 to 34 months (average greater than 1 year), 3% experienced a drug reaction characterized predominantly by a pruritic maculopapular skin eruption, which may be scaly or exfoliative. Current usage has shown that skin reactions occur with a frequency of less than 1%, although the reason for this reduction is not clear.

The incidence of skin rash may be heightened in patients with renal insufficiency, and concurrent use of ampicillin or amoxicillin has been associated with an increased frequency of skin rash among those receiving allopurinol tablets.

Additionally, cases of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome or drug hypersensitivity syndrome (DHS) have been reported in association with allopurinol use. This syndrome can be life-threatening and is characterized by severe reactions, including fever, extensive skin rash, elevated leukocyte and eosinophil counts, lymphadenopathy, and multi-organ involvement. Symptoms affecting the cardiac, gastrointestinal, lymphatic, pulmonary, and ophthalmic systems have also been documented. Onset of symptoms may occur approximately one week after initiating allopurinol therapy, although longer latency periods have been observed.

Patient Counseling

Patients should be cautioned to discontinue allopurinol tablets and consult their physician immediately at the first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth. It is important for patients to understand that the optimal benefit of allopurinol tablets for gouty attacks may be delayed for 2 to 6 weeks, and they should continue any drug therapy prescribed for these attacks during this period.

Patients should be encouraged to increase their fluid intake while on therapy to help prevent the formation of renal stones. In the event that a single dose of allopurinol tablets is occasionally forgotten, patients should be advised that there is no need to double the dose at the next scheduled time.

Healthcare providers should inform patients about the potential risks associated with the concomitant use of allopurinol tablets and medications such as dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics, emphasizing the importance of following their physician's instructions regarding these combinations.

Due to the occasional occurrence of drowsiness associated with allopurinol, patients should be advised to take precautions when engaging in activities that require alertness. Additionally, patients may wish to take allopurinol tablets after meals to minimize gastric irritation.

Storage and Handling

The product is supplied in packaging that ensures its integrity and stability. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to USP Controlled Room Temperature guidelines. It is essential to keep the product in a dry place and protect it from light to maintain its efficacy. Proper storage conditions are critical to ensure the product's quality and effectiveness throughout its shelf life.

Additional Clinical Information

The appropriate dosage and schedule for maintaining serum uric acid levels within the normal range should be guided by serum uric acid measurements. In patients with pre-existing liver disease, it is advisable to conduct periodic liver function tests during the initial phases of treatment.

Allopurinol and its primary active metabolite, oxipurinol, are primarily eliminated through the kidneys; thus, any alterations in renal function significantly impact dosing. For patients with reduced renal function or those with concurrent conditions that may affect renal performance, such as hypertension or diabetes mellitus, regular monitoring of renal function parameters, including BUN and serum creatinine or creatinine clearance, is essential. Additionally, for patients receiving dicumarol alongside allopurinol, periodic reassessment of prothrombin time is recommended.

FDA Insert (PDF)

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

View full prescribing information (PDF)