Allopurinol

Description

Allopurinol is chemically defined as 1,5-Dihydro-4 H-pyrazolo3,4-dpyrimidin-4-one and functions as a xanthine oxidase inhibitor. It is administered orally and has a molecular weight of 136.11, with the structural formula represented as C₅H₄N₄O. The solubility of allopurinol in water at 37°C is 80 mg/dL, with increased solubility observed in alkaline solutions.

Allopurinol Tablets USP are available in two strengths: 100 mg and 300 mg. The 100 mg formulation contains inactive ingredients including croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate. The 300 mg formulation additionally contains FD&C Yellow No. 6.

Uses and Indications

Allopurinol is indicated for 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.

This drug is also indicated for patients with leukemia, lymphoma, and other malignancies undergoing cancer therapy that results in elevated serum and urinary uric acid levels. Allopurinol treatment should be discontinued when the risk of uric acid overproduction is no longer present.

Additionally, Allopurinol is indicated for 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.

Dosage and Administration

The dosage of allopurinol 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 ranges from 400 to 600 mg per day. Dosages may be administered in divided doses or as a single equivalent dose using the 300 mg tablet. For patients requiring dosages exceeding 300 mg, it is recommended that these be given in divided doses. The minimal effective dosage is 100 to 200 mg daily, while the maximal recommended dosage is 800 mg daily.

To minimize the risk of acute gouty attacks, treatment should commence with a low dose of allopurinol at 100 mg daily, which can be increased by 100 mg at weekly intervals until a 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 one to three 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 two to three days is recommended, accompanied by a high fluid intake. In managing recurrent calcium oxalate stones in hyperuricosuric patients, a dosage of 200 to 300 mg per day is advised, either in divided doses or as a single equivalent, with adjustments made based on subsequent 24-hour urinary urate determinations.

In pediatric patients aged 6 to 10 years with secondary hyperuricemia related to malignancies, a daily dosage of 300 mg of allopurinol may be administered, while children under 6 years typically receive 150 mg daily. The therapeutic response should be evaluated after approximately 48 hours, with dosage adjustments made as necessary.

Allopurinol is generally better tolerated when taken after meals. It is also advisable to ensure adequate fluid intake to achieve a daily urinary output of at least 2 liters and to maintain urine that is neutral or slightly alkaline.

Contraindications

Patients who have developed a severe reaction to allopurinol should not be restarted on the drug due to the risk of exacerbating the adverse effects.

Warnings and Precautions

Allopurinol 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, urticarial, and purpuric lesions, as well as 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, with asymptomatic elevations in serum alkaline phosphatase or serum transaminase levels noted in certain cases. If patients experience anorexia, weight loss, or pruritus while on allopurinol, 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 about engaging in activities that require full alertness. The risk of hypersensitivity reactions to allopurinol may be heightened in patients with decreased renal function who are concurrently receiving thiazides. Therefore, such combinations should be administered with caution, and close observation of these patients is warranted.

An increase in acute gout attacks has been reported during the early phases of allopurinol treatment, 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 allopurinol administration. Although the underlying mechanism remains unclear, careful monitoring of renal function is essential during the early stages of treatment. If persistent abnormalities in renal function are observed, dosage adjustments or discontinuation of the drug may be necessary.

Renal failure associated with allopurinol 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 compared to those with normal renal function. It is recommended to initiate therapy with lower than standard doses in these patients and to monitor them closely during the early stages of treatment.

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

To ensure effective management of serum uric acid levels, the correct dosage and schedule should be guided by periodic assessments of serum uric acid levels. For patients with pre-existing liver disease, regular liver function tests are recommended during the initial treatment phase. In patients with decreased renal function or concurrent illnesses affecting renal function, such as hypertension and diabetes mellitus, periodic evaluations of renal parameters, including BUN and serum creatinine or creatinine clearance, should be conducted, and allopurinol dosages should be reassessed accordingly. Additionally, in patients receiving dicumarol, the prothrombin time should be periodically re-evaluated while on allopurinol.

Side Effects

The most common adverse reactions associated with allopurinol include gastrointestinal disturbances such as diarrhea, nausea, and increases in alkaline phosphatase and SGOT/SGPT levels. Additionally, patients may experience acute attacks of gout, which is the most frequently observed event following the initiation of therapy. Skin reactions, including rash and maculopapular rash, are also prevalent. Early clinical studies indicated that these adverse reactions occurred at a rate greater than 1%, but current analyses suggest that the incidence has decreased to less than 1%.

Less common adverse reactions, occurring at an incidence of less than 1%, encompass a variety of systems. Body-wide reactions may include ecchymosis, fever, and headache. Cardiovascular effects can manifest as necrotizing angiitis and vasculitis. Gastrointestinal issues may involve hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, and dyspepsia. Hematological reactions include thrombocytopenia, eosinophilia, leukocytosis, and leukopenia. Musculoskeletal symptoms may present as myopathy and arthralgias, while nervous system effects can include peripheral neuropathy, neuritis, paresthesia, and somnolence. Respiratory reactions such as epistaxis and various skin and appendage reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, hypersensitivity vasculitis, and pruritus, have also been reported. Special senses may be affected, leading to taste loss or perversion, and urogenital issues may include renal failure and uremia.

Certain adverse reactions have been reported with an incidence of less than 1%, but a causal relationship remains unknown. These include malaise, cardiovascular issues such as pericarditis and thrombophlebitis, endocrine effects like infertility in males and hypercalcemia, and gastrointestinal complications such as hemorrhagic pancreatitis and gastrointestinal bleeding. Hematological concerns may involve aplastic anemia and agranulocytosis, while musculoskeletal complaints can include myalgia. Neurological symptoms may range from optic neuritis to depression and insomnia. Respiratory issues may include bronchospasm and asthma, and skin reactions can involve furunculosis and facial edema. Special senses may also be affected, with reports of cataracts and amblyopia, while urogenital reactions may include nephritis and impotence.

It is critical to note that allopurinol should be discontinued at the first appearance of a skin rash or other signs indicative of an allergic reaction. Severe hypersensitivity reactions, including exfoliative dermatitis, urticarial and purpuric lesions, Stevens-Johnson syndrome, and generalized vasculitis, may follow a skin rash. In rare instances, these reactions can lead to irreversible hepatotoxicity and even death. 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 patients receiving allopurinol.

Drug Interactions

In patients receiving mercaptopurine or azathioprine, the concomitant administration of allopurinol at doses of 300-600 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 avoid potential toxicity.

Allopurinol has 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.

The use of uricosuric agents, which enhance urate excretion, may lead to increased excretion of oxipurinol, thereby diminishing the inhibitory effect of xanthine oxidase when used concurrently with allopurinol.

When allopurinol is used in conjunction with thiazide diuretics, there is a potential for increased toxicity of allopurinol. It is recommended that renal function be closely monitored in these patients, and dosage adjustments should be made conservatively if any decline in renal function is observed.

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

The combination of allopurinol with cyclophosphamide and other cytotoxic agents may lead to enhanced bone marrow suppression in patients with neoplastic diseases, excluding leukemia.

Allopurinol may also prolong the plasma half-life of chlorpropamide, which could elevate the risk of hypoglycemia, particularly in patients with renal insufficiency.

There are rare reports indicating that cyclosporine levels may be elevated during concurrent treatment with allopurinol. Therefore, monitoring of cyclosporine levels is advisable, and dosage adjustments may be necessary based on the observed levels.

Allopurinol is not known to affect the accuracy of laboratory tests, ensuring that test results remain reliable during treatment.

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 is rarely indicated for use in pediatric patients, with specific exceptions. It 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, especially in the context of renal function. It is essential to recognize that patients with decreased renal function necessitate lower doses of allopurinol compared to those with normal renal function. When initiating therapy in these patients, lower than recommended doses should be employed, and they should be closely monitored during the early stages of treatment.

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

Elderly patients with pre-existing renal disease or poor urate clearance have been observed to experience an increase in blood urea nitrogen (BUN) levels during allopurinol therapy. Although the underlying mechanism for this rise remains unclear, it is crucial that these patients are monitored closely during the initial treatment phase. Should any persistent abnormalities in renal function arise, it may be necessary to reduce the dosage or discontinue the medication.

Additionally, renal failure associated with allopurinol administration has been reported 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, especially when thiazides are co-administered. Therefore, caution is advised when using these combinations, and patients should be observed closely for any adverse effects.

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

Pregnancy

Pregnancy Category C. Reproductive studies conducted in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg/day) indicated 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 an increased number of dead fetuses in dams receiving the higher dose of 100 mg/kg, while no such effect was observed in those receiving 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 effects were due to direct fetal impact or secondary to maternal toxicity.

There are no adequate or well-controlled studies in pregnant women, and the limited experience with allopurinol during human pregnancy is partly due to the infrequent need for treatment in women of reproductive age. Although there are two unpublished reports and one published paper documenting normal offspring born to women who received allopurinol during pregnancy, the overall data is insufficient to establish safety. Therefore, allopurinol should be used during pregnancy only if clearly needed, as animal reproduction studies are not always predictive of human response.

Lactation

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

Renal Impairment

Patients with reduced renal function may experience an increased occurrence of hypersensitivity reactions when receiving thiazides concurrently with allopurinol. Therefore, in this clinical setting, it is recommended that such combinations be administered with caution. Close observation of these patients is advised to monitor for any adverse reactions.

Hepatic Impairment

Patients with hepatic impairment may experience reversible clinical hepatotoxicity while taking allopurinol. In some cases, asymptomatic elevations in serum alkaline phosphatase or serum transaminase levels have been observed.

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 liver function closely. Additionally, if patients develop symptoms such as anorexia, weight loss, or pruritus while on allopurinol, an evaluation of liver function should be included as part of their diagnostic workup.

No specific dosage adjustments are provided for patients with hepatic impairment; however, careful monitoring of liver function is essential to ensure patient safety.

Overdosage

In cases of allopurinol overdosage, 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 potential toxicity levels. In mice, the 50% lethal dose (LD50) is observed to be 160 mg/kg when administered intraperitoneally (i.p.), with fatalities occurring up to five days post-administration. When given orally (p.o.), the LD50 is significantly higher at 700 mg/kg, which is approximately 140 times the usual human dose, with deaths delayed up to three days. In rats, the acute LD50 is reported as 750 mg/kg i.p. and 6000 mg/kg p.o., equating to approximately 1200 times the human dose.

Management of allopurinol overdosage poses challenges, as there is currently no specific antidote available. Furthermore, there is a lack of clinical experience regarding the management of patients who have ingested massive amounts of allopurinol. In terms of supportive care, 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 overdosage remains uncertain.

Healthcare professionals are advised to monitor patients closely for any potential symptoms of toxicity and to provide supportive care as needed. Given the absence of established protocols for massive overdoses, clinical judgment should guide the management approach in these rare situations.

Nonclinical Toxicology

Pregnancy Category C. Reproductive studies conducted in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg/day) indicated no impaired fertility or harm to the fetus associated with allopurinol. However, a published study involving pregnant mice administered 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13 revealed an increased number of dead fetuses in dams receiving 100 mg/kg, while no such increase was observed in those receiving 50 mg/kg. 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. Given that animal reproduction studies are not always predictive of human response, allopurinol should be used during pregnancy only if clearly needed. Experience with allopurinol in human pregnancies is limited, as women of reproductive age rarely require treatment with this medication. There are two unpublished reports and one published paper documenting instances of women giving birth to normal offspring following allopurinol treatment during pregnancy.

Postmarketing Experience

Data derived from literature, unpublished clinical trials, and voluntary reports since the marketing of allopurinol 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 exact reason for this decline remains undetermined.

The most commonly reported adverse reaction to allopurinol is skin rash, which can be severe and occasionally fatal. Immediate discontinuation of allopurinol is recommended if a rash develops. In patients experiencing severe reactions, additional symptoms such as fever, chills, arthralgias, cholestatic jaundice, eosinophilia, and mild leukocytosis or leukopenia have been noted. Among a cohort of 55 patients treated with allopurinol for periods ranging from 3 to 34 months, a 3% incidence of a pruritic maculopapular skin eruption was observed, although current usage indicates that skin reactions now occur in less than 1% of patients. The reasons for this reduction are not clearly understood.

It has been noted that the incidence of skin rash may be heightened in patients with renal insufficiency and among those concurrently receiving ampicillin or amoxicillin.

The following adverse reactions have been reported, with varying degrees of incidence:

Most Common Reactions Probably Causally Related (Incidence Greater Than 1%):

• Gastrointestinal: diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase

• Metabolic and Nutritional: acute attacks of gout

• Skin and Appendages: rash, maculopapular rash

Incidence Less Than 1% Probably Causally Related:

• Body as a whole: ecchymosis, fever, headache

• Cardiovascular: necrotizing angiitis, vasculitis

• Gastrointestinal: hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, dyspepsia

• Hemic and Lymphatic: thrombocytopenia, eosinophilia, leukocytosis, leukopenia

• Musculoskeletal: myopathy, arthralgias

• Nervous: peripheral neuropathy, neuritis, paresthesia, somnolence

• Respiratory: epistaxis

• Skin and Appendages: 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, lichen planus

• Special Senses: taste loss/perversion

• Urogenital: renal failure, uremia

Incidence Less Than 1% Causal Relationship Unknown:

• Body as a whole: malaise

• Cardiovascular: pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation

• Endocrine: infertility (male), hypercalcemia, gynecomastia (male)

• Gastrointestinal: hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, anorexia

• Hemic and Lymphatic: aplastic anemia, agranulocytosis, eosinophilic fibrohistiocytic lesion of bone marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis

• Musculoskeletal: myalgia

• Nervous: optic neuritis, confusion, dizziness, vertigo, foot drop, decrease in libido, depression, amnesia, tinnitus, asthenia, insomnia

• Respiratory: bronchospasm, asthma, pharyngitis, rhinitis

• Skin and Appendages: furunculosis, facial edema, sweating, skin edema

• Special Senses: cataracts, macular retinitis, iritis, conjunctivitis, amblyopia

• Urogenital: nephritis, impotence, primary hematuria, albuminuria

Patient Counseling

Patients should be cautioned to discontinue allopurinol 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 they should continue the drug therapy prescribed for gouty attacks, as the optimal benefit of allopurinol may be delayed for two to six weeks.

Patients are encouraged to increase their fluid intake during therapy to help prevent the formation of renal stones. In the event that a single dose of allopurinol 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 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 after meals to minimize gastric irritation.

Storage and Handling

The product is supplied in a tight, light-resistant container equipped with a child-resistant closure. It should be stored at a temperature range of 20°-25°C (68°-77°F), in accordance with USP controlled room temperature guidelines. Additionally, it is essential to protect the product from light to maintain its integrity and efficacy.

Additional Clinical Information

The appropriate dosage and administration schedule for maintaining serum uric acid levels within the normal range should be guided by serum uric acid measurements. Clinicians are advised to monitor liver function tests periodically during the initial stages of therapy in patients with pre-existing liver disease.

Allopurinol and its active metabolite, oxipurinol, are primarily eliminated through the kidneys; thus, renal function significantly influences dosage requirements. In patients with impaired renal function or those with concurrent conditions that may affect renal health, such as hypertension or diabetes mellitus, regular assessments of renal function—specifically BUN, serum creatinine, or creatinine clearance—are essential for appropriate dosage adjustments. 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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)