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 tablets contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate. Additionally, the 300 mg formulation includes 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 the management of 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 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 increases to 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 less 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 vigorous 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 based on subsequent 24-hour urinary urate determinations.

In pediatric patients, the recommended dosage is 300 mg daily for those aged 6 to 10 years, while children under 6 years typically receive 150 mg daily. The response to therapy 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 a fluid intake sufficient to achieve a daily urinary output of at least 2 liters, while maintaining a neutral or slightly alkaline urine.

Contraindications

Patients who have experienced a severe reaction to allopurinol should not be reinitiated on the medication due to the risk of recurrence of adverse effects.

Warnings and Precautions

ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF A SKIN RASH OR OTHER SIGNS INDICATING AN ALLERGIC REACTION. Such reactions may escalate to more severe hypersensitivity events, including exfoliative dermatitis, urticarial and purpuric lesions, Stevens-Johnson Syndrome (erythema multiforme exudativum), generalized vasculitis, irreversible hepatotoxicity, and, in rare cases, death.

In patients receiving mercaptopurine or azathioprine, the concomitant administration of allopurinol at doses of 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.

Reversible clinical hepatotoxicity has been observed in some patients taking allopurinol, with asymptomatic elevations in serum alkaline phosphatase or serum transaminases noted. Should patients experience anorexia, weight loss, or pruritus while on allopurinol, a thorough evaluation of liver function should be included in their diagnostic workup.

Due to the potential for drowsiness, patients should be cautioned about engaging in activities that require full alertness. Additionally, the risk of hypersensitivity reactions may be heightened in patients with decreased renal function who are concurrently receiving thiazides and allopurinol. 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 initial stages of allopurinol therapy, even when serum uric acid levels are normal or subnormal. Consequently, prophylactic maintenance doses of colchicine are generally recommended when initiating allopurinol treatment.

To mitigate the theoretical risk of xanthine calculi formation and to prevent renal precipitation of urates in patients receiving concomitant uricosuric agents, it is advisable to maintain a fluid intake sufficient to yield a daily urinary output of at least 2 liters, along with the maintenance of neutral or slightly alkaline urine.

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

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 than those with normal renal function, and therapy should be initiated with lower than recommended doses in these patients, who should be closely monitored during the early stages of treatment.

Bone marrow depression has been reported in patients receiving allopurinol, particularly among those also 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 levels should be regularly monitored. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy. For patients with decreased renal function or concurrent illnesses affecting renal function, such as hypertension and diabetes mellitus, periodic assessments of renal function, particularly BUN and serum creatinine or creatinine clearance, should be conducted, and allopurinol dosage should be reassessed accordingly. Additionally, in patients receiving dicumarol, the prothrombin time should be periodically re-evaluated while on allopurinol.

Side Effects

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

The most common adverse reactions, occurring at a rate greater than 1% during early clinical studies, include gastrointestinal symptoms such as diarrhea, nausea, and increases in alkaline phosphatase and SGOT/SGPT levels. Additionally, acute attacks of gout are frequently observed following the initiation of therapy. Skin reactions such as rash and maculopapular rash are also noted. Current analyses suggest that the incidence of these reactions has decreased to less than 1%, potentially due to adherence to recommended usage guidelines.

Adverse reactions with an incidence of less than 1% encompass a variety of systems. In the body as a whole, patients may experience ecchymosis, fever, and headache. Cardiovascular effects can include necrotizing angiitis and vasculitis. Gastrointestinal reactions may manifest as hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, and dyspepsia. Hematological effects include thrombocytopenia, eosinophilia, leukocytosis, and leukopenia. Musculoskeletal symptoms may involve myopathy and arthralgias, while nervous system effects can include peripheral neuropathy, neuritis, paresthesia, and somnolence. Respiratory issues such as epistaxis and various skin 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 complications such as renal failure and uremia may occur.

Certain adverse reactions have been reported with an unknown causal relationship, also occurring at an incidence of less than 1%. These include malaise, cardiovascular issues such as pericarditis and peripheral vascular disease, and endocrine effects like male infertility and hypercalcemia. Gastrointestinal complications may involve hemorrhagic pancreatitis and gastrointestinal bleeding, while hematological concerns can include aplastic anemia and agranulocytosis. Musculoskeletal symptoms may present as myalgia, and neurological effects can range from confusion to tinnitus. Respiratory reactions may include bronchospasm and asthma, while skin reactions can involve furunculosis and facial edema. Special senses may be affected by cataracts and macular retinitis, and urogenital issues 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. In some cases, a skin rash may precede more severe hypersensitivity reactions, including exfoliative dermatitis, urticarial and purpuric lesions, Stevens-Johnson syndrome, generalized vasculitis, irreversible hepatotoxicity, and, in rare instances, death.

Drug Interactions

Concomitant administration of allopurinol with certain medications may lead to significant drug interactions that require careful consideration and monitoring.

Antineoplastic Agents In patients receiving mercaptopurine or azathioprine, the use 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. Enhanced bone marrow suppression has also been reported in patients with neoplastic disease (excluding leukemia) when allopurinol is used alongside cyclophosphamide and other cytotoxic agents.

Anticoagulants Allopurinol prolongs the half-life of dicumarol, although the clinical implications of this interaction remain unclear. Caution is advised when administering allopurinol to patients already on dicumarol therapy.

Uricosuric Agents The concomitant use of uricosuric agents with allopurinol has been associated with decreased excretion of oxypurines (hypoxanthine and xanthine) and increased urinary uric acid excretion compared to allopurinol alone.

Diuretics The combination of allopurinol and thiazide diuretics may enhance the toxicity of allopurinol in some patients. It is recommended that renal function be monitored in patients receiving both medications, and dosage adjustments should be made if renal impairment is detected.

Antibiotics Increased frequency of skin rash has been observed in patients taking ampicillin or amoxicillin concurrently with allopurinol compared to those not receiving both drugs.

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

Immunosuppressants Rare instances of elevated cyclosporine levels have been reported during concurrent treatment with allopurinol. Monitoring of cyclosporine levels is recommended, and dosage adjustments may be necessary.

Laboratory Tests Allopurinol is 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 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 often present with decreased renal function, necessitating careful consideration when prescribing allopurinol. It is recommended that lower than usual doses be utilized to initiate therapy in these patients, and they should be closely monitored during the early stages of treatment. For those with severely impaired renal function or diminished urate clearance, the half-life of oxipurinol in plasma is significantly prolonged. In such cases, a dose 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.

Additionally, renal failure has been observed in elderly patients receiving allopurinol, particularly among those with hyperuricemia secondary to neoplastic diseases. Patients with pre-existing renal disease or poor urate clearance may experience an increase in blood urea nitrogen (BUN) levels during allopurinol therapy. Therefore, it is crucial to assess renal function periodically in these patients, especially those with concurrent conditions such as hypertension and diabetes mellitus, and to adjust the allopurinol dosage accordingly.

Elderly patients should also be cautioned about the potential for drowsiness, which may impair their ability to engage in activities requiring alertness. Furthermore, the risk of hypersensitivity reactions to allopurinol may be heightened in patients with decreased renal function who are concurrently taking thiazide diuretics; thus, this combination should be administered with caution, and patients should be monitored closely.

For elderly patients with pre-existing liver disease, it is advisable to conduct periodic liver function tests during the initial stages of allopurinol therapy to ensure safety and efficacy.

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 published 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 100 mg/kg, while no such increase was observed in those receiving 50 mg/kg. Additionally, both doses were associated with increased external malformations in fetuses on gestation day 10 and increased skeletal malformations 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 the experience with allopurinol during human pregnancy is limited, as women of reproductive age rarely require treatment with this medication. Although there are two unpublished reports and one published paper documenting women giving birth to normal offspring after receiving allopurinol during pregnancy, caution is advised. Because animal reproduction studies are not always predictive of human response, allopurinol should be used during pregnancy only if clearly needed.

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 in conjunction with allopurinol. Therefore, 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 in their diagnostic workup to assess any potential impact on liver health.

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 treatment options, 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 of 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 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 cases of women who gave birth to normal offspring after receiving allopurinol 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%.

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 may include fever, chills, arthralgias, cholestatic jaundice, eosinophilia, and mild leukocytosis or leukopenia. Among a cohort of 55 patients treated with allopurinol for durations ranging from 3 to 34 months, a study observed that 3% developed a pruritic maculopapular skin eruption, which may be scaly or exfoliative. Current usage indicates that skin reactions are now observed in less than 1% of patients, although the incidence may be higher in those with renal insufficiency or when allopurinol is used concurrently with ampicillin or amoxicillin.

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

Most Common Reactions Probably Causally Related (Incidence ≥ 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

To report suspected adverse events, contact Actavis at 1-800-272-5525 or the FDA at 1-800-FDA-1088 or visit http://www.fda.gov/ for voluntary reporting of adverse reactions.

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, 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 such as hypertension and diabetes mellitus, regular assessments of renal function parameters, including BUN and serum creatinine or creatinine clearance, are essential for dosage adjustment. 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)