Zyloprim

Description

ZYLOPRIM (allopurinol) is chemically designated as 1,5-dihydro-4 H-pyrazolo 3,4-dpyrimidin-4-one and functions as a xanthine oxidase inhibitor. It is administered orally. The structural formula of ZYLOPRIM is provided.

The formulation includes scored white tablets, each containing 100 mg of allopurinol, along with inactive ingredients such as lactose, magnesium stearate, potato starch, and povidone. Additionally, scored peach tablets contain 300 mg of allopurinol, with inactive ingredients including corn starch, FD&C Yellow No. 6 Lake, lactose, magnesium stearate, and povidone.

ZYLOPRIM exhibits a solubility of 80.0 mg/dL in water at 37°C, with increased solubility in alkaline solutions.

Uses and Indications

ZYLOPRIM 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.

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

This medication is also 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 ZYLOPRIM is tailored to achieve optimal control of gout and to normalize serum uric acid levels, with variations based on disease severity.

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 either in divided doses or as a single equivalent dose using the 300-mg tablet. It is important to note that any dosage exceeding 300 mg should 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 mitigate the risk of acute gouty attacks, it is recommended to initiate treatment with a low dose of ZYLOPRIM at 100 mg daily, increasing 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 advised. 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 a high fluid intake.

In managing recurrent calcium oxalate stones in hyperuricosuric patients, a recommended dosage of 200 to 300 mg per day is suggested, either in divided doses or as a single equivalent, with adjustments made based on the control of hyperuricosuria.

For pediatric patients aged 6 to 10 years with secondary hyperuricemia related to malignancies, a daily dosage of 300 mg ZYLOPRIM is appropriate. For children under 6 years, a daily dosage of 150 mg is generally recommended. The response to therapy should be evaluated after approximately 48 hours, with dosage adjustments made as necessary.

Contraindications

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

Warnings and Precautions

ZYLOPRIM should be discontinued at the first appearance of any skin rash or 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 ZYLOPRIM, with instances of asymptomatic elevations in serum alkaline phosphatase or serum transaminases. If patients experience anorexia, weight loss, or pruritus while on ZYLOPRIM, 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.

The risk of hypersensitivity reactions to ZYLOPRIM may be heightened in patients with decreased renal function who are concurrently receiving thiazides. Therefore, caution is warranted when administering these combinations, and close observation of patients is essential.

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

Patients with pre-existing renal disease or poor urate clearance may experience an increase in blood urea nitrogen (BUN) levels during ZYLOPRIM treatment. Such patients should be closely monitored 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 ZYLOPRIM 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 ZYLOPRIM 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 treatment phase.

Bone marrow depression has been reported in patients receiving ZYLOPRIM, 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 should be used as a guiding index. For patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy. Additionally, 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 ZYLOPRIM should be reassessed accordingly. For patients receiving dicumarol, the prothrombin time should be periodically re-evaluated while on ZYLOPRIM.

Side Effects

Patients receiving treatment 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 may present as necrotizing angiitis and vasculitis. Gastrointestinal reactions can be more severe, including 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 may include epistaxis. Skin and appendage reactions can be serious, such as 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 reactions may include renal failure and uremia.

Adverse reactions with an incidence of less than 1% and an unknown causal relationship include malaise, cardiovascular issues such as pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, and vasodilation. Endocrine effects may include male infertility, hypercalcemia, and gynecomastia. Gastrointestinal reactions may involve hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, and anorexia. Hematological concerns may include 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 range from optic neuritis, confusion, dizziness, and vertigo to foot drop, decreased libido, depression, amnesia, tinnitus, asthenia, and insomnia. Respiratory issues may include bronchospasm, asthma, pharyngitis, and rhinitis. Skin and appendage reactions may involve furunculosis, facial edema, sweating, and skin edema. Special senses may be affected by cataracts, macular retinitis, iritis, conjunctivitis, and amblyopia. Urogenital reactions may include nephritis, impotence, primary hematuria, and albuminuria.

It is critical to note that ZYLOPRIM 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.

Drug Interactions

In patients receiving PURINETHOL (mercaptopurine) or IMURAN (azathioprine), the concomitant administration of ZYLOPRIM (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. Subsequent adjustments should be based on therapeutic response and the emergence of any toxic effects.

ZYLOPRIM 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 ZYLOPRIM to patients already on dicumarol therapy.

The use of uricosuric agents in conjunction with ZYLOPRIM has been associated with decreased excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared to ZYLOPRIM alone.

When ZYLOPRIM is used alongside thiazide diuretics, there may be an increased risk of allopurinol toxicity. It is recommended that renal function be monitored in patients receiving both thiazide diuretics and ZYLOPRIM, with conservative dosage adjustments made if diminished renal function is detected.

An increased incidence of skin rash has been reported in patients taking ampicillin or amoxicillin concurrently with ZYLOPRIM 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 the presence of ZYLOPRIM.

The conversion of tolbutamide to inactive metabolites may be catalyzed by xanthine oxidase, although the clinical significance of this interaction is not well established. Additionally, ZYLOPRIM may prolong the plasma half-life of chlorpropamide due to competition for renal tubular excretion, potentially increasing 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 ZYLOPRIM. Therefore, monitoring of cyclosporine levels and consideration of dosage adjustments are advised when these medications are co-administered.

ZYLOPRIM is not known to affect the accuracy of laboratory tests.

Packaging & NDC

The table below lists all NDC Code configurations of Zyloprim (allopurinol), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

ZYLOPRIM is rarely indicated for use in pediatric patients, with specific exceptions for children experiencing hyperuricemia secondary to malignancy or certain rare inborn errors of purine metabolism. Healthcare professionals should exercise caution when considering ZYLOPRIM for this population, ensuring that the benefits outweigh potential risks.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may require careful consideration when initiating therapy with ZYLOPRIM. It is essential to recognize that patients with decreased renal function necessitate lower doses compared to those with normal renal function. For these patients, lower than recommended doses should be employed to initiate therapy, and they should be closely monitored during the early stages of administration to ensure safety and efficacy.

In cases of severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the 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 maintain sufficient xanthine oxidase inhibition to effectively 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 ZYLOPRIM therapy. Additionally, renal failure has been reported in patients with hyperuricemia secondary to neoplastic diseases when treated with ZYLOPRIM. Consequently, it is imperative that renal function abnormalities are closely monitored in elderly patients during the initial phases of therapy.

Furthermore, the risk of hypersensitivity reactions to ZYLOPRIM may be heightened in patients with decreased renal function, especially when thiazides are administered concurrently. Such combinations should be approached with caution, and patients should be observed closely for any adverse reactions.

Lastly, due to the potential for drowsiness associated with ZYLOPRIM, elderly patients should be advised to exercise caution 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 per 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 because animal reproduction studies are not always predictive of human response, allopurinol should be used during pregnancy only if clearly needed. Experience with ZYLOPRIM during human pregnancy has been limited, as women of reproductive age rarely require treatment with this medication. Nonetheless, there are two unpublished reports and one published paper documenting women who gave birth to normal offspring after receiving ZYLOPRIM during pregnancy. Healthcare professionals should weigh the potential benefits against the risks when considering the use of allopurinol in pregnant patients.

Lactation

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

Renal Impairment

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

Hepatic Impairment

Patients with hepatic impairment may experience reversible clinical hepatotoxicity while taking ZYLOPRIM. 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, a thorough 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 on liver function.

Overdosage

In the event of an overdosage of ZYLOPRIM, 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 the drug. In mice, the 50% lethal dose (LD50) is observed to be 160 mg/kg when administered intraperitoneally (IP), with fatalities occurring up to 5 days post-administration. When given orally (PO), the LD50 is significantly higher at 700 mg/kg, which is approximately 140 times the usual human dose, with deaths delayed up to 3 days. In rats, the acute LD50 is reported as 750 mg/kg IP and 6000 mg/kg PO, equating to approximately 1200 times the human dose.

Management of ZYLOPRIM overdosage poses challenges, as there is no specific antidote available. Furthermore, there has been no clinical experience documented regarding the management of patients who have ingested massive amounts of ZYLOPRIM.

Both ZYLOPRIM and its active metabolite, oxipurinol, are known to be dialyzable; however, the efficacy of hemodialysis or peritoneal dialysis in the context of ZYLOPRIM overdose remains uncertain. Healthcare professionals should exercise caution and consider supportive care measures while monitoring the patient closely for any potential symptoms of toxicity.

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 per 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 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 resulted in a higher incidence of external malformations in fetuses on gestation day 10 and an increase in 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. Given that animal reproduction studies do not always predict human response, allopurinol should be used during pregnancy only if clearly needed. Experience with ZYLOPRIM during human pregnancy has been limited, as women of reproductive age rarely require treatment with this medication. Nonetheless, there are two unpublished reports and one published paper documenting instances of women giving birth to normal offspring after receiving ZYLOPRIM during pregnancy.

Postmarketing Experience

Data derived from literature, unpublished clinical trials, and voluntary reports since the marketing of ZYLOPRIM (allopurinol) began 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. Current analysis suggests that this incidence has decreased to less than 1%, although the reason for this reduction remains undetermined, potentially linked to a more gradual initiation of therapy.

The most commonly reported adverse reaction to ZYLOPRIM is skin rash, which can be severe and occasionally fatal. Immediate discontinuation of treatment is advised 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 with gout treated with ZYLOPRIM for periods ranging from 3 to 34 months (average exceeding 1 year), 3% developed a pruritic maculopapular skin eruption, which may be scaly or exfoliative. However, current usage has shown a decrease in skin reactions to less than 1%, with the reasons for this decline not clearly understood.

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.

Common reactions likely causally related to ZYLOPRIM include gastrointestinal symptoms such as diarrhea and nausea, as well as increases in alkaline phosphatase and SGOT/SGPT levels. Acute attacks of gout and skin reactions, particularly rash and maculopapular rash, are also frequently reported.

Adverse reactions with an incidence of less than 1% that may be causally related encompass a range of conditions across various systems, including but not limited to:

• Body As a Whole: Ecchymosis, fever, headache, malaise.

• Cardiovascular: Necrotizing angiitis, vasculitis, pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation.

• 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.

This information reflects the postmarketing experience with ZYLOPRIM and is based on voluntary reports and surveillance data.

Patient Counseling

Patients should be cautioned to discontinue ZYLOPRIM 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 ZYLOPRIM may be delayed for 2 to 6 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 ZYLOPRIM 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 ZYLOPRIM 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 ZYLOPRIM after meals to minimize gastric irritation.

Storage and Handling

The product is supplied in packaging that ensures its integrity during storage. It should be stored at a temperature range of 15° to 25°C (59° to 77°F) in a dry place. Additionally, it is essential to protect the product from light to maintain its efficacy. Proper handling and storage conditions are crucial to ensure the product's quality and effectiveness.

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 conduct periodic liver function tests in patients with pre-existing liver disease during the initial phases of therapy.

ZYLOPRIM and its active metabolite, oxipurinol, are primarily eliminated via 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 and diabetes mellitus, regular monitoring of renal function parameters, including BUN and serum creatinine or creatinine clearance, is essential. Additionally, for patients receiving dicumarol alongside ZYLOPRIM, periodic reassessment of prothrombin time is recommended.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Zyloprim as submitted by Prometheus Laboratories Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)