Allopurinol

INDICATIONS AND USAGE Allopurinol tablets are indicated for: • The management of adults with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy) • The management of adult and pediatric patients with leukemia, lymphoma and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels • The management of adult patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients, despite lifestyle changes (such as reduction of dietary sodium, non-dairy animal protein, oxalate rich foods, refined sugars and increases in oral fluids and fruits and vegetables) Limitations of Use Allopurinol tablets are not recommended for the treatment of asymptomatic hyperuricemia. Allopurinol tablets are a xanthine oxidase inhibitor indicated for the management of: • Adult patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy) ( 1 ) • Adult and pediatric patients with leukemia, lymphoma and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels ( 1 ) • Adult patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients, despite lifestyle changes ( 1 ) Limitations of Use Allopurinol tablets are not recommended for the treatment of asymptomatic hyperuricemia. ( 1 )

DOSAGE AND ADMINISTRATION Gout : Prior to initiating treatment assess serum uric acid level, complete blood count, chemistry panel, liver and kidney function tests. Prophylactic treatment for gout flares is recommended. ( 2.1 , 2.2 ) Patients with normal kidney function: Initial dosage is 100 mg orally daily. Increase by 100 mg weekly increments until serum uric acid of 6 mg/dl or less is reached (maximum 800 mg daily). ( 2.3 ) Patients with impaired kidney function: The initial dosage is 50 mg orally daily. Follow recommendations for titration in patients with renal impairment until target serum uric acid level is reached. ( 2.6 ) See complete information in the Full Prescribing Information (FPI). Hyperuricemia Associated with Cancer Therapy : The recommended dosage is: Adults: 300 mg to 800 mg orally daily. Pediatric patients: 100 mg/m 2 orally every 8 hours to 12 hours (10 mg/kg/day, maximum 800 mg/day) See complete information in the FPI. ( 2.4 , 2.6 ) Recurrent Calcium Oxalate Calculi : The recommended initial dosage in patients with normal kidney function is 200 mg to 300 mg orally daily. ( 2.5 ) Dosage in Patients with Renal Impairment: See FPI for dosage modifications in patients with renal impairment. ( 2.6 ) 2.1 Recommended Testing Prior to Treatment Initiation Prior to initiating treatment with allopurinol tablets in patients with gout, assess the following baseline tests: serum uric acid level, complete blood count, chemistry panel, liver function tests (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin), kidney function tests (serum creatinine and eGFR). 2.2 Recommended Prophylaxis for Gout Flares Gout flares may occur after initiation of allopurinol tablets due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with colchicine or an anti- inflammatory agent according to practice guidelines is recommended upon initiation of allopurinol tablets. While adjusting the dosage of allopurinol tablets in patients who are being treated with colchicine and/or anti-inflammatory agents, continue flare prophylaxis drugs until serum uric acid has been normalized and the patient has been free of gout flares for several months. If a gout flare occurs during allopurinol tablets treatment, allopurinol tablets need not be discontinued. Manage the gout flare concurrently, as appropriate for the individual patient [see Warnings and Precautions ( 5.2 )]. 2.3 Recommended Dosage for Gout The initial recommended dosage for the management of gout is 100 mg orally daily, with weekly increments of 100 mg, until a serum uric acid level of 6 mg/dL or less is reached. Initiating treatment with lower dosages of allopurinol tablets and titrating slowly, decreases the risk of gout flares and drug induced serious adverse reactions. In patients with renal impairment the initial dosage is 50 mg orally daily with lower dose increases until serum uric acid level of 6 mg/dL or less is reached. For complete dosage recommendations for patients with renal impairment see Table 1 [see Dosage and Administration ( 2.6 )]. The minimal effective dosage is 100 mg to 200 mg daily and the maximal recommended dosage is 800 mg daily. The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300 mg tablet. Doses in excess of 300 mg should be administered in divided doses. Monitor patients’ kidney function during the early stages of administration of allopurinol tablets and decrease the dosage or withdraw the drug if persistent abnormalities in kidney function occur [see Dosage and Administration (2.6), Warnings and Precautions (5.3), Use in Specific Populations ( 8.6 )]. The dosage of allopurinol tablets to achieve control of gout varies with the severity of the disease. In general, gout control is achieved with 200 mg to 300 mg daily in patients with mild gout, and with 400 mg to 600 mg daily in patients with moderate to severe tophaceous gout. Gout attacks usually become shorter and less severe after several months of therapy. If a dose of allopurinol tablets is missed, there is no need to double the dose at the next scheduled time. Allopurinol tablets is generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or preferably, slightly alkaline urine are desirable. Inform patients of the possibility of gout flares [see Warnings and Precautions ( 5.2 )]. Instruct them to remain on allopurinol tablets if this occurs and to increase fluid intake during therapy to prevent kidney stones. Concurrent Use of Uricosuric Agents Some patients, may benefit using uricosuric agents concurrently, to reduce serum uric acid to target levels. When transferring a patient from a uricosuric agent to allopurinol tablets, reduce the dose of the uricosuric agent over a period of several weeks and increase the dose of allopurinol tablets gradually to the required dose needed to maintain target serum uric acid level. 2.4 Recommended Dosage for Hyperuricemia Associated with Cancer Therapy Initiate therapy with allopurinol tablets 24 hours to 48 hours before the start of chemotherapy known to cause tumor cell lysis. Administer fluids sufficient to yield a daily urinary output of at least 2 liters in adults (at least 100 mL/m 2 /hour in pediatric patients) with a neutral or, preferably, slightly alkaline urine. The recommended dosage of allopurinol tablets is: Adult patients – 300 mg to 800 mg orally daily Pediatric patients - 100 mg/m 2 orally every 8 hours to 12 hours (10 mg/kg/day, maximum 800 mg/day). In patients with body surface area < 0.5 m 2 , consider using an alternative allopurinol formulation. The dosage of allopurinol tablets to maintain normal or near-normal serum uric acid varies with the severity of the disease. Monitor serum uric acid levels at least daily and administer allopurinol tablets at a dose and frequency to maintain the serum uric acid within the normal range. Discontinue allopurinol tablets when the risk of tumor lysis has abated (2 days to 3 days from start of chemotherapy). For complete dosage recommendations for patients with renal impairment, see Table 2 [see Dosage and Administration ( 2.6 )] . 2.5 Recommended Dosage for Management of Recurrent Calcium Oxalate Calculi in Hyperuricosuric Patients The recommended dosage for the management of recurrent calcium oxalate stones in hyperuricosuric patients is 200 mg to 300 mg orally daily in divided doses or as the single equivalent. This dose may be adjusted depending upon the resultant control of the hyperuricosuria based upon subsequent 24-hour urinary urate determinations. 2.6 Recommended Dosage in Patients with Renal Impairment The recommended initial dosages of allopurinol tablets in adult patients with renal impairment are shown in Tables 1 and 2 [see Use in Specific Populations ( 8.6 )] . Patients with Gout The recommended initial dosages in adult patients with gout with impaired kidney function are shown in Table 1 [see Use in Specific Populations ( 8.6 )]. Initiate treatment with a lower dose of allopurinol tablets and increase the dose gradually in 50 mg/day increments every 2 weeks to 4 weeks in patients with renal impairment to decrease the risk of drug induced serious adverse reactions. Use the lowest dose possible to achieve the desired effect on serum and/or urine uric acid. Monitor kidney function in gout patients with chronic kidney disease closely when initiating treatment with allopurinol tablets and decrease or withdraw the drug if increased abnormalities in kidney function appear and persist. Table 1. Recommended Initial Dosage in Adult Patients with Gout eGFR Initial Dosage > 60 mL/minute No dosage modification > 30 to 60 mL/minute 50 mg daily > 15 to 30 mL/minute 50 mg every other day 5 to 15 mL/minute 50 mg twice weekly < 5 mL/minute 50 mg once week

WARNINGS AND PRECAUTIONS Skin Rash and Hypersensitivity: Allopurinol has been associated with serious and sometimes fatal dermatological reactions. Discontinue allopurinol tablets at the first appearance of skin rash or other signs of hypersensitivity reaction. (5.1) Gout Flares: May occur during initiation of treatment. Concurrent prophylactic treatment with colchicine or anti-inflammatory agents is recommended. (5.2) Nephrotoxicity: Allopurinol may affect kidney function. Patients with decreased kidney function require lower doses of allopurinol tablets. (5.3) Hepatoxicity: Cases of reversible hepatotoxicity have occurred. If signs and symptoms of hepatotoxicity develop, evaluate liver function. (5.4) Myelosuppression: Bone marrow suppression has been reported with allopurinol. (5.5) Potential Effect on Driving and Use of Machinery: Drowsiness, somnolence and dizziness have been reported in patients taking allopurinol tablets. (5.6) 5.1 Skin Rash and Hypersensitivity Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking allopurinol [see Adverse Reactions (6) ] . These reactions occur in approximately 5 in 10,000 (0.05%) patients taking allopurinol. Other serious hypersensitivity reactions that have been reported include exfoliative, urticarial and purpuric lesions, generalized vasculitis, and irreversible hepatotoxicity. Discontinue allopurinol tablets permanently at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction. The HLA-B*58:01 allele is a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients who carry the HLA-B*58:01 allele are at a higher risk of allopurinol hypersensitivity syndrome (AHS), but hypersensitivity reactions have been reported in patients who do not carry this allele. The frequency of this allele is higher in individuals of African, Asian (e.g., Han Chinese, Korean, Thai), and Native Hawaiian/Pacific Islander ancestry [see Clinical Pharmacology (12.5) ] . The use of allopurinol tablets is not recommended in HLA- B*58:01 positive patients unless the benefits clearly outweigh the risks. Consider screening for HLA-B*5801 before starting treatment with allopurinol tablets in patients from populations in which the prevalence of this HLA-B*5801 allele is known to be high. Screening is generally not recommended in patients from populations in which the prevalence of HLA-B*58:01 is low, or in current allopurinol users, as the risk of SJS/TEN/DRESS is largely confined to the first few months of therapy, regardless of HLA- B*58:01 status. Hypersensitivity reactions to allopurinol tablets may be increased in patients with decreased kidney function receiving thiazide diuretics and allopurinol tablets concurrently. Concomitant use of the following drugs may also increase the risk of skin rash, which may be severe: bendamustine, ampicillin and amoxicillin [see Drug Interactions (7.1) ] . Discontinue allopurinol tablets immediately if a skin rash develops. Instruct patients to stop taking allopurinol tablets immediately and seek medical attention promptly if they develop a rash. 5.2 Gout Flares Gout flares have been reported during initiation of treatment with allopurinol tablets, even when normal or subnormal serum uric acid levels have been attained due to the mobilization of urates from tissue deposits. Even with adequate therapy with allopurinol tablets, it may require several months to deplete the uric acid pool sufficiently to achieve control of the flares. The flares typically become shorter and less severe after several months of therapy. In order to prevent gout flares when treatment with allopurinol tablets is initiated, concurrent prophylactic treatment with colchicine or an anti-inflammatory agent is recommended [see Dosage and Administration (2.2) ] . Advise patients to continue allopurinol tablets and prophylactic treatment even if gout flares occur, as it may take months to achieve control of gout flares. 5.3 Nephrotoxicity Treatment with allopurinol tablets may result in acute kidney injury due to formation of xanthine calculi or due to precipitation of urates in patients receiving concomitant uricosuric agents. Patients with pre-existing kidney disease, including chronic kidney disease or history of kidney stones, may be at increased risk for worsening of kidney function or acute kidney injury due to xanthine calculi while receiving treatment with allopurinol tablets. In patients receiving allopurinol tablets for the management of gout or the management of recurrent calcium oxalate calculi, monitor kidney function frequently during the early stages of allopurinol administration. Maintain fluid intake sufficient to yield a urinary output of at least 2 liters per day of neutral or, preferably, slightly alkaline urine to avoid the possibility of formation of xanthine calculi and help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents. In patients receiving allopurinol tablets for the management of tumor lysis syndrome, monitor kidney function at least daily during the early stages of allopurinol administration. Maintain fluid intake sufficient to yield a urinary output of at least 2 liters per day in adults and at least 2 liters/m 2 /day (or at least 100 mL/m 2 /hour) in pediatric patients [see Dosage and Administration (2.4) ] . 5.4 Hepatotoxicity Cases of reversible clinical hepatotoxicity have occurred in patients taking allopurinol tablets, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol tablets, evaluate liver enzymes. In patients with pre-existing liver disease, monitor liver enzymes periodically. Discontinue allopurinol tablets in patients with elevated liver enzymes. 5.5 Myelosuppression Myelosuppression, manifested by anemia, leukopenia or thrombocytopenia, has been reported in patients receiving allopurinol tablets. The cytopenias have occurred as early as 6 weeks up to 6 years after the initiation of therapy of allopurinol tablets. Concomitant use of allopurinol tablets with cytotoxic drugs associated with myelosuppression may increase the risk of myelosuppression. Monitor blood counts more frequently when cytotoxic drugs are used concomitantly [see Drug Interactions (7.2) ] . Concomitant use with allopurinol increases the exposure of either mercaptopurine or azathioprine which may increase the risk of myelosuppression. Reduce the dosage of mercaptopurine or azathioprine as recommended in their respective prescribing information when used concomitantly with allopurinol tablets [see Drug Interactions (7.2) ] . 5.6 Potential Effect on Driving and Use of Machinery Drowsiness, somnolence and dizziness have been reported in patients taking allopurinol tablets [see Adverse Reactions (6) ] . Inform patients also that the central nervous system depressant effects of allopurinol tablets may be additive to those of alcohol and other CNS depressants. Advise patients to avoid operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness when starting allopurinol tablets or increasing the dose, until they know how the drug affects them. 5.1 Skin Rash and Hypersensitivity Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking allopurinol [see Adverse Reactions (6) ] . These reactions occur in approximately 5 in 10,000 (0.05%) patients taking allopurinol. Other serious hypersensitivity reactions that have been reported include exfoliative, urticarial and purpuric lesions, genera

CONTRAINDICATIONS Allopurinol Tablets are contraindicated in patients with a history of hypersensitivity reaction to allopurinol or to any of the ingredients of Allopurinol Tablets. Known hypersensitivity to allopurinol or to any of the ingredients of allopurinol tablets. ( 4 )

DRUG INTERACTIONS The following drugs may increase the risk of serious skin reactions: bendamustine, thiazide diuretics, ampicillin and amoxicillin. (7.1) Capecitabine: Avoid concomitant use. (7.2) Mercaptopurine or Azathioprine: Reduce mercaptopurine or azathioprine dose as recommended in the respective prescribing information. (7.2) Pegloticase: Discontinue and refrain from initiating treatment with allopurinol tablets. (7.2) See FPI for complete list of significant drug interactions. (7.2) 7.1 Drugs Known to Affect the Occurrence of Skin Rash and Hypersensitivity Concomitant use of the following drugs may increase the risk of skin rash, which may be severe: bendamustine, thiazide diuretics, ampicillin and amoxicillin. Renal impairment may further increase risk with concomitant use of thiazide diuretics [see Warnings and Precautions (5.1, 5.2) and Clinical Pharmacology (12.2) ] . Monitor kidney function and reduce the dose of allopurinol tablets in patients with concomitant thiazide diuretic use and impaired renal function [see Dosage and Administration (2.6), Warnings and Precautions (5.1) ]. Discontinue allopurinol tablets at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction when use concomitantly with these drugs [see Warnings and Precautions (5.1) ] . 7.2 Drugs Known to Have Clinically Important Drug Interactions with Allopurinol Tablets Table 3: Interventions for Clinically Important Drug Interactions with Allopurinol Tablets Capecitabine Clinical Impact Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites, which may decrease capecitabine efficacy. Intervention Avoid the use of allopurinol tablets during treatment with capecitabine Chlorpropamide Clinical Impact Allopurinol tablets prolongs the half-life of chlorpropamide as both compete for renal tubular excretion. In patients with renal insufficiency, the risk of hypoglycemia may be increased due to this mechanism. Intervention Monitor patients with renal insufficiency for hypoglycemia when administering chlorpropamide and allopurinol tablets concomitantly. Cyclosporine Clinical Impact Concomitant use of allopurinol increases cyclosporine concentrations, which may increase the risk of adverse reactions. Intervention Increase frequency of monitoring cyclosporine concentrations as reflected in its prescribing information and modify the dosage of cyclosporine as appropriate when used concomitantly with allopurinol tablets. Cyclophosphamide and Other Cytotoxic Agents Clinical Impact Concomitant use of allopurinol with cyclophosphamide and other cytotoxic agents (doxorubicin, bleomycin, procarbazine, mechloroethamine) increases bone marrow suppression among patients with neoplastic disease, except leukemia. Intervention Blood count monitoring and regular physician follow-up are recommended. Dicumarol Clinical Impact Allopurinol tablets prolongs the half-life of the anticoagulant, dicumarol. The mechanism of this drug interaction has not been established but should be noted when allopurinol tablets is given to patients already on dicumarol therapy. Intervention Monitor prothrombin time. Adjust the dosage of dicumarol accordingly when allopurinol tablets are added to anticoagulant therapy. Fluorouracil Clinical Impact Based on non-clinical data, allopurinol may decrease anti-tumor activity due to suppression of phosphorylation of 5-fluorouracil. Intervention Concomitant administration with fluorouracil should be avoided. Mercaptopurine or Azathioprine Clinical Impact Allopurinol inhibits xanthine oxidase mediated metabolism of mercaptopurine and azathioprine. Concomitant use of allopurinol increases the exposure of either mercaptopurine or azathioprine which may increase the risk of their adverse reactions, including myelosuppression [see Warnings and Precautions 5.5 ]. Intervention In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300 mg to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one third to one fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects. Pegloticase Clinical Impact Concomitant use of allopurinol tablets and pegloticase may potentially blunt the rise of serum uric acid levels and increase the risk of pegloticase related anaphylaxis in patients whose uric acid level increase to above 6 mg/dL. Intervention Discontinue and do not institute allopurinol tablets therapy during treatment with pegloticase. Theophylline Clinical Impact Concomitant use of allopurinol doses greater than or equal to 600 mg/day may decrease the clearance of theophylline Intervention Monitor and adjust theophylline doses as reflected in the prescribing information. Uricosuric Drugs Clinical Impact Uricosuric agents increase the excretion of the active allopurinol metabolite oxypurinol. Concomitant use with uricosuric agents decreases oxypurinol exposure which may reduce the inhibition of xanthine oxidase by oxypurinol and increases the urinary excretion of uric acid. The net effect of such combined therapy may be useful in some patients in achieving minimum serum uric acid levels provided the total urinary uric acid load does not exceed the competence of the patient's kidney function. Intervention Monitor uric acid levels due to the increased chance of hypouricemic effects. Warfarin Clinical Impact Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect. Intervention Monitor patients on concomitant therapy for excessive anticoagulation. Assess INR frequently and adjust warfarin dosage accordingly when allopurinol is added to warfarin therapy. 7.1 Drugs Known to Affect the Occurrence of Skin Rash and Hypersensitivity Concomitant use of the following drugs may increase the risk of skin rash, which may be severe: bendamustine, thiazide diuretics, ampicillin and amoxicillin. Renal impairment may further increase risk with concomitant use of thiazide diuretics [see Warnings and Precautions (5.1, 5.2) and Clinical Pharmacology (12.2) ] . Monitor kidney function and reduce the dose of allopurinol tablets in patients with concomitant thiazide diuretic use and impaired renal function [see Dosage and Administration (2.6), Warnings and Precautions (5.1) ]. Discontinue allopurinol tablets at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction when use concomitantly with these drugs [see Warnings and Precautions (5.1) ] . 7.2 Drugs Known to Have Clinically Important Drug Interactions with Allopurinol Tablets Table 3: Interventions for Clinically Important Drug Interactions with Allopurinol Tablets Capecitabine Clinical Impact Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites, which may decrease capecitabine efficacy. Intervention Avoid the use of allopurinol tablets during treatment with capecitabine Chlorpropamide Clinical Impact Allopurinol tablets prolongs the half-life of chlorpropamide as both compete for renal tubular excretion. In patients with renal insufficiency, the risk of hypoglycemia may be increased due to this mechanism. Intervention Monitor patients with renal insufficiency for hypoglycemia when administering chlorpropamide and allopurinol tablets concomitantly. Cyclosporine Clinical Impact Concomitant use of allopurinol increases cyclosporine concentrations, which may increase the risk of adverse reactions. Intervention Increase frequency of monitoring cyclosporine concentrations as reflected in its prescribing information and modify the dosage of cyclosporine as appropriate when used concomitantly with allopurinol tablets. Cyclophosphamide and Other Cytotoxic Agents Clinical Impact Concomitant use of allopurinol with cyclophosphamide and other cytotoxi

ADVERSE REACTIONS Data upon which the following estimates of incidence of adverse reactions are made are derived from experiences reported in the literature, unpublished clinical trials and voluntary reports since marketing of allopurinol tablets began. Past experience suggested that the most frequent event following the initiation of allopurinol treatment was an increase in acute attacks of gout (average 6% in early studies). An analysis of current usage suggests that the incidence of acute gouty attacks has diminished to less than 1%. The explanation for this decrease has not been determined but may be due in part to initiating therapy more gradually (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). The most frequent adverse reaction to allopurinol tablets is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol tablets should be discontinued immediately if a rash develops (see WARNINGS ). Some patients with the most severe reaction also had fever, chills, arthralgias, cholestatic jaundice, eosinophilia and mild leukocytosis or leukopenia. Among 55 patients with gout treated with allopurinol tablets for 3 to 34 months (average greater than 1 year) and followed prospectively, Rundles observed that 3% of patients developed a type of drug reaction which was predominantly a pruritic maculopapular skin eruption, sometimes scaly or exfoliative. However, with current usage, skin reactions have been observed less frequently than 1%. The explanation for this decrease is not obvious. The incidence of skin rash may be increased in the presence of renal insufficiency. The frequency of skin rash among patients receiving ampicillin or amoxicillin concurrently with allopurinol tablets has been reported to be increased (see PRECAUTIONS ). Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome or drug hypersensitivity syndrome (DHS) has been reported in association with allopurinol use. The syndrome includes many of the severe reactions described above, and is potentially life-threatening and fatal. The syndrome is often characterized by fever, severe and profuse skin rash, elevated leukocyte counts and in particular, elevated eosinophil counts, lymphadenopathy, and multi-organ pathologies. Systemic symptoms often included, but were not limited to, the hepatic and renal systems. Symptoms involving the cardiac, gastrointestinal, lymphatic, pulmonary, and ophthalmic systems were also reported as occurring as part of the syndrome. It has been reported that symptoms may develop in approximately 1 week from initiating allopurinol therapy, but longer latency periods have also been reported. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most Common Reactions* Probably Causally Related: Gastrointestinal : Diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase. Metabolic and Nutritional: Acute attacks of gout. Skin and Appendages: Rash, maculopapular rash. *Early clinical studies and incidence rates from early clinical experience with allopurinol tablets suggested that these adverse reactions were found to occur at a rate of greater than 1%. The most frequent event observed was acute attacks of gout following the initiation of therapy. Analyses of current usage suggest that the incidence of these adverse reactions is now less than 1%. The explanation for this decrease has not been determined, but it may be due to following recommended usage (see ADVERSE REACTIONS introduction, INDICATIONS AND USAGE , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ). 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 (see PRECAUTIONS ). 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.

CLINICAL PHARMACOLOGY Allopurinol acts on purine catabolism, without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. Allopurinol is metabolized to the corresponding xanthine analogue, oxipurinol (alloxanthine), which also is an inhibitor of xanthine oxidase. It has been shown that reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxipurinol. This reutilization does not disrupt normal nucleic acid anabolism, however, because feedback inhibition is an integral part of purine biosynthesis. As a result of xanthine oxidase inhibition, the serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol for treatment of hyperuricemia is usually in the range of 0.3 to 0.4 mg/dL compared to a normal level of approximately 0.15 mg/dL. A maximum of 0.9 mg/dL of these oxypurines has been reported when the serum urate was lowered to less than 2 mg/dL by high doses of allopurinol. These values are far below the saturation levels at which point their precipitation would be expected to occur (above 7 mg/dL). The renal clearance of hypoxanthine and xanthine is at least 10 times greater than that of uric acid. The increased xanthine and hypoxanthine in the urine have not been accompanied by problems of nephrolithiasis. Xanthine crystalluria has been reported in only three patients. Two of the patients had Lesch-Nyhan syndrome, which is characterized by excessive uric acid production combined with a deficiency of the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). This enzyme is required for the conversion of hypoxanthine, xanthine, and guanine to their respective nucleotides. The third patient had lymphosarcoma and produced an extremely large amount of uric acid because of rapid cell lysis during chemotherapy. Allopurinol is approximately 90% absorbed from the gastrointestinal tract. Peak plasma levels generally occur at 1.5 hours and 4.5 hours for allopurinol and oxipurinol, respectively, and after a single oral dose of 300 mg allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol are produced. Approximately 20% of the ingested allopurinol is excreted in the feces. Because of its rapid oxidation to oxipurinol and a renal clearance rate approximately that of the glomerular filtration rate, allopurinol has a plasma half-life of about 1-2 hours. Oxipurinol, however, has a longer plasma half-life (approximately 15 hours), and therefore effective xanthine oxidase inhibition is maintained over a 24-hour period with single daily doses of allopurinol. Whereas allopurinol is cleared essentially by glomerular filtration, oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid. The clearance of oxipurinol is increased by uricosuric drugs, and as a consequence, the addition of a uricosuric agent reduces to some degree the inhibition of xanthine oxidase by oxipurinol and increases to some degree the urinary excretion of uric acid. In practice, the net effect of such combined therapy may be useful in some patients in achieving minimum serum uric acid levels provided the total urinary uric acid load does not exceed the competence of the patient’s renal function. Hyperuricemia may be primary, as in gout, or secondary to diseases such as acute and chronic leukemia, polycythemia vera, multiple myeloma, and psoriasis. It may occur with the use of diuretic agents, during renal dialysis, in the presence of renal damage, during starvation or reducing diets, and in the treatment of neoplastic disease where rapid resolution of tissue masses may occur. Asymptomatic hyperuricemia is not an indication for allopurinol treatment (see INDICATIONS AND USAGE ). Gout is a metabolic disorder which is characterized by hyperuricemia and resultant deposition of monosodium urate in the tissues, particularly the joints and kidneys. The etiology of this hyperuricemia is the overproduction of uric acid in relation to the patient’s ability to excrete it. If progressive deposition of urates is to be arrested or reversed, it is necessary to reduce the serum uric acid level below the saturation point to suppress urate precipitation. Administration of allopurinol generally results in a fall in both serum and urinary uric acid within two to three days. The degree of this decrease can be manipulated almost at will since it is dose-dependent. A week or more of treatment with allopurinol may be required before its full effects are manifested; likewise, uric acid may return to pretreatment levels slowly (usually after a period of seven to ten days following cessation of therapy). This reflects primarily the accumulation and slow clearance of oxipurinol. In some patients a dramatic fall in urinary uric acid excretion may not occur, particularly in those with severe tophaceous gout. It has been postulated that this may be due to the mobilization of urate from tissue deposits as the serum uric acid level begins to fall. Allopurinol’s action differs from that of uricosuric agents, which lower the serum uric acid level by increasing urinary excretion of uric acid. Allopurinol reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid. The use of allopurinol to block the formation of urates avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs. Allopurinol can substantially reduce serum and urinary uric acid levels in previously refractory patients even in the presence of renal damage serious enough to render uricosuric drugs virtually ineffective. Salicylates may be given conjointly for their antirheumatic effect without compromising the action of allopurinol. This is in contrast to the nullifying effect of salicylates on uricosuric drugs. Allopurinol also inhibits the enzymatic oxidation of mercaptopurine, the sulfur-containing analogue of hypoxanthine, to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates mercaptopurine. Hence, the inhibition of such oxidation by allopurinol may result in as much as a 75% reduction in the therapeutic dose requirement of mercaptopurine when the two compounds are given together. Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. Allopurinol is metabolized to the corresponding xanthine analogue, oxipurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.