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1 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, oxylate 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 )

2 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…

12.2 Pharmacodynamics Allopurinol tablets reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation in a dose dependent manner. The pharmacological action of allopurinol is generally believed to be mediated by its oxypurinol metabolite. Effect on Hypoxanthine and Xanthine Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol tablets 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 tablets for treatment of hyperuricemia is usually in the range of 0.3 mg/dL 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 tablets. These values are far below the saturation levels at which point their precipitation would be expected to occur (above 7 mg/dL). The increased xanthine and hypoxanthine in the urine in patients who were treated with oral allopurinol have not been accompanied by problems of nephrolithiasis; however, there are isolated case reports of xanthine crystalluria. Drug Interaction Studies Fluorouracil: Based on non-clinical data, allopurinol may decrease anti-tumor activity due to suppression of phosphorylation of 5-fluorouracil. Pegloticase : Concomitant use of allopurinol tablets and pegloticase may potentially blunt the rise of serum uric acid levels required for monitoring the safe use of pegloticase. Cytotoxic Agents : Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of…

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Skin Rash and Hypersensitivity [see Warnings and Precautions ( 5.1 )] Nephrotoxicity [see Warnings and Precautions ( 5.3 )] Hepatoxicity [see Warnings and Precautions ( 5.4 )] Myelosuppression [see Warnings and Precautions ( 5.5 )] Potential Effect on Driving and Use of Machinery [see Warnings and Precautions ( 5.6 )] The following adverse reactions associated with the use of allopurinol tablets were identified in literature, unpublished clinical trials or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequent adverse reaction to allopurinol tablets is skin rash. Most Common Adverse Reactions (≥ 1%) Gastrointestinal : Diarrhea, nausea, alkaline phosphatase increase, AST/ALT increase. Metabolic and Nutritional : Acute attacks of gout. Skin and Appendages : Rash, maculopapular rash. Less Common Adverse Reactions (< 1%) 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, hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, anorexia. Hemic and Lymphatic: Thrombocytopenia, eosinophilia, leukocytosis, leukopenia, aplastic anemia, agranulocytosis, eosinophilic fibrohistiocytic lesion of bone marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis. Musculoskeletal: Myopathy, arthralgias, myalgia. Nervous: Peripheral…

4 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.

5 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-B58:01 allele is a genetic marker for severe skin reactions indicative of hypersensitivity to allopurinol. Patients who carry the HLA-B58:01 allele are at a higher risk of allopurinol hypersensitivity syndrome (AHS), but hypersensitivity reactions have been reported in patients who do not carry this…

7 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 prolong 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…