Allopurinol

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, 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 )

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) o 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) o 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) o See complete information in the Full Prescribing Information (FPI). • Hyperuricemia Associated with Cancer Therapy: The recommended dosage is: o Adults: 300 mg to 800 mg orally daily. o Pediatric patients: 100 mg/m 2 orally every 8 hours to 12 hours (10 mg/kg/day, maximum 800 mg/day) o 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 pati …

3 DOSAGE FORMS AND STRENGTHS Allopurinol tablets, USP 100 mg, 200 mg and 300 mg have functional scoring and are available in the following strengths: • 100 mg: White to off-white colored, flat faced beveled edged, functionally scored, round tablet, debossed on the scored side with “0” above the score and “21” below the score and debossed on the non-scored side with “100”. • 200 mg: White to off white colored, biconvex, functionally scored, round tablet, debossed on the scored side with “B” on one side of score, “1” on another side of score and plain on the non-scored side. • 300 mg: Peach colored, flat faced beveled edged, functionally scored, round tablet, debossed on the scored side with “300” above the score and “020” below the score and plain on the non-scored side. Allopurinol tablets, USP: 100 mg, 200 mg and 300 mg, functionally scored

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. ( 4 )

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 Lympha …

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 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 m …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animals, allopurinol tablets may cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been described in exposed animals (see Data). Allopurinol and its metabolite oxypurinol have been shown to cross the placenta following administration of maternal allopurinol. Available limited published data on allopurinol use in pregnant women do not demonstrate a clear pattern or increase in frequency of adverse developmental outcomes. Among approximately 50 pregnancies described in published literature, 2 infants with major congenital malformations have been reported with following maternal allopurinol exposure. Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Experience with allopurinol tablets during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol tablets. A case report published in 2011 described the outcome of a full-term pregnancy in a 35-year-old woman who had recurrent kidney stones since age 18 who took allopurinol throughout the pregnancy. The child had multiple complex birth defects and died at 8 days of life. A second report in 2013 provided data on 31 prospectively ascertained pregnancies involving mothers exposed to allopurinol for varying durations during the first trimester. The overall rate of major fetal malformations and spontaneous abortions was reported to be within the normal expected range; however, one child had severe malformations similar to those described in the cited earlier case report. Animal Data There was no evidence of fetotoxicity or teratogenicity in rats or rabbits treated during the period of organogenesis with oral allopurinol at doses up to 200 mg/kg/day and up to 100 mg/kg/day, respectively (about 2.4 times the human dose on a mg/m 2 basis). However, there is a published report in pregnant mice that single intraperitoneal doses of 50 mg/kg or 100 mg/kg (about 0.3 or 0.6 times the human dose on a mg/m 2 basis) of allopurinol on gestation days 10 or 13 produced significant increases in fetal deaths and teratogenic effects (cleft palate, harelip, and digital defects). It is uncertain whether these findings represented a fetal effect or an effect secondary to maternal toxicity. 8.2 Lactation Risk Summary Allopurinol and oxypurinol are present in human milk. Based on information from a single case report, allopurinol and its active metabolite, oxypurinol, were detected in the milk of a mother receiving 300 mg of allopurinol daily at 5 weeks postpartum. The estimated relative infant dose were 0.14 mg/kg and 0.2 mg/kg of allopurinol and between 7.2 mg/kg to 8 mg/kg of oxypurinol daily. There was no report of effects of allopurinol on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatments with allopurinol tablets and for one week after the last dose. 8.3 Nursing Mothers 8.4 Pediatric Use Hyperuricemia Associated with Cancer Therapy The safety and effectiveness of allopurinol for the management of pediatric patients with leukemia, lymphoma and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels have been established in approximately 200 pediatric patients. The efficacy and safety profile observed in this patient population were similar to that observed in adults. Primary or Seco …

12.1 Mechanism of Action Allopurinol Tablets (allopurinol) is a structural analogue of the natural purine base, hypoxanthine. 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. 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 humans. Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.

11 DESCRIPTION Allopurinol is a xanthine oxidase inhibitor. It has the following structural formula: Allopurinol is known chemically as 1, 5-dihydro-4 H -pyrazolo [3, 4-d]pyrimidin-4-one. and it has a molecular weight of 136.11 g/mol. Its solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution. It is a xanthine oxidase inhibitor which is administered orally. Each scored white to off white round tablet contains 100 mg allopurinol and the inactive ingredients crospovidone, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone. Each scored white to off white round tablet contains 200 mg allopurinol and the inactive ingredients crospovidone, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, and povidone. Each scored peach round tablet contains 300 mg allopurinol and the inactive ingredients crospovidone, colloidal silicon dioxide, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, pregelatinized starch and povidone. Allopurinol structure 1

OVERDOSAGE Massive overdosing or acute poisoning by allopurinol tablets has not been reported. In mice, the 50% lethal dose (LD 50 ) is 160 mg/kg given intraperitoneally (IP) with deaths delayed up to 5 days and 700 mg/kg orally (PO) (approximately 140 times the usual human dose) with deaths delayed up to 3 days. In rats, the acute LD 50 is 750 mg/kg IP and 6000 mg/kg PO (approximately 1200 times the human dose). In the management of overdosage there is no specific antidote for allopurinol tablets. There has been no clinical experience in the management of a patient who has taken massive amounts of allopurinol tablets. Both allopurinol and oxipurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol tablets is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Allopurinol is available in multiple tablet strengths with functional scoring and package sizes as listed in Table 4. TABLE 4: Allopurinol Tablets Presentations Tablet Strength Tablet Description Package Sizes (NDC) 100 mg White to off white scored, flat cylindrical tablet with "I" and '135' on either side of the break line on one side and plain on other side. Bottles of: 30 tablets with child-resistant closure, (NDC 14445- 170 -30) 100 tablets with child-resistant closure, (NDC 14445- 170 -01) 500 tablets (NDC 14445- 170 -05) 1,000 tablets (NDC 14445- 170 -00) 200 mg White to off white round shape beveled concave tablets embossed with "E" and "35" on the either side of break line on upper punch and plain on lower punch. Bottles of: 90 tablets with child-resistant closure, (NDC 14445- 172 -90) 100 tablets with child-resistant closure, (NDC 14445- 172 -01) 500 tablets with child-resistant closure, (NDC 14445- 172 -05) 1,000 tablets with child-resistant closure, (NDC 14445- 172 -00) 100 Tablets (10 x 10 Unit dose) (NDC 14445- 172 -10) 300 mg Peach, scored, flat cylindrical tablet with "I" and '136' on either side of the break line on one side and plain on other side. Bottles of: 100 tablets with child-resistant closure,(NDC 14445- 171 -01) 500 tablets (NDC 14445- 171 -05) 1000 tablets (NDC 14445- 171 -00) Storage and Handling Store at 20°C to 25°C (USP Controlled Room Temperature) (68°F to 77°F) in a dry place. Dispense in a tight container as defined in the USP.