Allopurinol

Allopurinol tablet is 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 tablet is not recommended for the treatment of asymptomatic hyperuricemia. Allopurinol tablet is 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 tablet is not recommended for the treatment of asymptomatic hyperuricemia. ( 1 )

Allopurinol tablets have functional scoring and are available in the following strengths: 100 mg: A flat-faced raised hexagon, beveled edge, white to off-white tablet, one side engraved “ZYLOPRIM 100” with a score bar and the other side plain. 200 mg: White to off-white, biconvex, round, scored tablets, imprinted “ZYLOPRIM” about the upper periphery, and 200 on the lower half, below the score and plain on the other side. 300 mg: A flat-faced raised hexagon, beveled edge, peach tablet, one side engraved “ZYLOPRIM 300” with a score bar and the other side plain. Tablets: 100 mg, 200 mg, and 300 mg, functionally scored.

Allopurinol tablet is 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.

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.

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 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 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 neuropathy, neuritis, paresthesia, somnolence, optic neuritis, confusion, dizziness, vertigo, foot drop, decrease in libido, depression, amnesia, tinnitus, asthenia, insomnia. Respiratory : Epistaxis, bronchospasm, asthma, pharyngitis, rhinitis. 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, furunculosis, facial edema, sweating, skin edema. Special Senses : Taste loss/perversion, cataracts, macular retinitis, iritis, conjunctivitis, amblyopia. Urogenital : Renal failure, uremia, nephritis, impotence, primary hematuria, albuminuria. Endocrine : Infertility (male), hypercalcemia, gynecomastia (male). Most common adverse reactions (incidence > 1%) are nausea, diarrhea, and increase in liver function tests. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 tablet is given to patients already on dicumarol therapy. Intervention Monitor prothrombin time. Adjust the dosage of dicumarol accordingly when allopurinol tablet is 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 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 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.

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 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 during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol. 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 and for one week after the last dose.

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 Secondary Gout The safety and effectiveness of allopurinol have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. Recurrent Calcium Oxalate Calculi The safety and effectiveness of allopurinol have not been established for the management of pediatric patients with recurrent calcium oxalate calculi. Inborn Errors of Metabolism The safety and effectiveness of allopurinol have not been established in pediatric patients with rare inborn errors of purine metabolism.

8.6 Renal Impairment Allopurinol and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore, changes in renal function have a profound effect on exposure. In patients with decreased renal function or who have concurrent illnesses which can affect renal function, perform periodic laboratory parameters of renal function and reassess the patient's dosage of allopurinol [ see Dosage and Administration (2.6) , Warnings and Precautions (5.3) ].

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.