ALLOPURINOL- allopurinol_tablet

Allopurinol is a structural analogue of the natural purine base, hypoxanthine. Allopurinol 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 Drug Interaction Studies Fluorouracil Pegloticase Cytotoxic Agents Thiazide Diuretics Absorption Elimination Metabolism Excretion Drug Interaction Studies Capecitabine Cyclosporine Mercaptopurine or Azathioprine Theophylline Uricosuric Agents Warfarin HLA-B*5801 allele.

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 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 1.

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). 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. 6 See complete information in the Full Prescribing Information (FPI). Hyperuricemia Associated with Cancer Therapy Adults: 300 mg to 800 mg orally daily. Pediatric patients: 100 mg/m 2 See complete information in the FPI. 6 Recurrent Calcium Oxalate Calculi 2. 5 Dosage in Patients with Renal Impairment: See FPI for dosage modifications in patients with renal impairment. 6 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). 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) 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. see Dosage and Administration (2. 6) see Dosage and Administration (2. 6) Warnings and Precautions (5. 3) Use in Specific Populations (8. 6 ) see Warnings and Precautions (5. 2) 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 Adult patients en dash 300 mg to 800 mg orally daily Pediatric patients - 100 mg/m 2 2 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) 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. 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) see Use in Specific Populations (8. 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 weekly The maximum dosage that should be used in patients with various levels of renal impairment is not defined at different eGFR levels. Patients with Recurrent Calcium Oxalate Calculi see Warnings and Precautions 5. 3 Use in Specific Populations 8. 6 see Use in Specific Populations (8. Recommended Dosage of Allopurinol Tablets in Adult Patients for Management of Hyperuricemia Associated with Cancer Therapy with Renal Impairment eGFR Recommended Dosage > 20 mL/min to 60 mL/min No dosage modification 10 mL/min to 20 mL/min 200 mg/day < 10 mL/min 100 mg/day On dialysis 50 mg every 12 hours, or Treatment with allopurinol tablets have not been studied in pediatric patients with severe renal impairment (eGFR < 20 mL/min) or on dialysis. There is insufficient information to establish dosing for allopurinol tablets in pediatric patients with renal impairment. In these patients, consider the risks and potential benefits before initiating treatment with allopurinol tablets [ see Warnings and Precautions (5.

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 Metabolic and Nutritional Skin and Appendages Less Common Adverse Reactions (< 1%) Body As a Whole Cardiovascular Gastrointestinal Hemic and Lymphatic Musculoskeletal Nervous Respiratory Skin and Appendages Special Senses Urogenital Endocrine Most common adverse reactions (incidence > 1%) are nausea, diarrhea, and increase in liver function tests. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

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.

Pregnancy: May cause fetal harm. 1 Lactation: Advise not to breastfeed. 2 Risk Summary see Data Data Human Data Animal Data 2 2 Risk Summary Hyperuricemia Associated with Cancer Therapy Primary or Secondary Gout Recurrent Calcium Oxalate Calculi Inborn Errors of Metabolism 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.

The following drugs may increase the risk of serious skin reactions: bendamustine, thiazide diuretics, ampicillin and amoxicillin. 1 Capecitabine: Avoid concomitant use. 2 Mercaptopurine or Azathioprine: Reduce mercaptopurine or azathioprine dose as recommended in the respective prescribing information. 2 Pegloticase: Discontinue and refrain from initiating treatment with allopurinol tablets. 2 See FPI for complete list of significant drug interactions. 2 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. 2 Clinical Pharmacology (12. 2) see Dosage and Administration 2. 6 Warnings and Precautions 5. 1 see Warnings and Precautions 5. 1 Table 3: Interventions for Clinically Important Drug Interactions with Allopurinol 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 during treatment with capecitabine Chlorpropamide Clinical Impact Allopurinol 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 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. 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 prolongs the half-life of the anticoagulant, dicumarol. The mechanism of this drug interaction has not been established but should be noted when allopurinol is given to patients already on dicumarol therapy. Intervention Monitor prothrombin time. Adjust the dosage of dicumarol accordingly when allopurinol 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 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. 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.

OVERDOSAGE
In the management of overdosage there is no specific antidote for allopurinol. Both allopurinol and oxipurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol is unknown.
NONCLINICAL TOXICOLOGY
No evidence of tumorigenicity was observed in male or female mice or rats that received oral allopurinol for the majority of their life spans (greater than 88 weeks) at doses up to 20 mg/kg/day (0.1 and 0.2 times the MRHD on a mg/m 2 2

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