ALLOPURINOL- allopurinol_tablet

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 2
CLINICAL PHARMACOLOGY
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. 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. 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 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. 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. Based on non-clinical data, allopurinol may decrease anti-tumor activity due to suppression of phosphorylation of 5-fluorouracil. 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. Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of allopurinol tablets. Reports that the concomitant administration of allopurinol and thiazide diuretics contributed to increased allopurinol toxicity were reviewed; however, a causal mechanism or cause-and-effect relationship was not found. 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. After a single oral dose of 300 mg allopurinol tablets, maximum plasma levels of about 3 mcg/mL of allopurinol and 6. 5 mcg/mL of oxipurinol are produced. The half-life of allopurinol and oxipurinol are approximately 1 hour to 2 hours and 15 hours following oral dose of allopurinol tablets, respectively. Allopurinol tablets and its primary active metabolite, oxipurinol, are eliminated by the kidneys. Approximately 20% of the ingested allopurinol tablets are excreted in the feces. Oxipurinol is primarily eliminated unchanged in urine by glomerular filtration and tubular reabsorption. Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites, which may decrease capecitabine efficacy. Concomitant use of allopurinol increases cyclosporine concentrations which may increase the risk of adverse reactions. 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. Concomitant use of allopurinol doses greater than or equal to 600 mg/day may decrease the clearance of theophylline. 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. Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect. The HLA-B * * * Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) can still occur in patients who are found to be negative for HLA-B *.
Metabolism
Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.
Excretion
Allopurinol tablets and its primary active metabolite, oxipurinol, are eliminated by the kidneys. Approximately 20% of the ingested allopurinol tablets are excreted in the feces. Oxipurinol is primarily eliminated unchanged in urine by glomerular filtration and tubular reabsorption.

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 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 is not recommended for the treatment of asymptomatic hyperuricemia.

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. 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 are 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) 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. 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 The recommended dosage of allopurinol tablets is: 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) 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. 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 Data are insufficient to provide dosage recommendations for the treatment of recurrent calcium oxalate calculi in patients with renal impairment. Allopurinol and its metabolites are excreted by the kidney, and accumulation of the drug can occur in renal failure [see Warnings and Precautions (5. 6) Hyperuricemia Associated with Cancer Therapy The recommended dosage of allopurinol tablets for the management of hyperuricemia associated with cancer therapy in adult patients with renal impairment is shown in Table 2 [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 has 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 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: 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, Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 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 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. 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. 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. 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 2 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. 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. The safety and effectiveness of allopurinol tablets have not been established for the treatment of signs and symptoms of primary or secondary gout in pediatric patients. The safety and effectiveness of allopurinol tablets have not been established for the management of pediatric patients with recurrent calcium oxalate calculi. The safety and effectiveness of allopurinol tablets have not been established in pediatric patients with rare inborn errors of purine metabolism. Allopurinol tablets 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 tablets [see Dosage and Administration (2. 6) Warnings and Precautions (5.

DRUG INTERACTIONS
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) 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) 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, mechlorethamine) 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 prolong the half-life of the anticoagulant, dicumarol. The mechanism of this drug interaction has not been established but should be noted when allopurinol tablets are 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 Impac 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.
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 allopurinol tablets.
Thiazide Diuretics
Reports that the concomitant administration of allopurinol and thiazide diuretics contributed to increased allopurinol toxicity were reviewed; however, a causal mechanism or cause-and-effect relationship was not found.
Capecitabine
Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites, which may decrease capecitabine efficacy.
Cyclosporine
Concomitant use of allopurinol increases cyclosporine concentrations which may increase the risk of adverse reactions.
Mercaptopurine or Azathioprine
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.
Theophylline
Concomitant use of allopurinol doses greater than or equal to 600 mg/day may decrease the clearance of theophylline.
Uricosuric Agents
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.
Warfarin
Allopurinol may inhibit the metabolism of warfarin, possibly enhancing its anticoagulant effect.

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.
OVERDOSAGE
In the management of overdosage there is no specific antidote for 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.
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 Allopurinol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay. Allopurinol administered intravenously to rats (50 mg/kg) was not incorporated into rapidly replicating intestinal DNA. No evidence of clastogenicity was observed in lymphocytes taken from patients treated with allopurinol (mean duration of treatment 40 months), or in an in vitro assay with human lymphocytes. Allopurinol oral doses of 20 mg/kg/day had no effect on male or female fertility in rats or rabbits (approximately 0.2 or 0.5 times the MRHD on a mg/m 2

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