NADLORIC

Gout is a disease that occurs by the deposition of monosodium urate crystals (MSU) in body tissues, especially around joints 7.

This disease has been well-documented in historical medical records and appears in the biographies of several prominent, historically recognized individuals 7.

Allopurinol is a xanthine oxidase enzyme inhibitor that is considered to be one of the most effective drugs used to decrease urate levels and is frequently used in the treatment of chronic gout 6.

It was initially approved by the

FDA in 1966 12 and is now formulated by several manufacturers 13.

Allopurinol is indicated in

Label: 1) the management of patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy). 2) the management of patients with leukemia, lymphoma and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels.

Treatment with allopurinol should be discontinued when the potential for overproduction of uric acid is no longer present. 3) the management of 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.

Therapy in such patients should be carefully assessed initially and reassessed periodically to determine in each case that treatment is beneficial and that the benefits outweigh the risks.

Allopurinol decreases the production of uric acid by stopping the biochemical reactions that precede its formation Label.

This process decreases urate and relieves the symptoms of gout, which may include painful tophi, joint pain, inflammation, redness, decreased range of motion, and swelling 2.

This drug is about 90% absorbed from the gastrointestinal tract.

Peak plasma levels normally occur at 1.5 hours and 4.5 hours post-dose for allopurinol and oxipurinol respectively.

Following one oral dose of 300 mg of allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol were measured Label.

Allopurinol and oxypurinol are both substrates for the enzyme xanthine oxidase, which is present in the cytoplasm of endothelial cells of capillaries, including sinusoids, with the highest activity demonstrated in the liver and intestinal lining.

Tissue concentrations of allopurinol have not yet been reported in humans, however, it is probable that allopurinol and the metabolite oxypurinol would be measured in the highest concentrations in the abovementioned tissues.

In animals, allopurinol concentrations are found to reach the highest levels in the blood, liver, intestine and heart, and lowest in the brain and lung tissues 9.

Allopurinol is rapidly metabolized to the corresponding xanthine analog, oxipurinol (alloxanthine), which is also an inhibitor of xanthine oxidase enzyme Label.

Both allopurinol and oxypurinol inhibit the action of this enzyme.

Allopurinol and oxypurinol are also converted by the purine salvage pathway to their respective ribonucleotides.

The effect of these ribonucleotides related to the hypouricemic action of allopurinol in humans is not fully elucidated to this date.

These metabolites may act to inhibit de novo purine biosynthesis by inhibiting the enzyme, amidophosphoribosyltransferase.

The ribonucleotides have not been found to be incorporated in DNA 8.

Hover over products below to view reaction partners Allopurinol oxypurinol.

Approximately 80% of Oral ingested allopurinol is found excreted in the urine as various metabolites 9.

About 20% of ingested allopurinol is excreted in the feces Label.

The plasma half-life of allopurinol is 1-2 hours, due to its rapid renal clearance Label.

Since allopurinol and its metabolites are mainly eliminated by the kidney, accumulation of this drug can occur in patients with renal dysfunction or failure, and the dose of allopurinol should, therefore, be reduced.

With a creatinine clearance of 10-20 mL/min, a daily dosage of 200 mg of allopurinol is suitable.

When the creatinine clearance is less than 10 mL/min, the daily dosage should not be higher than 100 mg. With severe renal impairment (creatinine clearance measured at less than 3 mL/min) a longer interval between doses may be required Label.

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TDLO (rat): 10 mg/kg; Oral LD50 (mouse): 78 mg/kg; Oral TDLO (mouse) : 100 mg/kg 14 Use in pregnancy Reproductive studies have been completed using rats and rabbit models at doses up to twenty times the normal human dose ( about 5 mg/kg per day), and it was concluded that fertility was not impaired and there was no fetal harm.

There is a published report of a study in pregnant mice administered 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13.

There were increased numbers of dead fetuses in dams administered 100 mg/kg allopurinol, however, death did not occur in those given 50 mg/kg. There were higher numbers of external malformations in fetuses at both doses of allopurinol on gestation day and higher numbers of skeletal malformations in fetuses at both doses on gestation day 13.

Despite the above findings, there are no adequate or well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if it is absolutely required Label.

Use in nursing

Both allopurinol and the metabolite oxipurinol have been found in the milk of a mother who was receiving allopurinol.

Since the effect of allopurinol on the nursing infant is unknown, it is advisable to exercise caution when allopurinol is taken by a nursing woman Label.

Mutagenicity and carcinogenicity

Cytogenic studies demonstrate that allopurinol does not induce chromosomal abnormalities in human blood cells in vitro at concentrations up to 100 g/mL and in vivo at doses up to 60 mg/day for an average duration of 40 months.

Allopurinol does not form nitroso compounds (which may be carcinogenic) or affect lymphocyte transformation in vitro.

Evidence suggests that allopurinol does not have deleterious effects on DNA at any stage of the cell cycle and was not found to be mutagenic.

No evidence of carcinogenicity has been observed in mice treated with allopurinol for up to a 2 year period 15.

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.

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.

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).

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.

See complete information in the Full Prescribing Information (FPI).

The recommended dosage is: Adults: 300 mg to 800 mg orally daily.

Pediatric patients: 100 mg/m 2 orally every 8 hours to 12 hours (10 mg/kg/day, maximum 800 mg/day) See complete information in the FPI.

The recommended initial dosage in patients with normal kidney function is 200 mg to 300 mg orally daily.

See FPI for dosage modifications in patients with renal impairment. 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. 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.

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.

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 is 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.

Instruct them to remain on allopurinol tablets if this occurs and to increase fluid intake during therapy to prevent kidney stones.

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. 2.4 Recommended Dosage for Hyperuricemia Associated with Cancer Therapy 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 /hour in pediatric patients) with a neutral or, preferably, slightly alkaline urine.

The recommended dosage of allopurinol tablets is: Adult patients – 300 mg to 800 mg orally daily Pediatric patients.

• 100 mg/m 2 orally every 8 hours to 12 hours (10 mg/kg/day, maximum 800 mg/day).

In patients with body surface area < 0.5 m 2, consider using an alternative allopurinol formulation.

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. 2.5 Recommended Dosage for Management of Recurrent Calcium Oxalate Calculi in Hyperuricosuric Patients 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. 2.6 Recommended Dosage in Patients with Renal Impairment The recommended initial dosages of allopurinol tablets in adult patients with renal impairment are shown in Tables and 2.

The recommended initial dosages in adult patients with gout with impaired kidney function are shown in Table 1.

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.

Table 1.

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 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.

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.

Table 2.

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 100 mg every 24 hours 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.

mg Orange, round and biconvex tablets.

The upper layer is bisected and debossed with “2084/V”.

The lower layer is plain.

They are supplied as follows

Bottles of 1000: 63629-2113-1 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.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

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.

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.

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 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.

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.