ALLOPURINOL- allopurinol tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ALLOPURINOL (UNII: 63CZ7GJN5I) (ALLOPURINOL - UNII:63CZ7GJN5I)
Available from:
Cardinal Health
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF ASYMPTOMATIC HYPERURICEMIA. Allopurinol reduces serum and urinary uric acid concentrations. Its use should be individualized for each patient and requires an understanding of its mode of action and pharmacokinetics (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). Allopurinol is indicated in: Patients who have developed a severe reaction to allopurinol should not be restarted on the drug.
Product summary:
100 mg (white) scored, flat-faced beveled edge round tablets debossed with "2083/V". They are supplied as follows: Overbagged with 10 tablets per bag, NDC 55154-7892-0 300 mg (orange) scored, round tablets debossed with "2084/V". They are supplied as follows: Overbagged with 10 tablets per bag, NDC 55154-7981-0 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
55154-7892-0, 55154-7981-0

ALLOPURINOL- allopurinol tablet

Cardinal Health

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Allopurinol Tablets USP

Rx only

DESCRIPTION

Allopurinol, USP has the following structural formula:

Allopurinol, USP is known chemically as 1, 5-dihydro-4 H-pyrazolo [3, 4- d] pyrimidin-4-one. It is a

xanthine oxidase inhibitor which is administered orally. Each scored white tablet contains 100 mg

allopurinol and the inactive ingredients colloidal silicon dioxide, lactose monohydrate, magnesium

stearate, microcrystalline cellulose and sodium starch glycolate. Each scored orange tablet contains

300 mg allopurinol and the inactive ingredients colloidal silicon dioxide, FD&C Yellow No. 6 Lake,

lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Soluble in solutions of potassium and sodium hydroxides, very slightly soluble in water and in alcohol;

practically insoluble in chloroform and in ether.

CLINICAL PHARMACOLOGY

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.

Allopurinol is a structural analogue of the natural purine base, hypoxanthine. 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 man. Allopurinol is metabolized to the

corresponding xanthine analogue, oxipurinol (alloxanthine), which also is an inhibitor of xanthine

oxidase.

It has been shown that 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 for treatment of hyperuricemia is usually

in the range of 0.3 to 0.4 mg/dL compared to a normal level of approximately 0.15 mg/dL. 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. These values are far below the saturation levels at which point

their precipitation would be expected to occur (above 7 mg/dL).

The renal clearance of hypoxanthine and xanthine is at least 10 times greater than that of uric acid. The

increased xanthine and hypoxanthine in the urine have not been accompanied by problems of

nephrolithiasis. Xanthine crystalluria has been reported in only three patients. Two of the patients had

Lesch-Nyhan syndrome, which is characterized by excessive uric acid production combined with a

deficiency of the enzyme, hypoxanthineguanine phosphoribosyltransferase (HGPRTase). This enzyme

is required for the conversion of hypoxanthine, xanthine, and guanine to their respective nucleotides.

The third patient had lymphosarcoma and produced an extremely large amount of uric acid because of

rapid cell lysis during chemotherapy.

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, and after a single

oral dose of 300 mg allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5

mcg/mL of oxipurinol are produced.

Approximately 20% of the ingested allopurinol is excreted in the feces. Because of its rapid oxidation

to oxipurinol and a renal clearance rate approximately that of glomerular filtration rate, allopurinol has a

plasma half-life of about 1 to 2 hours. Oxipurinol, however, has a longer plasma half-life

(approximately 15 hours) and therefore effective xanthine oxidase inhibition is maintained over a 24-

hour period with single daily doses of allopurinol. Whereas allopurinol is cleared essentially by

glomerular filtration, oxipurinol is reabsorbed in the kidney tubules in a manner similar to the

reabsorption of uric acid.

The clearance of oxipurinol is increased by uricosuric drugs, and as a consequence, the addition of a

uricosuric agent reduces to some degree the inhibition of xanthine oxidase by oxipurinol and increases

to some degree the urinary excretion of uric acid. In practice, 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 renal function.

Hyperuricemia may be primary, as in gout, or secondary to diseases such as acute and chronic leukemia,

polycythemia vera, multiple myeloma, and psoriasis. It may occur with the use of diuretic agents, during

renal dialysis, in the presence of renal damage, during starvation or reducing diets, and in the treatment

of neoplastic disease where rapid resolution of tissue masses may occur. Asymptomatic hyperuricemia

is not an indication for treatment with allopurinol (see INDICATIONS AND USAGE).

Gout is a metabolic disorder which is characterized by hyperuricemia and resultant deposition of

monosodium urate in the tissues, particularly the joints and kidneys. The etiology of this hyperuricemia

is the overproduction of uric acid in relation to the patient's ability to excrete it. If progressive

deposition of urates is to be arrested or reversed, it is necessary to reduce the serum uric acid level

below the saturation point to suppress urate precipitation.

Administration of allopurinol generally results in a fall in both serum and urinary uric acid within 2 to 3

days. The degree of this decrease can be manipulated almost at will since it is dose-dependent. A week

or more of treatment with allopurinol may be required before its full effects are manifested; likewise,

uric acid may return to pretreatment levels slowly (usually after a period of 7 to 10 days following

cessation of therapy). This reflects primarily the accumulation and slow clearance of oxipurinol. In

some patients a dramatic fall in urinary uric acid excretion may not occur, particularly in those with

severe tophaceous gout. It has been postulated that this may be due to the mobilization of urate from

tissue deposits as the serum uric acid level begins to fall.

The action of allopurinol differs from that of uricosuric agents, which lower the serum uric acid level

by increasing urinary excretion of uric acid. Allopurinol reduces both the serum and urinary uric acid

levels by inhibiting the formation of uric acid. The use of allopurinol to block the formation of urates

avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs.

Allopurinol can substantially reduce serum and urinary uric acid levels in previously refractory patients

even in the presence of renal damage serious enough to render uricosuric drugs virtually ineffective.

Salicylates may be given conjointly for their antirheumatic effect without compromising the action of

allopurinol. This is in contrast to the nullifying effect of salicylates on uricosuric drugs.

Allopurinol also inhibits the enzymatic oxidation of mercaptopurine, the sulfur-containing analogue of

hypoxanthine, to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates

mercaptopurine. Hence, the inhibition of such oxidation by allopurinol may result in as much as a 75%

reduction in the therapeutic dose requirement of mercaptopurine when the two compounds are given

together.

INDICATIONS AND USAGE

THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF

ASYMPTOMATIC HYPERURICEMIA.

Allopurinol reduces serum and urinary uric acid concentrations. Its use should be individualized for

each patient and requires an understanding of its mode of action and pharmacokinetics (see CLINICAL

PHARMACOLOGY, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Allopurinol is indicated in:

the management of patients with signs and symptoms of primary or secondary gout (acute attacks,

tophi, joint destruction, uric acid lithiasis, and/or nephropathy).

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.

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

CONTRAINDICATIONS

Patients who have developed a severe reaction to allopurinol should not be restarted on the drug.

WARNINGS

ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH

OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION. In some instances a skin

rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial, and

purpuric lesions, as well as Stevens-Johnson syndrome (erythema multiforme exudativum), Drug Rash

with Eosinophilia and Systemic Symptoms (DRESS) and/or generalized vasculitis, irreversible

hepatotoxicity, and, on rare occasions, death (see ADVERSE REACTIONS).

In patients receiving PURINETHOL (mercaptopurine) or IMURAN (azathioprine), the concomitant

administration of 300 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 (see CLINICAL PHARMACOLOGY).

A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol, 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, evaluation of liver

function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic

liver function tests are recommended during the early stages of therapy.

Due to the occasional occurrence of drowsiness, patients should be alerted to the need for due

precaution when engaging in activities where alertness is mandatory.

The occurrence of hypersensitivity reactions to allopurinol may be increased in patients with decreased

renal function receiving thiazides and allopurinol concurrently. For this reason, in this clinical setting,

such combinations should be administered with caution and patients should be observed closely.

PRECAUTIONS

General: An increase in acute attacks of gout has been reported during the early stages of administration

of allopurinol, even when normal or subnormal serum uric acid levels have been attained. Accordingly,

maintenance doses of colchicine generally should be given prophylactically when allopurinol is begun.

In addition, it is recommended that the patient start with a low dose of allopurinol (100 mg daily) and

increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but

without exceeding the maximum recommended dose (800 mg per day). The use of colchicine or anti-

inflammatory agents may be required to suppress gouty attacks in some cases. The attacks usually

become shorter and less severe after several months of therapy. The mobilization of urates from tissue

deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these

episodes. Even with adequate therapy with allopurinol, it may require several months to deplete the uric

acid pool sufficiently to achieve control of the acute attacks.

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 to (1) avoid the theoretical possibility of formation

of xanthine calculi under the influence of therapy with allopurinol and (2) help prevent renal

precipitation of urates in patients receiving concomitant uricosuric agents.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during

administration of allopurinol. Although the mechanism responsible for this has not been established,

patients with impaired renal function should be carefully observed during the early stages of

treatment is beneficial and that the benefits outweigh the risks.

administration of allopurinol and the dosage decreased or the drug withdrawn if increased abnormalities

in renal function appear and persist.

Renal failure in association with administration of allopurinol has been observed among patients with

hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and

congestive myocardial disease were present among those patients whose renal dysfunction increased

after allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy and

rarely with hypersensitivity reactions associated with allopurinol. Albuminuria has been observed

among patients who developed clinical gout following chronic glomerulonephritis and chronic

pyelonephritis.

Patients with decreased renal function require lower doses of allopurinol than those with normal renal

function. Lower than recommended doses should be used to initiate therapy in any patients with

decreased renal function and they should be observed closely during the early stages of administration

of allopurinol. In patients with severely impaired renal function or decreased urate clearance, the half-

life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg

twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to

reduce serum urate levels.

Bone marrow depression has been reported in patients receiving allopurinol, most of whom received

concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to

as long as 6 years after the initiation of therapy of allopurinol. Rarely, a patient may develop varying

degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol

alone.

Information for Patients: Patients should be informed of the following:

(1) They should be cautioned to discontinue allopurinol and to consult their physician immediately at the

first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the

lips or mouth. (2) They should be reminded to continue drug therapy prescribed for gouty attacks since

optimal benefit of allopurinol may be delayed for 2 to 6 weeks. (3) They should be encouraged to

increase fluid intake during therapy to prevent renal stones. (4) If a single dose of allopurinol is

occasionally forgotten, there is no need to double the dose at the next scheduled time. (5) There may be

certain risks associated with the concomitant use of allopurinol and dicumarol, sulfinpyrazone,

mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics, and they should follow the

instructions of their physician. (6) Due to the occasional occurrence of drowsiness, patients should take

precautions when engaging in activities where alertness is mandatory. (7) Patients may wish to take

allopurinol after meals to minimize gastric irritation.

Laboratory Tests: The correct dosage and schedule for maintaining the serum uric acid within the

normal range is best determined by using the serum uric acid as an index.

In patients with pre-existing liver disease, periodic liver function tests are recommended during the

early stages of therapy (see WARNINGS).

Allopurinol and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore,

changes in renal function have a profound effect on dosage. In patients with decreased renal function or

who have concurrent illnesses which can affect renal function such as hypertension and diabetes

mellitus, periodic laboratory parameters of renal function, particularly BUN and serum creatinine or

creatinine clearance, should be performed and the patient's dosage of allopurinol reassessed.

The prothrombin time should be reassessed periodically in the patients receiving dicumarol who are

given allopurinol.

Drug Interactions: In patients receiving mercaptopurine or IMURAN (azathioprine), the concomitant

administration of 300 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 (see CLINICAL PHARMACOLOGY).

It has been reported that allopurinol prolongs the half-life of the anticoagulant, dicumarol. The clinical

basis of this drug interaction has not been established but should be noted when allopurinol is given to

patients already on dicumarol therapy.

Since the excretion of oxipurinol is similar to that of urate, uricosuric agents, which increase the

excretion of urate, are also likely to increase the excretion of oxipurinol and thus lower the degree of

inhibition of xanthine oxidase. The concomitant administration of uricosuric agents and allopurinol has

been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an

increase in urinary uric acid excretion compared with that observed with allopurinol alone. Although

clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on

allopurinol alone or in combination with uricosuric agents, the possibility should be kept in mind.

The reports that the concomitant use of allopurinol and thiazide diuretics may contribute to the

enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a

cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that

the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out

decreased renal function secondary to hypertensive nephropathy were not often performed. In those

patients in whom renal insufficiency was documented, however, the recommendation to lower the dose

of allopurinol was not followed. Although a causal mechanism and a cause-and-effect relationship have

not been established, current evidence suggests that renal function should be monitored in patients on

thiazide diuretics and allopurinol even in the absence of renal failure, and dosage levels should be even

more conservatively adjusted in those patients on such combined therapy if diminished renal function is

detected.

An increase in the frequency of skin rash has been reported among patients receiving ampicillin or

amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs. The

cause of the reported association has not been established.

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. However, in a

well-controlled study of patients with lymphoma on combination therapy, allopurinol did not increase

the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine,

and/or mechlorethamine.

Tolbutamide's conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase

from rat liver. The clinical significance, if any, of these observations is unknown.

Chlorpropamide's plasma half-life may be prolonged by allopurinol, since allopurinol and

chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to

this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the

presence of renal insufficiency.

Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with

allopurinol. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should

be considered when these drugs are co-administered.

Drug/Laboratory Test Interactions: Allopurinol is not known to alter the accuracy of laboratory tests.

Pregnancy: Teratogenic Effects:Reproductive studies have been performed in rats and rabbits at doses

up to twenty times the usual human dose (5 mg/kg per day), and it was concluded that there was no

impaired fertility or harm to the fetus due to allopurinol. There is a published report of a study in

pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There

were increased numbers of dead fetuses in dams given 100 mg/kg allopurinol but not in those given 50

mg/kg. There were increased numbers of external malformations in fetuses at both doses of allopurinol

on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on

gestation day 13. It cannot be determined whether this represented a fetal effect or an effect secondary

to maternal toxicity. There are, however, 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 clearly needed.

Experience with allopurinol during human pregnancy has been limited partly because women of

reproductive age rarely require treatment with allopurinol. However, in 2011, a literature publication

case report describes 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 (Hoeltzenbein M et al (2013);

PLoS ONE 8(6): e66637), 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.

Nursing Mothers: Allopurinol and 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, caution should be

exercised when allopurinol is administered to a nursing woman.

Pediatric Use: Allopurinol is rarely indicated for use in children with the exception of those with

hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism (see

INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).

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 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 is skin rash. Skin reactions can be severe and

sometimes fatal. Therefore, treatment with allopurinol 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 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 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 Par Pharmaceutical at 1-800-828-

9393 or FDA at 1-800-FDA-1088 or http://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 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 Lymphatic: Thrombocytopenia, eosinophilia, leukocytosis, leukopenia.

Musculoskeletal: Myopathy, arthralgias.

Nervous: Peripheral neuropathy, neuritis, paresthesia, somnolence.

Respiratory: Epistaxis.

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.

Special Senses: Taste loss/perversion.

Urogenital: Renal failure, uremia (see PRECAUTIONS).

Incidence Less Than 1% Causal Relationship Unknown:

Body As a Whole: Malaise.

Cardiovascular: Pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation.

Endocrine: Infertility (male), hypercalcemia, gynecomastia (male).

Gastrointestinal: Hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling,

hyperlipidemia, tongue edema, anorexia.

Hemic and Lymphatic: Aplastic anemia, agranulocytosis, eosinophilic fibrohistiocytic lesion of bone

marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia,

reticulocytosis, lymphadenopathy, lymphocytosis.

Musculoskeletal: Myalgia.

Nervous: Optic neuritis, confusion, dizziness, vertigo, foot drop, decrease in libido, depression,

amnesia, tinnitus, asthenia, insomnia.

Respiratory: Bronchospasm, asthma, pharyngitis, rhinitis.

Skin and Appendages: Furunculosis, facial edema, sweating, skin edema.

Special Senses: Cataracts, macular retinitis, iritis, conjunctivitis, amblyopia.

Urogenital: Nephritis, impotence, primary hematuria, albuminuria.

OVERDOSAGE

Massive overdosing or acute poisoning by allopurinol has not been reported.

In mice, the 50% lethal dose (LD ) 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 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. There has been no

clinical experience in the management of a patient who has taken massive amounts of 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.

DOSAGE AND ADMINISTRATION

The dosage of allopurinol to accomplish full control of gout and to lower serum uric acid to normal or

near-normal levels varies with the severity of the disease. The average is 200 to 300 mg/day for

patients with mild gout and 400 to 600 mg/day for those with moderately severe tophaceous gout. The

appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300

mg-tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The

minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily.

To reduce the possibility of flare-up of acute gouty attacks, it is recommended that the patient start with

a low dose of allopurinol (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric

acid level of 6 mg/dL or less is attained but without exceeding the maximal recommended dosage.

Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about 7

mg/dL for men and postmenopausal women and 6 mg/dL for premenopausal women. Too much reliance

should not be placed on a single serum uric acid determination since, for technical reasons, estimation

of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using

uricosuric agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as

low as 2 to 3 mg/dL and keep it there indefinitely.

While adjusting the dosage of allopurinol in patients who are being treated with colchicine and/or anti-

inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized

and there has been freedom from acute gouty attacks for several months.

In transferring a patient from a uricosuric agent to allopurinol, the dose of the uricosuric agent should

be gradually reduced over a period of several weeks and the dose of allopurinol gradually increased to

the required dose needed to maintain a normal serum uric acid level.

It should also be noted that allopurinol 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.

Since allopurinol and its metabolites are primarily eliminated only by the kidney, accumulation of the

drug can occur in renal failure, and the dose of allopurinol should consequently be reduced. With a

creatinine clearance of 10 to 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 exceed 100 mg. With extreme

renal impairment (creatinine clearance less than 3 mL/min) the interval between doses may also need to

be lengthened.

The correct size and frequency of dosage for maintaining the serum uric acid just within the normal

range is best determined by using the serum uric acid level as an index.

For the prevention of uric acid nephropathy during the vigorous therapy of neoplastic disease, treatment

with 600 to 800 mg daily for 2 or 3 days is advisable together with a high fluid intake. Otherwise

similar considerations to the above recommendations for treating patients with gout govern the

regulation of dosage for maintenance purposes in secondary hyperuricemia.

The dose of allopurinol recommended for management of recurrent calcium oxalate stones in

hyperuricosuric patients is 200 to 300 mg/day in divided doses or as the single equivalent. This dose

may be adjusted up or down depending upon the resultant control of the hyperuricosuria based upon

subsequent 24 hour urinary urate determinations. Clinical experience suggests that patients with

recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal

protein, sodium, refined sugars, oxalate rich foods, and excessive calcium intake, as well as an increase

in oral fluids and dietary fiber.

Children, 6 to 10 years of age, with secondary hyperuricemia associated with malignancies may be

given 300 mg allopurinol daily while those under 6 years are generally given 150 mg daily. The

response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if

necessary.

HOW SUPPLIED

100 mg (white) scored, flat-faced beveled edge round tablets debossed with "2083/V".

They are supplied as follows:

Overbagged with 10 tablets per bag, NDC 55154-7892-0

300 mg (orange) scored, round tablets debossed with "2084/V".

They are supplied as follows:

Overbagged with 10 tablets per bag, NDC 55154-7981-0

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

IMURAN is a registered trademark of Sebela International Bermuda Limited, Hamilton, Bermuda

PURINETHOL is a registered trademark of Stason Pharmaceutical, Inc., Irvine, CA

Dist. by:

Par Pharmaceutical

Chestnut Ridge, NY 10977 U.S.A.

Distributed By:

MAJOR® PHARMACEUTICALS

17177 N Laurel Park Dr., Suite 233

Livonia, MI 48152

Refer to package label for Distributor's NDC Number

Distributed by:

Cardinal Health

Dublin, OH 43017

L54669250519

L54988600219

Revised: 07/2019

Package/Label Display Panel

Allopurinol Tablets, USP

100 mg

10 Tablets

Package/Label Display Panel

Allopurinol Tablets, USP

300 mg

10 Tablets

ALLOPURINOL

allopurinol tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:55154-78 9 2(NDC:0 9 0 4-6 571)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ALLO PURINO L (UNII: 6 3CZ7GJN5I) (ALLOPURINOL - UNII:6 3CZ7GJN5I)

ALLOPURINOL

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics

Color

WHITE

S core

2 pieces

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

20 8 3;V

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:55154-78 9 2-0

10 in 1 BAG

0 6 /27/20 0 3

1

1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7579 8

0 6 /27/20 0 3

ALLOPURINOL

allopurinol tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:55154-79 8 1(NDC:0 9 0 4-6 572)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ALLO PURINO L (UNII: 6 3CZ7GJN5I) (ALLOPURINOL - UNII:6 3CZ7GJN5I)

ALLOPURINOL

30 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics

Color

ORANGE

S core

2 pieces

S hap e

ROUND

S iz e

11mm

Flavor

Imprint Code

20 8 4;V

Contains

Cardinal Health

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:55154-79 8 1-0

10 in 1 BAG

0 6 /27/20 0 3

1

1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7579 8

0 6 /27/20 0 3

Labeler -

Cardinal Health (603638201)

Revised: 7/2019

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