
Prescription Drug Name:
ALLOPURINOL TABLETS, USP , Rx Only
ID:
457d1969-77ba-47c3-904e-95b1b3fa1db2
Code:
34391-3
DESCRIPTION
id: d4215042-b052-4abb-8cb6-7106d46f2fd0
displayName: Description Section
FDA Article Code: 34089-3
CLINICAL PHARMACOLOGY
id: 7a302f51-e33e-492b-82bd-919d788c6d26
displayName: Clinical Pharmacology Section
FDA Article Code: 34090-1
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.
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 tablets, 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 tablets. 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 tablets (see
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 tablets 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 tablets 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 tablets differs from that of uricosuric agents, which lower the serum uric acid level by increasing urinary excretion of uric acid. Allopurinol tablets reduce both the serum and urinary uric acid levels by inhibiting the formation of uric acid. The use of allopurinol tablets to block the formation of urates avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs.
Allopurinol tablets 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 tablets. This is in contrast to the nullifying effect of salicylates on uricosuric drugs.
Allopurinol tablets also inhibit 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 tablets 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
id: 13325596-8b45-43d1-96e7-285da3fa5167
displayName: Indications & Usage Section
FDA Article Code: 34067-9
Allopurinol tablets reduce 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
Allopurinol tablets are indicated in:
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 tablets 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.
CONTRAINDICATIONS
id: 5b075b87-5df7-4282-8905-bcc468201158
displayName: Contraindications Section
FDA Article Code: 34070-3
WARNINGS
id: 2baa0641-f8ec-448c-b7de-f2c2a17346b0
displayName: Warnings Section
FDA Article Code: 34071-1
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
A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol tablets, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol tablets, 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 tablets may be increased in patients with decreased renal function receiving thiazides and allopurinol tablets concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.
ADVERSE REACTIONS
id: f7a2886f-d9a9-4495-a548-031fd8a90046
displayName: Adverse Reactions Section
FDA Article Code: 34084-4
The most frequent adverse reaction to allopurinol tablets is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol tablets should be discontinued immediately if a rash develops (see
*Early clinical studies and incidence rates from early clinical experience with allopurinol tablets 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
OVERDOSAGE
id: f4612735-b062-465d-abd4-5938bf8075a7
displayName: Overdosage Section
FDA Article Code: 34088-5
In mice, the 50% lethal dose (LD50) 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 LD50 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 tablets. There has been no clinical experience in the management of a patient who has taken massive amounts of 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.
DOSAGE & ADMINISTRATION
id: d1d5e45c-9b95-4c9b-ad00-509a48ca765d
displayName: Dosage & Administration Section
FDA Article Code: 34068-7
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 tablets 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 tablets, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of allopurinol tablets gradually increased to the required dose needed to maintain a normal serum uric acid level.
It should also be noted that 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.
Since allopurinol tablets and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of allopurinol tablets should consequently be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of allopurinol tablets 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 tablets 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 tablets 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
id: b5d5c3c2-4eda-429c-aa99-7988d1c598d1
displayName: How Supplied Section
FDA Article Code: 34069-5
Manufactured for:
Ingenus Pharmaceuticals, LLC
4190 Millenia Boulevard
Orlando, FL 32839-6408
Customer complaint toll free number: 1-877-748-1970
Manufactured by:
Indoco Remedies Ltd.
L-32, 33, 34, Verna Industrial Area,
Verna Goa. 403 722, India.
January 2018
PURINETHOL® (mercaptopurine) is registered Trademark of Teva Biologics and Specialty Products.
IMURAN® (azathioprine) is registered Trademark of Prometheus Laboratories Inc.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
id: 3e6bc47f-2951-49d0-8b29-8cbc2e181da4
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
1000 Tablets NDC 50742-135-10
Allopurinol Tablets USP
Each scored tablet contains
100 mg
Rx Only
500 Tablets NDC 50742-136-05
Allopurinol Tablets USP
Each scored tablet contains
300 mg
Rx Only