Allopurinol (Page 4 of 5)

8.2 Lactation

Risk Summary 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.

8.4 Pediatric Use

Hyperuricemia Associated with Cancer Therapy
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.

Primary or Secondary Gout
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.
Recurrent Calcium Oxalate Calculi
The safety and effectiveness of allopurinol tablets have not been established for the management of pediatric patients with recurrent calcium oxalate calculi.
Inborn Errors of Metabolism The safety and effectiveness of allopurinol tablets have not been established in pediatric patients with rare inborn errors of purine metabolism.

8.6 Renal Impairment

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 (5.3)].

10 OVERDOSAGE

In the management of overdosage there is no specific antidote for allopurinol tablets. Both allopurinol tablets and oxipurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol tablets are unknown.

11 DESCRIPTION

Allopurinol is a xanthine oxidase inhibitor. It has the following structural formula:

Allopurinol-Struct

Allopurinol tablets are known chemically as 1, 5-dihydro-4H -pyrazolo [3, 4-d ]pyrimidin-4-one and it has a molecular weight of 136.11 g/mol. Its solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution. It is a xanthine oxidase inhibitor which is administered orally.
Each scored white, flat cylindrical tablet contains 100 mg allopurinol and the inactive ingredients corn starch, lactose monohydrate, magnesium stearate, povidone and purified water. Each scored peach, flat cylindrical tablet contains 300 mg allopurinol and the inactive ingredients corn starch, FD&C Yellow No. 6 Aluminium Lake, lactose monohydrate, magnesium stearate, povidone and purified water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Allopurinol tablets reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation in a dose dependent manner. The pharmacological action of allopurinol is generally believed to be mediated by its oxypurinol metabolite.

Effect on Hypoxanthine and Xanthine

Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol tablets 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 0.15 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 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.

Drug Interaction Studies

Fluorouracil: Based on non-clinical data, allopurinol may decrease anti-tumor activity due to suppression of phosphorylation of 5-fluorouracil.
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.

12.3 Pharmacokinetics

Absorption
Allopurinol tablets are approximately 90% absorbed from the gastrointestinal tract. Peak plasma levels generally occur at 1.5 hours and 4.5 hours for allopurinol tablets and oxipurinol respectively. After a single oral dose of 300 mg allopurinol tablets, maximum plasma levels of about 3 mcg/mL of allopurinol tablets and 6.5 mcg/mL of oxipurinol are produced.
Elimination
The half-life of allopurinol and oxipurinol are approximately 1 hour to 2 hours and 15 hours following oral dose of allopurinol tablets, respectively.

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 is excreted in the feces. Oxipurinol is primarily eliminated unchanged in urine by glomerular filtration and tubular reabsorption.

Drug Interaction Studies

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.

12.5 Pharmacogenomics

HLA-B*5801 allele
The HLA-B*5801 allele is a genetic marker that has shown to be associated with risk of developing allopurinol tablets related hypersensitivity syndrome (DRESS) and SJS/TEN. The frequency of the HLA- B*58:01 allele ranges from 8 to 10% in Han Chinese populations, about 8% in Thai populations, and about 6% in Korean populations based upon published literature and available databases. The frequency of the HLA-B*58:01 allele is about 4% in Blacks, about 1 % to 2 % in indigenous peoples of the Americas and Hispanic populations, and < 1% in people from European descent and Japanese. Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) can still occur in patients who are found to be negative for HLA-B*5801 irrespective of ethnic origin.

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