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Apo-allopurinol
Allopurinol Tablets USP 100mg and 300mg

Xanthine Oxidase Inhibitor

 

Pharmacology

Allopurinal is structural analogue of the natural purine base, hypoxanthine. It is a potent inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid. When taken orally, allopurinol is rapidly absorbed and rapidly metabolized. The main metabolite is oxypurinol, which is itself a xanthine oxidase inhibitor. Allopurinol and its metabolites are excreted by the kidney but the renal handling is such that allopurinol has a plasma half-life about 1 hour, whereas that of oxypurinol exceeds 18 hours. Thus, the therapeutic effect can be achieved by a once a day allopurinol dosage in patients taking 300mg or less/day.

 

Administration of allopurinol generally results in a fall in both serum and urinary uric acid within 2 to 3 days. The magnitude of this decrease can be manipulated almost ad lib since it is dose dependent to a limited extent. A week or more of treatment with allopurinol may be required for full effects of the drug to be manifest since the serum uric acid concentration falls gradually; likewise uric acid may return to pretreatment concentration slowly, usually after a period of 7 to 10 days following cessation of therapy. This reflects primarily the slow accumulation and clearance of oxypurinol. In some patients, particularly those with tophaceous gout, a significant fall in urinary uric acid excretion may not occur. It has been postulated that this fall may be due to the mobilization of orate from the tissue deposits as the serum uric acid concentration begins to fall.

 

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. This reutilization and the normal feedback inhibition which would result train an increase in available purine nucleotides serve to regulate purine biosynthesis, and, in essence, the defect of the over-producer of uric acid is thereby compensated. Accompanying the decrease in uric acid produced by allopurinol is an increase in serum and urine concentrations of hypoxanthine and xanthine.

 

Plasma concentrations of these oxypurines do not, however, rise commensurately with the fall in serum orate concentrations and are often 20 to 30% less than would be expected in view of orate concentrations prior to allopurinol therapy. This discrepancy occurs because renal clearance of the oxypurines is at least 10 times greater than that of uric acid. In addition, normal urinary put no output is almost exclusively uric acid, but after treatment with allopurinol, it is composed of uric acid, xanthine, and hypoxanthine, each having independent solubility. Thus the risk of crystalluria is reduced.

 

Alkalinization of the urine increases the solubility of the purines, further minimizing the risk of crystalluria. The glomerular filtration rate and orate clearance in patients receiving allopurinol do not differ significantly from those obtained prior to therapy. The rapid renal clearance of oxypurines suggests that allopurinol therapy should be of value in allowing a patient with gout to increase his total purine excretion. Innate deficiency of xanthine oxidase, which occurs in patients with xanthinuria as an inborn error of metabolism, has been shown to be compatible with comparative well-being. While urinary concentrations of oxypurines attained with full doses of allopurinol may in exceptional cases equal those (250 to 600mg/day) which in xanthinuric subjects have caused formation of urinary calculi, they usually fall in the range of 50 to 200mg and no evidence of renal damage has been observed clinically.

 

Xanthine crystalluria has been reported in a few exceptional cases. Reproductive studies in rats and rabbits indicated that allopurinol did not affect litter size, the mean weight of the progeny at birth or at 3 weeks postpartum, nor did it cause an increase in animals born dead or with malformations.


Indications

The treatment of gout, either primary, or secondary to hyperuricemia which occurs in polycythemia vera, myeloid metaplasia or other blood dyscrasias. Also indicated in the treatment of primary or secondary uric acid nephropathy with or without accompanying symptoms of gout.

 

May be useful in patients with gouty nephropathy, in those who form renal orate stones, and in those with unusually severe disease. May be given prophylactically to prevent tissue orate deposition or renal calculi as well as acute orate nephropathy and resultant renal failure in patients with leukemias, lymphomas or other malignancies who are receiving radiation therapy or antineoplastic drugs with their resultant elevating effect upon serum uric acid concentrations. To prevent occurrence and recurrence of uric acid stones and renal calcium lithiasis in patients with hyperuricemia and/or hyperuricosuria.

Contraindications

Allopurinol should not be given to patients who are hypersensitive to it or who have previously developed a severe reaction to this drug. Should not be given to nursing mothers and children (except in those with hyperuricemia secondary to malignancy or genetic disorders of purine metabolism).


Warning

Allopurinol should be discontinued at the first appearance of skin rash or other signs which may indicate an allergic reaction. Hypersensitivity to allopurinol usually appears after some weeks of therapy, and more rarely immediately after beginning treatment.

 

In some instances, a skin rash may be followed by more severe reactions such as exfoliative urticarial and purpuric lesions as well as Stevens-Johnson syndrome, and/or generalized vasculitis, irreversible hepatotoxicity and even death. Hypersensitivity reactions, frequently marked by fever and eosinophilia, usually begin 2 to 4 weeks after start of therapy and appear related to pre-existing renal dysfunction, elevated oxypurinol plasma levels and/or concurrent thiazide therapy. Periodic liver function tests, renal function tests and complete blood cell counts should be performed in all patients on allopurinol.

 

Alterations in liver function test results, including transient elevation of serum alkaline phosphatase, urinary urobilinogen, serum elevations of serum alkaline phosphatase, urinary urobilinogen, serum AST (SGOT) and ALT (SGPT) and decreases in sufobromophthalein excretion have occurred in some patients. Reversible hepatomegaly, hepatocellular damage (including necrosis), granulomatous changes, hepatitis and jaundice have also occurred. Observe patients with impaired renal or hepatic functions carefully during the early stages of allopurinol administration and withdraw the drug if increased abnormalities in hepatic or renal functions appear.

 

In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300 to 600 mg/day of allopurinol will require a reduction in dose to approximately 33% to 25% of the usual dose of mercaptopurine or azathioprine since their elimination will be prolonged. Make subsequent adjustment of doses of mercaptopurine or azathioprine on the basis of therapeutic response and any toxic effects.


Occupational hazards: Drowsiness may occur. Patients should be cautioned not to engage in activities where alertness is mandatory until their response to the drug is known.


Children: Allopurinol should not be given to children except those with hyperuricemia secondary to malignancy or with Lesch-Nyhan syndrome, because safety and effectiveness have not been established in other conditions.

 

Pregnancy: Allopurinol is not recommended for use during pregnancy or in women of childbearing potential unless the potential benefits outweigh the possible risks to the fetus.

 

Lactation: See contraindications.


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