Allopurinol Tablets USP 100mg and 300mg
Xanthine Oxidase Inhibitor
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
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
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.
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.
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
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
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
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.
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.