Allopurinol Information
Allopurinol (Allopurinol)
Allopurinol (Allopurinol) Description
Allopurinol (Allopurinol) has the following structural formula:
Allopurinol (Allopurinol) Clinical Pharmacology
Allopurinol (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 (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 (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 (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 (Allopurinol) for treatment for 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 (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 syn- drome, which is characterized by excessive uric acid production combined with a deficiency of the enzyme, hypoxanthine-guanine
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 (Allopurinol) is approximately 90% absorbed from the gastrointestinal
tract. Peak plasma levels generally occur at 1.5 hours and 4.5 hours for
Allopurinol (Allopurinol) and oxipurinol respectively, and after a single oral dose of 300 mg
Allopurinol (Allopurinol) , maximum plasma levels of about 3 mcg/mL of Allopurinol (Allopurinol) and 6.5 mcg/mL of oxipurinol are produced.
Approximately 20% of the ingested Allopurinol (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 (Allopurinol) has a plasma
half-life of about 1-2 hours. Oxipurinol, however, has a longer plasma
half-life (approximately 15.0 hours) and therefore effective xanthine oxidase
inhibition is maintained over a 24-hour period with single daily doses of
Allopurinol (Allopurinol) . Whereas Allopurinol (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 Allopurinol (Allopurinol)
treatment (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 (Allopurinol) generally results in a fall in both serum
and urinary uric acid within two to three 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 (Allopurinol) may be required before its full effects are
manifested; likewise, uric acid may return to pretreatment levels slowly
(usually after a period of seven to ten 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.
Allopurinol (Allopurinol) ’s action differs from that of uricosuric agents, which
lower the serum uric acid level by increas- ing urinary excretion of uric acid.
Allopurinol (Allopurinol) reduces both the serum and urinary uric acid levels by inhibiting
the formation of uric acid. The use of Allopurinol (Allopurinol) to block the formation of
urates avoids the hazard of increased renal excretion of uric acid posed by
uricosuric drugs.
Allopurinol (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 (Allopurinol) . This is in contrast to the nullifying effect of
salicylates on uricosuric drugs.
Allopurinol (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 (Allopurinol) may result in
as much as a 75% reduction in the therapeutic dose requirement of
mercaptopurine when the two compounds are given together.
Allopurinol (Allopurinol) Indications And Usage
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE
TREATMENT OF ASYMPTOMATIC HYPERURICEMIA. Allopurinol (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
and ).
Allopurinol (Allopurinol) is indicated in:
Allopurinol (Allopurinol) Contraindications
Patients who have developed a severe reaction to Allopurinol (Allopurinol) should
not be restarted on the drug.
Allopurinol (Allopurinol) Warnings
Allopurinol (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), and/or generalized vasculitis,
irre- versible hepatotoxicity and on rare occasions death.
In patients receiving Purinethol® (mercaptopurine) or Imuran®
(azathioprine), the concomitant administration of 300-600 mg of Allopurinol (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 (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 (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 (Allopurinol) may be increased in patients with decreased renal function receiving
thiazides and Allopurinol (Allopurinol) concurrently. For this reason, in this clinical
setting, such combinations should be administered with caution and patients
should be observed closely.
Allopurinol (Allopurinol) Precautions
An increase in acute attacks of gout has been reported during the
early stages of Allopurinol (Allopurinol) administration, even when normal or sub-
normal serum uric acid levels have been attained. Accordingly,
maintenance doses of colchicine generally should be given
prophylactically when Allopurinol (Allopurinol) is begun. In addition, it is
recommended that the patient start with a low dose of Allopurinol (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 Allopurinol (Allopurinol)
therapy, 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 two 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
Allopurinol (Allopurinol) therapy 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 allo- purinol administration.
Although the mechanism responsible for this has not been established,
patients with impaired renal function should be carefully observed
during the early stages of Allopurinol (Allopurinol) administration and dosage
decreased or the drug withdrawn if increased abnormalities in renal
function appear and persist.
Renal failure in association with Allopurinol (Allopurinol) administration
has been observed among patients with hyper- uricemia 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 (Allopurinol) was begun. Renal failure is
also frequently associated with gouty nephropathy and rarely with
Allopurinol (Allopurinol) -associated hypersensitivity reactions. 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 (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 Allopurinol (Allopurinol) administration. 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 (Allopurinol) , most of whom received concomitant drugs with the potential
for causing this reaction. This has occurred as early as six weeks to as
long as six years after the initiation of Allopurinol (Allopurinol) therapy. Rarely a
patient may develop varying degrees of bone marrow depression, affecting
one or more cell lines, while receiving Allopurinol (Allopurinol) alone.
Information for Patients:
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
).
Allopurinol (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 that can affect renal function such as
hypertension and diabetes mellitus, periodic lab- oratory parameters of
renal function, particularly BUN and serum creatinine or creatinine
clearance, should be performed and the patient’s Allopurinol (Allopurinol) dosage
reassessed.
The prothrombin time should be reassessed periodically in the
patients receiving dicumarol who are given Allopurinol (Allopurinol) .
In patients receiving Purinethol® (mercaptopurine) or Imuran® (azathioprine), the concomitant administration of 300-600 mg of
Allopurinol (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 ).
It has been reported that Allopurinol (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 (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 (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 (Allopurinol) alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on
Allopurinol (Allopurinol) alone or in combination with uricosuric agents, the
possibility should be kept in mind.
The reports that concomitant use of Allopurinol (Allopurinol) and thiazide
diuretics may contribute to the enhancement of Allopurinol (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 (Allopurinol) was
not followed. Although a causal mechanism and cause-and-effect relationship have not been established, current evidence suggests that
renal function should be monitored in patients on thiazide diuretics and
Allopurinol (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 (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 (Allopurinol) . However, in a
well-controlled study of patients with lymphoma on combination therapy,
Allopurinol (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 (Allopurinol) , since Allopurinol (Allopurinol) and chlorpropamide may compete for
excretion in the renal tubule. The risk of hypoglycemia secondary to this
mechanism may be increased if Allopurinol (Allopurinol) and chlorpropamide are given
concomitantly in the presence of renal insufficiency.
Reproductive studies have been performed in rats and rabbits at
doses up to twenty times the usual human dose (5 mg/kg/day), and it was
concluded that there was no impaired fertility or harm to the fetus due
to Allopurinol (Allopurinol) . There is a published report of a study in pregnant mice
given 50 or 100 mg/kg Allopurinol (Allopurinol) intraperitoneally on gestation days 10
or 13. There were increased numbers of dead fetuses in dams given 100
mg/kg Allopurinol (Allopurinol) but not in those given 50 mg/kg. There were increased
numbers of external malformations in fetuses at both doses of
Allopurinol (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 (Allopurinol) during human pregnancy has been
limited partly because women of reproductive age rarely require
treatment with Allopurinol (Allopurinol) . There are two unpublished reports and one
published paper of women giving birth to normal offspring after receiving
Allopurinol (Allopurinol) during pregnancy.
Allopurinol (Allopurinol) 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 (Allopurinol) began. Past experience suggested that the most frequent event
following the initiation of Allopurinol (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
and ).
The most frequent adverse reaction to Allopurinol (Allopurinol) is skin rash. Skin
reactions can be severe and sometimes fatal. Therefore, treatment with
Allopurinol (Allopurinol) should be discontinued immediately if a rash develops (see
). 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 (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 (Allopurinol) has been reported to be increased
(see ).
Allopurinol (Allopurinol) Overdosage
Massive overdosing or acute poisoning by Allopurinol (Allopurinol) has not been
reported. In mice the 50% lethal dose (LD) is 160 mg/kg given
intraperitoneally (i.p.) with deaths delayed up to five days and 700
mg/kg orally (p.o.) (approximately 140 times the usual human dose) with deaths
delayed up to three days. In rats the acute LD is 750 mg/kg i.p. and 6000
mg/kg p.o. (approximately 1200 times the human dose).
In the management of overdosage there is no specific antidote for
Allopurinol (Allopurinol) . There has been no clinical experience in the management of a
patient who has taken massive amounts of Allopurinol (Allopurinol) .
Both Allopurinol (Allopurinol) and oxipurinol are dialyzable, however, the
usefulness of hemodialysis or peritoneal dialysis in the management of an
Allopurinol (Allopurinol) overdose is unknown.
Allopurinol (Allopurinol) Dosage And Administration
The dosage of Allopurinol (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 per day for patients with mild
gout and 400 to 600 mg per 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 maximal recommended dosage is 800 mg daily. To
reduce the possibility of flareup of acute gouty attacks, it is recommended
that the patient start with a low dose of Allopurinol (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 one to three 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 (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 (Allopurinol) , the
dose of the uricosuric agent should be gradually reduced over a period of
several weeks and the dose of Allopurinol (Allopurinol) gradually increased to the
required dose needed to maintain a normal serum uric acid level.
It should also be noted that Allopurinol (Allopurinol) is generally better tolerated
if taken following meals. A fluid intake sufficient to yield a daily urinary
output of at least two liters and the maintenance of a neutral or, preferably,
slightly alkaline urine are desirable.
Since Allopurinol (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 (Allopurinol) should consequently be reduced. With a creatinine clearance of
10 to 20 mL/min, a daily dosage of 200 mg of Allopurinol (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 clear- ance 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 are 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 two or three 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 (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 (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.
Allopurinol (Allopurinol) How Supplied
Bottles of 100 NDC 55111-729-01
Bottles of 1000 NDC 55111-729-10
Bottles of 100 NDC 55111-730-01
Bottles of 500 NDC 55111-730-05
Bottles of 1000 NDC 55111-730-10
Store at 15°-30°C (59°-86°F) and protect from moisture.
QUESTIONS OR COMMENTS? Call toll free 1-888-375-3784.You may report
side effects to FDA at 1-800-FDA-1088.
Distributed by
Issued August,
2009
150019989-01
Allopurinol (Allopurinol) Principal Display Panel
100 Tablets
NDC 55111-729-01
Rx only
1000 Tablets
NDC 55111-730-10
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