Allopurinol
DESCRIPTION:
ZYLORIC (allopurinol) is known chemically as 1.5-dihydro-4H-pyrazolo(3,4-
d)pyrimidin-4-one. It is a xanthine oxidase inhibitor which is administered
orally. Each scored white tablet contains 100 mg allopurinol and the inactive
ingredients lactose, magnesium stearate, potato starch, and povidone. Each
scored peach tablet contains 300 mg allopurinol and the inactive ingredients
corn starch, FD&C Yellow No. 6 Lake, lactose, magnesium stearate, and povidone.
Its solubility in water at 37 deg C is 80.0 mg/dL and is greater in an alkaline
solution.
ACTIONS/CLINICAL PHARMACOLOGY:
ZYLORIC (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.
ZYLORIC 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. ZYLORIC 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 ZYLORIC 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 ZYLORIC for treatment of 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 ZYLORIC. 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
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.
ZYLORIC is approximately 90% absorbed from the gastrointestinal tract. Peak
plasma levels generally occur at 1.5 hours and 4.5 hours for ZYLORIC and
oxipurinol respectively, and after a single oral dose of 300 mg ZYLORIC,
maximum plasma levels of about 3 mcgm/mL of ZYLORIC and 6.5 mcgm/mL of
oxipurinol are produced.
Approximately 20% of the ingested ZYLORIC is excreted in the feces. Because of
its rapid oxidation to oxipurinol and a renal clearance rate approximately that
of glomerular filtration rate, ZYLORIC has a plasma half-life of about 1 to 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 ZYLORIC. Whereas ZYLORIC 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 ZYLORIC
treatment (see INDICATIONS AND USAGE).
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 ZYLORIC 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 ZYLORIC 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.
The action of ZYLORIC differs from that of uricosuric agents, which lower the
serum uric acid level by increasing urinary excretion of uric acid. ZYLORIC
reduces both the serum and urinary uric acid levels by inhibiting the formation
of uric acid. The use of ZYLORIC to block the formation of urates avoids the
hazard of increased renal excretion of uric acid posed by uricosuric drugs.
ZYLORIC 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 ZYLORIC. This is in contrast to the nullifying effect of salicylates on
uricosuric drugs.
ZYLORIC 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 ZYLORIC 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:
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF
ASYMPTOMATIC HYPERURICEMIA.
ZYLORIC (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 ACTIONS/CLINICAL PHARMACOLOGY,
CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).
ZYLORIC is 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 ZYLORIC 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:
Patients who have developed a severe reaction to ZYLORIC (allopurinol) should
not be restarted on the drug.
WARNINGS:
ZYLORIC (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, irreversible
hepatotoxicity and on rare occasions death.
In patients receiving PURINETHOL(R) (mercaptopurine) or IMURAN(R)
(azathioprine), the concomitant administration of 300 to 600 mg of ZYLORIC 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 ACTIONS/CLINICAL
PHARMACOLOGY).
A few cases of reversible clinical hepatotoxicity have been noted in patients
taking ZYLORIC, 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 ZYLORIC, 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 ZYLORIC may be increased in
patients with decreased renal function receiving thiazides and ZYLORIC
concurrently. For this reason, in this clinical setting, such combinations
should be administered with caution and patients should be observed closely.
PRECAUTIONS:
GENERAL: An increase in acute attacks of gout has been reported during the early
stages of ZYLORIC (allopurinol) administration, even when normal or subnormal
serum uric acid levels have been attained. Accordingly, maintenance doses of
colchicine generally should be given prophylactically when ZYLORIC is begun. In
addition, it is recommended that the patient start with a low dose of ZYLORIC
(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 therapy with ZYLORIC, 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 therapy with ZYLORIC 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 administration with ZYLORIC. Although the mechanism
responsible for this has not been established, patients with impaired renal
function should be carefully observed during the early stages of ZYLORIC
administration and dosage decreased or the drug withdrawn if increased
abnormalities in renal function appear and persist.
Renal failure in association with administration of ZYLORIC has been observed
among patients with hyperuricemia secondary to neoplastic diseases. Concurrent
conditions such as multiple myeloma and congestive myocardial disease were
present among those patients whose renal dysfunction increased after ZYLORIC
was begun. Renal failure is also frequently associated with gouty nephropathy
and rarely with hypersensitivity reactions associated with ZYLORIC. 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 ZYLORIC 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 administration of ZYLORIC. 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 ZYLORIC, 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 therapy of ZYLORIC. Rarely a patient may develop varying degrees
of bone marrow depression, affecting one or more cell lines, while receiving
ZYLORIC alone.
INFORMATION FOR PATIENTS: Patients should be informed of the following:
(1) They should be cautioned to discontinue ZYLORIC (allopurinol) and to
consult their physician immediately at the first sign of a skin rash, painful
urination, blood in the urine, irritation of the eyes, or swelling of the lips
or mouth. (2) They should be reminded to continue drug therapy prescribed for
gouty attacks since optimal benefit of ZYLORIC may be delayed for two to six
weeks. (3) They should be encouraged to increase fluid intake during therapy to
prevent renal stones. (4) If a single dose of ZYLORIC is occasionally
forgotten, there is no need to double the dose at the next scheduled time. (5)
There may be certain risks associated with the concomitant use of ZYLORIC and
dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin
and thiazide diuretics and they should follow the instructions of their
physician. (6) Due to the occasional occurrence of drowsiness, patients should
take precautions when engaging in activities where alertness is mandatory. (7)
Patients may wish to take ZYLORIC after meals to minimize gastric irritation.
LABORATORY TESTS: 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 WARNINGS).
ZYLORIC (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 which can affect renal function such as hypertension and
diabetes mellitus, periodic laboratory parameters of renal function,
particularly BUN and serum creatinine or creatinine clearance, should be
performed and the patient's dosage of ZYLORIC reassessed.
The prothrombin time should be reassessed periodically in the patients receiving
dicumarol who are given ZYLORIC.
DRUG INTERACTIONS: In patients receiving PURINETHOL (mercaptopurine) or IMURAN
(azathioprine), the concomitant administration of 300 to 600 mg of ZYLORIC
(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
ACTIONS/CLINICAL PHARMACOLOGY).
It has been reported that ZYLORIC prolongs the half-life of the anticoagulant
dicumarol. The clinical basis of this drug interaction has not been established
but should be noted when ZYLORIC 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 ZYLORIC 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 ZYLORIC alone. Although clinical evidence to date has not
demonstrated renal precipitation of oxypurines in patients either on ZYLORIC
alone or in combination with uricosuric agents, the possibility should be kept
in mind.
The reports that the concomitant use of ZYLORIC and thiazide diuretics may
contribute to the enhancement of 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 ZYLORIC was not followed.
Although a causal mechanism and a cause-and-effect relationship have not been
established, current evidence suggests that renal function should be monitored
in patients on thiazide diuretics and ZYLORIC 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 ZYLORIC 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 ZYLORIC. However, in a well-controlled study of patients with
lymphoma on combination therapy, ZYLORIC 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 ZYLORIC, since ZYLORIC
and chlorpropamide may compete for excretion in the renal tubule. The risk of
hypoglycemia secondary to this mechanism may be increased if ZYLORIC and
chlorpropamide are given concomitantly in the presence of renal insufficiency.
Rare reports indicate that cyclosporine levels may be increased during
concomitant treatment with ZYLOPRIM. Monitoring of cyclosporine levels and
possible adjustment of cyclosporine dosage should be considered when these drugs
are co- administered.
Rare reports indicate that cyclosporine levels may be increased during
concomitant treatment with ZYLORIC. Monitoring of cyclosporine levels and
possible adjustment of cyclosporine dosage should be considered when these drugs
are co- administered.
DRUG/LABORATORY TEST INTERACTIONS: ZYLORIC (allopurinol) is not known to alter
the accuracy of laboratory tests.
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category C. 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 ZYLORIC (allopurinol). There is a published report of
a study in pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on
gestation days 10 or 13. There were increased numbers of dead fetuses in dams
given 100 mg/kg allopurinol but not in those given 50 mg/kg. There were
increased numbers of external malformations in fetuses at both doses of
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 ZYLORIC during human pregnancy has been limited partly because
women of reproductive age rarely require treatment with ZYLORIC. There are two
unpublished reports and one published paper of women giving birth to normal
offspring after receiving ZYLORIC during pregnancy.
NURSING MOTHERS: ZYLORIC (allopurinol) and oxipurinol have been found in the
milk of a mother who was receiving ZYLORIC. Since the effect of ZYLORIC on the
nursing infant is unknown, caution should be exercised when ZYLORIC is
administered to a nursing woman.
PEDIATRIC USE: ZYLORIC (allopurinol) is rarely indicated for use in children
with the exception of those with hyperuricemia secondary to malignancy or to
DOSAGE AND ADMINISTRATION).
DRUG INTERACTIONS:
In patients receiving PURINETHOL(R) (mercaptopurine) or IMURAN(R)
(azathioprine), the concomitant administration of 300 to 600 mg of ZYLORIC
(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
ACTIONS/CLINICAL PHARMACOLOGY).
It has been reported that ZYLORIC prolongs the half-life of the anticoagulant
dicumarol. The clinical basis of this drug interaction has not been established
but should be noted when ZYLORIC 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 ZYLORIC 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 ZYLORIC alone. Although clinical evidence to date has not
demonstrated renal precipitation of oxypurines in patients either on ZYLORIC
alone or in combination with uricosuric agents, the possibility should be kept
in mind.
The reports that the concomitant use of ZYLORIC and thiazide diuretics may
contribute to the enhancement of 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 ZYLORIC was not followed.
Although a causal mechanism and a cause-and-effect relationship have not been
established, current evidence suggests that renal function should be monitored
in patients on thiazide diuretics and ZYLORIC 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 ZYLORIC 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 ZYLORIC. However, in a well-controlled study of patients with
lymphoma on combination therapy, ZYLORIC 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 ZYLORIC, since ZYLORIC
and chlorpropamide may compete for excretion in the renal tubule. The risk of
hypoglycemia secondary to this mechanism may be increased if ZYLORIC and
chlorpropamide are given concomitantly in the presence of renal insufficiency.
Rare reports indicate that cyclosporine levels may be increased during
concomitant treatment with ZYLORIC. Monitoring of cyclosporine levels and
possible adjustment of cyclosporine dosage should be considered when these drugs
are co- administered.
(See Also WARNINGS and PRECAUTIONS)
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 ZYLORIC (allopurinol)
began. Past experience suggested that the most frequent event following the
initiation of 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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).
The most frequent adverse reaction to ZYLORIC is skin rash. Skin reactions can
be severe and sometimes fatal. Therefore, treatment with ZYLORIC should be
discontinued immediately if a rash develops (see WARNINGS). 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 ZYLORIC 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 ZYLORIC has been reported
to be increased (see PRECAUTIONS).
MOST COMMON REACTIONS*
PROBABLY CAUSALLY RELATED
Gastrointestinal: diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT
increase
Metabolic and Nutritional: acute attacks of gout
Skin and Appendages: rash, maculopapular rash
-----------
*Early clinical studies and incidence rates from early clinical experience with
ZYLORIC 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 ADVERSE REACTIONS introduction, INDICATIONS AND USAGE,
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
-----------
INCIDENCE LESS THAN 1%
PROBABLY CAUSALLY RELATED
Body as a whole: ecchymosis, fever, headache
Cardiovascular: necrotizing angiitis, vasculitis
Gastrointestinal: hepatic necrosis, granulomatous hepatitis, hepatomegaly,
hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain,
gastritis, dyspepsia
Hemic and Lymphatic: thrombocytopenia, eosinophilia, leukocytosis, leukopenia
Musculoskeletal: myopathy, arthralgias
Nervous: peripheral neuropathy, neuritis, paresthesia, somnolence
Respiratory: epistaxis
Skin and Appendages: erythema multiforme exudativum (Stevens-Johnson syndrome),
toxic epidermal necrolysis (Lyell's syndrome), hypersensitivity vasculitis,
purpura, vesicular bullous dermatitis, exfoliative dermatitis, eczematoid
dermatitis, pruritus, urticaria, alopecia, onycholysis, lichen planus
Special Senses: taste loss/perversion
Urogenital: renal failure, uremia (see PRECAUTIONS)
INCIDENCE LESS THAN 1%
CAUSAL RELATIONSHIP UNKNOWN
Body as a whole: malaise
Cardiovascular: pericarditis, peripheral vascular disease, thrombophlebitis,
bradycardia, vasodilation
Endocrine: infertility (male), hypercalcemia, gynecomastia (male)
Gastrointestinal: hemorrhagic pancreatitis, gastrointestinal bleeding,
stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, anorexia
Hemic and Lymphatic: aplastic anemia, agranulocytosis, eosinophilic
fibrohistiocytic lesion of bone marrow, pancytopenia, prothrombin decrease,
anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis
Musculoskeletal: myalgia
Nervous: optic neuritis, confusion, dizziness, vertigo, foot drop, decrease in
libido, depression, amnesia, tinnitus, asthenia, insomnia
Respiratory: bronchospasm, asthma, pharyngitis, rhinitis
Skin and Appendages: furunculosis, facial edema, sweating, skin edema
Special Senses: cataracts, macular retinitis, iritis, conjunctivitis, amblyopia
Urogenital: nephritis, impotence, primary hematuria, albuminuria
OVERDOSAGE:
Massive overdosing or acute poisoning by ZYLORIC (allopurinol) has not been
reported.
In mice the 50% lethal dose (LD50) 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 LD50 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 ZYLORIC.
There has been no clinical experience in the management of a patient who has
taken massive amounts of ZYLORIC.
Both ZYLOPRIM and oxipurinol are dialyzable; however, the usefulness of
hemodialysis or peritoneal dialysis in the management of overdosage of ZYLOPRIM
is unknown.
DOSAGE AND ADMINISTRATION:
The dosage of ZYLORIC (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 300mg tablet. Dosage requirements in excess of 300 mg
should be administered in divided doses. The minimal effective dosage is 100 to
200 mg daily and the maximal recommended dosage is 800 mg daily. To reduce the
possibility of flare- up of acute gouty attacks, it is recommended that the
patient start with a low dose of ZYLORIC (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 ZYLORIC 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 ZYLORIC, the dose of the
uricosuric agent should be gradually reduced over a period of several weeks and
the dose of ZYLORIC gradually increased to the required dose needed to maintain
a normal serum uric acid level.
It should also be noted that ZYLORIC 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 ZYLORIC and its metabolites are primarily eliminated only by the kidney,
accumulation of the drug can occur in renal failure, and the dose of ZYLORIC
should consequently be reduced. With a creatinine clearance of 10 to 20 mL/min,
a daily dosage of 200 mg of ZYLORIC 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 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 ZYLORIC 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 ZYLORIC 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.
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