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Allopurinol
Overview
What is Allopurinol?
Allopurinol is known chemically as 1,5-Dihydro-4-pyrazolo[3,4-]pyrimidin-4-one. It is a xanthine oxidase inhibitor which is
administered orally. Its solubility in water at 37°C is 80 mg/dL and is greater
in an alkaline solution. The structural formula is represented below:
CHNO M.W. 136.11
Allopurinol Tablets USP, 100 mg and 300 mg contain the following inactive
ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, pregelatinized starch and sodium lauryl sulfate.
Allopurinol Tablets USP, 300 mg also contain FD&C Yellow No. 6.
What does Allopurinol look like?
What are the available doses of Allopurinol?
Sorry No records found.
What should I talk to my health care provider before I take Allopurinol?
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How should I use Allopurinol?
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE
TREATMENT OF ASYMPTOMATIC HYPERURICEMIA.
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 is indicated in:
The dosage of 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 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 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 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, the dose of
the uricosuric agent should be gradually reduced over a period of several weeks
and the dose of allopurinol gradually increased to the required dose needed to
maintain a normal serum uric acid level.
It should also be noted that allopurinol is generally better tolerated if
taken following meals. A fluid intake sufficient to yield a daily urinary output
of at least 2 liters and the maintenance of a neutral or, preferably, slightly
alkaline urine are desirable.
Since 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 should consequently be reduced. With a creatinine clearance of 10 to
20 mL/min, a daily dosage of 200 mg of 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 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 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 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.
What interacts with Allopurinol?
Patients who have developed a severe reaction to allopurinol should not be restarted on the drug.
What are the warnings of Allopurinol?
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
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 mercaptopurine or azathioprine, the concomitant
administration of 300 to 600 mg of 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, 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, 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 may be increased
in patients with decreased renal function receiving thiazides and allopurinol
concurrently. For this reason, in this clinical setting, such combinations
should be administered with caution and patients should be observed closely.
What are the precautions of Allopurinol?
An increase in acute attacks of gout has been reported during the
early stages of 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 allopurinol is begun.
In addition, it is recommended that the patient start with a low dose of
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 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 2
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 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 allopurinol 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
administration and the dosage decreased or the drug withdrawn if increased
abnormalities in renal function appear and persist.
Renal failure in association with allopurinol administration 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
allopurinol was begun. Renal failure is also frequently associated with gouty
nephropathy and rarely with hypersensitivity reactions associated with
allopurinol. 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
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
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,
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 therapy. Rarely a patient may develop varying
degrees of bone marrow depression, affecting one or more cell lines, while
receiving allopurinol alone.
Patients should be informed of the following:(1) They should
be cautioned to discontinue 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 allopurinol 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 allopurinol 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 allopurinol 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 allopurinol after meals to minimize gastric
irritation.
The correct dosage and schedule for maintaining the serum uric
acid within the normal range is best determined by using the serum uric acid
level as an index.
In patients with pre-existing liver disease, periodic liver function tests
are recommended during the early stages of therapy (see ).
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
allopurinol dosage reassessed.
The prothrombin time should be reassessed periodically in the patients
receiving dicumarol who are given allopurinol.
In patients receiving mercaptopurine or azathioprine, the
concomitant administration of 300-600 mg of 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 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 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 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 alone. Although clinical evidence to date has not
demonstrated renal precipitation of oxypurines in patients either on allopurinol
alone or in combination with uricosuric agents, the possibility should be kept
in mind.
The reports that the concomitant use of allopurinol 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 allopurinol 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 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 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. However, in a well-controlled study of
patients with lymphoma on combination therapy, 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 this observation is unknown.
Chlorpropamide’s plasma half-life may be prolonged by allopurinol, since
allopurinol and chlorpropamide may compete for excretion in the renal tubule.
The risk of hypoglycemia secondary to this mechanism may be increased if
allopurinol and chlorpropamide are given concomitantly in the presence of renal
insufficiency.
Rare reports indicate that cyclosporine levels may be increased during
concomitant treatment with allopurinol. Monitoring of cyclosporine levels and
possible adjustment of cyclosporine dosage should be considered when these drugs
are co-administered.
Allopurinol is not known to alter the accuracy of laboratory
tests.
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
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 allopurinol during human pregnancy has been limited partly
because women of reproductive age rarely require treatment with allopurinol.
There are two unpublished reports and one published paper of women giving birth
to normal offspring after receiving allopurinol during pregnancy.
Allopurinol and oxipurinol have been found in the milk of a
mother who was receiving allopurinol. Since the effect of allopurinol on the
nursing infant is unknown, caution should be exercised when allopurinol is
administered to a nursing woman.
Allopurinol is rarely indicated for use in children with the
exception of those with hyperuricemia secondary to malignancy or to certain rare
inborn errors of purine metabolism (see and ).
What are the side effects of Allopurinol?
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
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 and ).
The most frequent adverse reaction to allopurinol is skin rash. Skin
reactions can be severe and sometimes fatal. Therefore, treatment with
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
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 has been reported to be increased (see ).
Gastrointestinal:
Metabolic and Nutritional:
Skin and Appendages:
*Early clinical studies and incidence rates from early clinical experience
with allopurinol 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 introduction,
, and ).
Body as a whole:
Cardiovascular:
Gastrointestinal:
Hemic and Lymphatic:
Musculoskeletal:
Nervous:
Respiratory:
Skin and Appendages:
Special Senses:
Urogenital:
Body as a whole:
Cardiovascular:
Endocrine:
Gastrointestinal:
Hemic and Lymphatic:
Musculoskeletal:
Nervous:
Respiratory:
Skin and appendages:
Special Senses:
Urogenital:
What should I look out for while using Allopurinol?
Patients who have developed a severe reaction to allopurinol should not be
restarted on the drug.
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 mercaptopurine or azathioprine, the concomitant
administration of 300 to 600 mg of 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, 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, 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 may be increased
in patients with decreased renal function receiving thiazides and allopurinol
concurrently. For this reason, in this clinical setting, such combinations
should be administered with caution and patients should be observed closely.
What might happen if I take too much Allopurinol?
Massive overdosing or acute poisoning by 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. There has been no clinical experience in the management of a
patient who has taken massive amounts of allopurinol.
Both allopurinol and oxipurinol are dialyzable; however, the usefulness of
hemodialysis or peritoneal dialysis in the management of an allopurinol
overdosage is unknown.
How should I store and handle Allopurinol?
Store below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyStore below 30° C (86° F) [see USP].Dispense in a tight, light-resistant container as defined in USP/NF.BIBLIOGRAPHYAvailable on request.Manufactured by:Patheon Pharmaceuticals Inc.Cincinnati, OH 45215 USAFor: Corona, CA 92880This Product was Repackaged By:State of Florida DOH Central PharmacyAllopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Allopurinol Tablets USP, 100 mg are scored, round, white tablets imprinted and supplied in:bottles of 30 NDC 54868-0075-0bottles of 60 NDC 54868-0075-3bottles of 90 NDC 54868-0075-5bottles of 100 NDC 54868-0075-4.Allopurinol Tablets USP, 300 mg are scored, round, orange tablets imprinted and supplied in:bottles of 30 NDC 54868-0076-6bottles of 60 NDC 54868-0076-2bottles of 90 NDC 54868-0076-7bottles of 100 NDC 54868-0076-3bottles of 180 NDC 54868-0076-8.Dispense in a tight, light-resistant container with child-resistant closure.Store Watson Laboratories, Inc.Revised: January 2006Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 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 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 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 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 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
syndrome, 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 is approximately 90% absorbed from the gastrointestinal tract.
Peak plasma levels generally occur at 1.5 hours and 4.5 hours for allopurinol
and oxipurinol, respectively, and after a single oral dose of 300 mg
allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5
mcg/mL of oxipurinol are produced.
Approximately 20% of the ingested allopurinol is excreted in the feces.
Because of its rapid oxidation to oxipurinol and a renal clearance rate
approximately that of the glomerular filtration rate, allopurinol has a plasma
half-life of about 1-2 hours. Oxipurinol, however, has a longer plasma half-life
(approximately 15 hours), and therefore effective xanthine oxidase inhibition is
maintained over a 24-hour period with single daily doses of allopurinol. Whereas
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 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 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 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’s action differs from that of uricosuric agents, which lower the
serum uric acid level by increasing urinary excretion of uric acid. Allopurinol
reduces both the serum and urinary uric acid levels by inhibiting the formation
of uric acid. The use of allopurinol to block the formation of urates avoids the
hazard of increased renal excretion of uric acid posed by uricosuric drugs.
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. This is in contrast to the nullifying effect of salicylates on
uricosuric drugs.
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 may result in as much as a 75%
reduction in the therapeutic dose requirement of mercaptopurine when the two
compounds are given together.
Non-Clinical Toxicology
Patients who have developed a severe reaction to allopurinol should not be restarted on the drug.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 mercaptopurine or azathioprine, the concomitant administration of 300 to 600 mg of 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, 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, 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 may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.
Both pharmacodynamic and pharmacokinetic interactions have been reported with benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression.
An increase in acute attacks of gout has been reported during the early stages of 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 allopurinol is begun. In addition, it is recommended that the patient start with a low dose of 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 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 2 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 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 allopurinol 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 administration and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.
Renal failure in association with allopurinol administration 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 allopurinol was begun. Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with allopurinol. 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 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 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, 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 therapy. Rarely a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol alone.
Patients should be informed of the following:(1) They should be cautioned to discontinue 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 allopurinol 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 allopurinol 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 allopurinol 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 allopurinol after meals to minimize gastric irritation.
The correct dosage and schedule for maintaining the serum uric acid within the normal range is best determined by using the serum uric acid level as an index.
In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy (see ).
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 allopurinol dosage reassessed.
The prothrombin time should be reassessed periodically in the patients receiving dicumarol who are given allopurinol.
In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300-600 mg of 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 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 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 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 alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on allopurinol alone or in combination with uricosuric agents, the possibility should be kept in mind.
The reports that the concomitant use of allopurinol 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 allopurinol 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 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 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. However, in a well-controlled study of patients with lymphoma on combination therapy, 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 this observation is unknown.
Chlorpropamide’s plasma half-life may be prolonged by allopurinol, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the presence of renal insufficiency.
Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co-administered.
Allopurinol is not known to alter the accuracy of laboratory tests.
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 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 allopurinol during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving allopurinol during pregnancy.
Allopurinol and oxipurinol have been found in the milk of a mother who was receiving allopurinol. Since the effect of allopurinol on the nursing infant is unknown, caution should be exercised when allopurinol is administered to a nursing woman.
Allopurinol is rarely indicated for use in children with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism (see and ).
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 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 and ).
The most frequent adverse reaction to allopurinol is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with 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 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 has been reported to be increased (see ).
Gastrointestinal:
Metabolic and Nutritional:
Skin and Appendages:
*Early clinical studies and incidence rates from early clinical experience with allopurinol 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 introduction, , and ).
Body as a whole:
Cardiovascular:
Gastrointestinal:
Hemic and Lymphatic:
Musculoskeletal:
Nervous:
Respiratory:
Skin and Appendages:
Special Senses:
Urogenital:
Body as a whole:
Cardiovascular:
Endocrine:
Gastrointestinal:
Hemic and Lymphatic:
Musculoskeletal:
Nervous:
Respiratory:
Skin and appendages:
Special Senses:
Urogenital:
Reference
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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Interactions
Interactions
A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).