INFORMATION FOR PATIENTS

Information for PatientsPatients 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.

Laboratory TestsThe 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 WARNINGS).

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.

Drug InteractionsIn 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 CLINICAL PHARMACOLOGY).

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.

Drug/Laboratory Test InteractionsAllopurinol 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 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.

Nursing MothersAllopurinol 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.

Pediatric UseAllopurinol 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 INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).