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ACTAVIS PHARMA/
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00591554310

allopurinol 100 mg tablet

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Uses

Gout

Allopurinol is used to lower serum and urinary uric acid concentrations in the management of primary and secondary gout. The drug is indicated in patients with frequent disabling attacks of gout. Because therapy with allopurinol is not without some serious risks, the drug is not recommended for the management of asymptomatic hyperuricemia; however, some clinicians have suggested that therapy should be initiated when serum urate concentrations exceed 9 mg/dL (by the colorimetric method) because these concentrations are often associated with increased joint changes and renal complications. Allopurinol is used for the management of gout when uricosurics cannot be used because of adverse effects, allergy, or inadequate response; when there are visible tophi or radiographic evidence of uric acid deposits and stones; or when serum urate concentrations are greater than 8.5-9 mg/dL and a family history of tophi and low urate excretion exists. Allopurinol also is used for the management of primary or secondary gouty nephropathy with or without secondary oliguria. The goal of therapy is to lower serum urate concentration to about 6 mg/dL. Allopurinol will often promote resolution of tophi and uric acid crystals by decreasing serum urate concentrations.

Since allopurinol has no analgesic or anti-inflammatory activity, it is of no value in the treatment of acute gout attacks and will prolong and exacerbate inflammation during the acute phase. Allopurinol may increase the frequency of acute attacks during the first 6-12 months of therapy, even when normal or subnormal serum urate concentrations have been maintained. Therefore, prophylactic doses of colchicine should generally be administered concurrently during the first 3-6 months of allopurinol therapy. Acute attacks may occur in spite of such therapy, but usually become less severe and are of briefer duration after several months of allopurinol therapy. During these acute attacks, allopurinol should be continued without changing dosage and full therapeutic doses of colchicine or other anti-inflammatory agents should be administered.

In early uncomplicated gout, either allopurinol or a uricosuric agent may be used. Since uricosuric agents tend to increase urinary uric acid concentrations and the risk of stone formation, allopurinol is preferred in patients with urinary uric acid excretion of greater than 900 mg daily or with gouty nephropathy, urinary tract stones or obstruction, or azotemia. The activity of allopurinol and uricosurics is additive and, when administered concomitantly, smaller doses of each drug can be used. Combined use of the two types of drugs is especially effective in the presence of tophaceous deposits.

Chemotherapy-induced Hyperuricemia

Allopurinol and allopurinol sodium are used for the management of patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing chemotherapy expected to result in tumor lysis and subsequent elevations of serum and urinary uric acid concentrations. For patients unable to tolerate oral therapy, allopurinol sodium for injection may be used. Allopurinol is especially useful in preventing hyperuricemia and uric acid nephropathy resulting from tissue breakdown after cancer chemotherapy or radiation therapy. Allopurinol therapy should be discontinued when the potential for hyperuricemia is no longer present.

In one compassionate treatment program in patients undergoing chemotherapy for the management of malignancies, administration of IV allopurinol sodium was shown to reduce serum uric acid concentrations in 93% of patients with hyperuricemia (68% of whom achieved normal serum urate concentrations) and to maintain normal serum uric acid concentrations in 97% of those patients in whom the drug was initiated while having normal serum urate concentrations. However, because of study design, clinical outcome associated with IV allopurinol sodium therapy could not be assessed.

Results of a randomized, open-labeled comparative study in pediatric patients 4 months to 17 years of age with leukemia or lymphoma and a high risk for developing tumor lysis suggest that oral allopurinol may be slower and less effective in decreasing plasma uric acid concentrations than IV rasburicase. (See Uses: Chemotherapy-induced Hyperuricemia, in Rasburicase 44:00.) At the time of this study, IV allopurinol was unavailable. However, the different routes of administration for the drugs (i.e., oral versus IV) are not believed to account for the differences that were observed. Further study is needed to determine whether the more rapid control and reduction of plasma uric acid concentrations that is achieved with rasburicase therapy than is achieved with allopurinol therapy also will result in substantial decreases in metabolic complications and morbidity associated with tumor lysis syndrome, or the need for additional renal support (dialysis or hemofiltration).

Recurrent Renal Calculi

Allopurinol is used in the management of recurrent calcium oxalate renal calculi in males whose urinary urate excretion exceeds 800 mg daily and in females whose urinary urate excretion exceeds 750 mg daily. Therapy with the drug has reduced the rate of calculus events (passage of a new calculus or radiographic evidence of a new or enlarged calculus) and has prolonged the time to recurrence in patients with hyperuricosuria and normocalciuria and a history of recurrent calcium oxalate renal calculi. The use of allopurinol for this disorder must be carefully evaluated initially and reevaluated periodically to determine that therapy with the drug is beneficial and outweighs the risks. Clinical experience suggests that patients with recurrent calcium oxalate renal calculi may also benefit from dietary changes such as reductions in animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as increases in oral fluids and dietary fiber. Allopurinol is also used for the prevention of uric acid renal calculi in patients with a history of recurrent stone formation.

Other Uses

Allopurinol has been used to reduce hyperuricemia secondary to glucose-6-phosphate dehydrogenase deficiency, Lesch-Nyhan syndrome, polycythemia vera, sarcoidosis, and secondary to the administration of thiazides or ethambutol.

Dosage and Administration

Administration

Allopurinol is administered orally. Allopurinol also has been administered rectally. Allopurinol sodium is administered by IV infusion. IV therapy with the drug generally is used in patients who do not tolerate oral therapy.

In all patients receiving allopurinol, fluid intake should be sufficient to yield a daily urine output of at least 2 L and maintenance of a neutral or, preferably, alkaline urine is desirable.

Oral Administration

Oral allopurinol usually is administered in a single daily dose, preferably after meals. The manufacturers recommend that oral doses greater than 300 mg be administered in divided doses.

IV Infusion

Allopurinol sodium powder for injection is reconstituted by adding 25 mL of sterile water for injection to a vial labeled as containing allopurinol sodium equivalent to 500 mg of allopurinol to provide a solution containing 20 mg of allopurinol per mL. Reconstituted solutions should be further diluted prior to administration with 0.9% sodium chloride injection or 5% dextrose injection to a final concentration not exceeding 6 mg of allopurinol per mL Allopurinol solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit. The injection should be discarded if discoloration or particulate matter is present.

Rectal Administration

Extemporaneously prepared allopurinol suppositories have been given rectally in patients unable to tolerate oral medications, particularly during cancer chemotherapy, but pharmacokinetic studies indicate that little if any of the drug is absorbed systemically following this route of administration.

Dosage

Dosage of allopurinol varies with the severity of the disease and should be adjusted according to the response and tolerance of the patient. Dosage of allopurinol also may be adjusted according to results of serum uric acid concentrations, which should be maintained within the normal range.

Gout

To reduce the possibility of flare-up of acute gouty attacks, the manufacturers recommend that patients be started on oral allopurinol dosages of 100 mg daily and that the daily dose of the drug be increased by 100 mg at weekly intervals until the serum urate concentration falls to 6 mg/dL or less, or until the maximum recommended dosage of 800 mg daily is reached. In the management of mild gout, the usual adult dosage may range from 200-300 mg daily and, for moderately severe tophaceous gout, from 400-600 mg daily. Serum urate concentrations are often reduced more slowly with allopurinol than with uricosuric drugs and minimum concentrations may not be reached for 1-3 weeks. After serum urate concentrations are controlled, it may be possible to reduce dosage; the average adult maintenance dosage is 300 mg daily and the minimum effective dosage is 100-200 mg daily. Allopurinol therapy should be continued indefinitely; irregular dosage schedules may lead to increased serum urate concentrations.

When allopurinol is added to a therapeutic regimen of colchicine, uricosuric agents, and/or anti-inflammatory agents, a transition period of several months may be necessary before the latter drugs can be discontinued. During this period, the drugs should be administered concomitantly, and allopurinol dosage should be adjusted until serum urate concentrations are normal and freedom from acute gouty attacks is maintained for several months. When the uricosuric agent is being withdrawn, dosage of the uricosuric agent should be gradually reduced over several weeks.

Chemotherapy-induced Hyperuricemia

Oral Dosage

For the prevention of acute uric acid nephropathy in patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing chemotherapy which are expected to result in tumor lysis and subsequent elevations of serum and urinary uric acid concentrations, adults may receive 600-800 mg of allopurinol daily for 2-3 days; most clinicians recommend that this therapy begin 1-2 days before initiating chemotherapy. When allopurinol is used with mercaptopurine or azathioprine, dosage of the latter drugs must be reduced. (See Drug Interactions: Antineoplastic Agents.) In the initial management of hyperuricemia secondary to neoplastic disease, children younger than 6 years of age may receive 150 mg of allopurinol daily and children 6-10 years of age may receive 300 mg daily. After about 48 hours of therapy, dosage should be adjusted according to the response of the patient.

IV Dosage

Dosage of allopurinol sodium is expressed in terms of allopurinol.

For patients who cannot tolerate oral allopurinol therapy, the manufacturer of allopurinol sodium for injection recommends that adults and children older than 10 years of age receive an allopurinol dosage of 200-400 mg/m daily and children 10 years and younger receive an initial dosage of 200 mg/m daily (both by continuous infusion or in equally divided intermittent IV infusions administered at 6-, 8-, or 12-hour intervals) beginning 24-48 hours before initiation of chemotherapy. In adults and children greater than 10 years of age daily IV allopurinol dosages should not exceed 600 mg since higher dosages do not appear to provide additional benefit.

Recurrent Calcium Oxalate Renal Calculi

For the management of recurrent calcium oxalate renal calculi in patients with hyperuricosuria, the recommended initial dosage of allopurinol is 200-300 mg daily. Subsequent dosage may be increased or decreased depending on control of hyperuricosuria assessed by 24-hour urinary urate excretion determinations.

Dosage in Renal Impairment

In patients with impaired renal function, allopurinol and particularly its metabolite oxypurinol may accumulate and, thus, dosage should be reduced. Initial dosages in these patients should be lower than those used in patients with normal renal function. For oral dosing, the manufacturers recommend 200 mg of allopurinol daily when creatinine clearance is 10-20 mL/minute and that dosage not exceed 100 mg daily in patients with creatinine clearances less than 10 mL/minute. In patients with severely impaired renal function, a dosage of 100 mg daily or 300 mg twice weekly (or possibly lower doses and/or use of longer dosing intervals) may be sufficient to reduce serum urate concentrations. Some clinicians recommend the following maintenance dosages of allopurinol based on the patient's creatinine clearance:

Creatinine Clearance (mL/minute) Maintenance Dosage
100 mg every 3 days
10 100 mg every 2 days
20 100 mg daily
40 150 mg daily
60 200 mg daily
80 250 mg daily

For IV dosing, the manufacturer states that patients with creatinine clearances of 10-20 mL/minute can receive 200 mg daily, those with creatinine clearances of 3-10 mL/minute can receive 100 mg daily, and those with creatinine clearances less than 3 mL/minute may receive 100 mg daily at extended intervals.

Cautions

Results of early clinical studies and experience suggested that some allopurinol-induced adverse effects (e.g., acute attacks of gout, rash) occurred in more than 1% of patients, but current experience suggests that adverse effects of the drug occur in less than 1% of patients. The reduced incidence in adverse effects observed with more recent experience may have resulted in part from initiating therapy with the drug more gradually and following current prescribing precautions and recommendations.

Dermatologic and Local Effects

The most common adverse effect of oral allopurinol is a pruritic maculopapular rash. Dermatitides of the exfoliative, urticarial, erythematous, eczematoid, hemorrhagic, and purpuric types have also occurred. Alopecia, fever, and malaise may also occur alone or in conjunction with dermatitis. In addition, severe furunculoses of the nose, cellulitis, and ichthyosis have been reported. The incidence of rash may be increased in patients with renal insufficiency. Skin reactions may be delayed and have been reported to occur as long as 2 years after initiating allopurinol therapy. Rarely, skin rash may be followed by severe hypersensitivity reactions which may sometimes be fatal. (See Cautions: Hypersensitivity Reactions.) Some patients who have developed severe dermatitis have also developed cataracts (including a case of toxic cataracts), but the exact relationship between allopurinol and cataracts has not been established. Pruritus, onycholysis, and lichen planus have also occurred rarely in patients receiving allopurinol. Facial edema, sweating, and skin edema have also occurred rarely, but a causal relationship to the drug has not been established.

Local injection site reactions have been reported in patients receiving allopurinol sodium IV.

Dermatologic and Sensitivity Reactions

Hypersensitivity or idiosyncratic reactions to allopurinol have been reported rarely. These reactions are characterized by fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, rash, pruritus, nausea, and vomiting.

Serious and fatal cases of toxic epidermal necrolysis, hypersensitivity angiitis, and allergic vasculitis involving erythematous maculopapular rash with desquamation, severe exfoliative dermatitis, Stevens-Johnson syndrome, vesicular bullous dermatitis, arterial nephrosclerosis, oliguria, congestive heart failure, and acute onset of permanent deafness have also been reported during therapy with the drug. Allopurinol-induced hepatotoxicity may also be a hypersensitivity reaction to the drug. (See Cautions: Hepatic Effects.) In addition, renal failure may be associated rarely with hypersensitivity reactions to allopurinol. A generalized hypersensitivity vasculitis has rarely led to irreversible hepatotoxicity and death. The frequency of allopurinol-induced hypersensitivity reactions may be increased in patients with decreased renal function who receive allopurinol and a thiazide diuretic concomitantly. (See Cautions: Precautions and Contraindications and Drug Interactions: Uricosuric Agents and Diuretics.)Allopurinol should usually not be administered to patients who have previously shown hypersensitivity to it or who have had a serious reaction to the drug. (See Cautions: Precautions and Contraindications.) However, successful desensitization has been performed in at least one patient with allopurinol allergy and may be useful when xanthine oxidase inhibition is absolutely necessary to reduce serum urate concentrations and arrest the progression of renal failure.

Hepatic Effects

Alterations in liver function test results, including transient elevations of serum alkaline phosphatase, urinary urobilinogen, AST (SGOT), and ALT (SGPT), and decreases in sulfobromophthalein excretion have occurred in some patients. Reversible hepatomegaly, hepatocellular damage (including necrosis), granulomatous changes, liver failure, hepatitis, hyperbilirubinemia, and jaundice have also occurred. The mechanism of some hepatotoxic reactions to allopurinol has been described as a hypersensitivity reaction, since fever, rash, peripheral eosinophilia, and liver biopsy findings of eosinophilia and noncaseating granulomas occurred; however, other mechanisms may also have been involved.

Hematologic Effects

Leukocytosis, leukopenia, eosinophilia, thrombocytopenia, blast crisis, hemorrhage, bone marrow aplasia, neutropenia, ecchymosis, disseminated intravascular coagulation, and fatal bone marrow suppression and granulocytopenia have been reported rarely in patients receiving allopurinol. Most patients in whom bone marrow suppression was reported during allopurinol therapy were also receiving other drugs with myelosuppressive potential concomitantly. Bone marrow suppression may occur as early as 6 weeks and as late as 6 years after initiation of allopurinol. Mild reticulocytosis, lymphocytosis, agranulocytosis, pancytopenia, anemia, hemolytic anemia, aplastic anemia, decreased prothrombin levels, and eosinophilic fibrohistiocytic bone marrow lesions have also occurred rarely, but a causal relationship to allopurinol has not been established.

GI Effects

Adverse GI effects of allopurinol may include nausea, vomiting, diarrhea, intermittent abdominal pain, enlarged abdomen, constipation, flatulence, intestinal obstruction, proctitis, alteration or loss of taste, gastritis, and dyspepsia. Anorexia, GI bleeding, hemorrhagic pancreatitis, stomatitis, mucositis, salivary gland swelling, and tongue edema have also occurred rarely in patients receiving allopurinol, but a causal relationship to the drug has not been established.

Nervous System Effects

Peripheral neuropathy, neuritis, paresthesia, headache, generalized seizure, status epilepticus, myoclonus, hypotonia, twitching, agitation, changes in mental status, cerebral infarction, coma, dystonia, paralysis, tremor, and somnolence have occurred rarely in patients receiving allopurinol. Optic neuritis, dizziness, vertigo, depression, confusion, amnesia, insomnia, asthenia, and foot drop have also occurred rarely in patients receiving allopurinol, but a causal relationship to the drug has not been established.

Other Adverse Effects

Other reported adverse effects of allopurinol include fever, diaphoresis, myopathy, arthralgias, and epistaxis. Renal failure, decreased renal function, hematuria, increased creatinine, oliguria, hypercuricemia,and urinary tract infection also have been reported. Patients receiving allopurinol also have developedlactic acidosis, metabolic acidosis, water intoxication, hyperphosphatemia, hypomagnesemia, hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypercalcemia, and other electrolyte abnormalities. Tumor lysis syndrome, sepsis, septic shock, and other infections also have been reported.

Other adverse effects reported with allopurinol include respiratory failure/insufficiency, acute respiratory distress syndrome (ARDS), increased respiratory rate, and apnea. Hypervolemia, heart failure, cardiorespiratory arrest, hypotension, hypertension, pulmonary embolism, decreased venous pressure, flushing, stroke, ECG abnormalities, ventricular fibrillation, splenomegaly, hyperglycemia, glycosuria, and uremia also have been reported. Malaise, pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation, hypercalcemia, hyperlipidemia, gynecomastia in males, lymphadenopathy, myalgia, bronchospasm, pharyngitis, rhinitis, asthma, macular retinitis, iritis, conjunctivitis, amblyopia, tinnitus, nephritis, albuminuria, primary hematuria, and decreased libido have occurred rarely in patients receiving allopurinol, but a causal relationship to the drug has not been established.

Patients with renal disease have shown either an increase or a decrease in BUN concentrations, pyelonephritis, renal colic, bilateral ureteral obstruction, xanthine stones, and oxypurinol stones and sludge during allopurinol therapy. In cancer patients who develop hyperuricemia, changes in renal function may be associated with the underlying malignancy, rather than with administration of allopurinol. In several patients in whom renal function deteriorated during allopurinol therapy, concurrent conditions (e.g., multiple myeloma, congestive myocardial disease) were present before initiation of allopurinol therapy.

One study in rats indicated that the concentration of iron stored in the liver was increased during administration of allopurinol. This disturbance in iron storage has not been demonstrated clinically. In another study, however, a reversible rise in serum iron concentrations and decrease in total iron binding capacity occurred in patients receiving 500-600 mg of allopurinol daily; these effects reverted to normal when dosage was reduced to 300 mg daily.

Precautions and Contraindications

Allopurinol should be discontinued at the first appearance of rash or any sign that may indicate an allergic reaction, since severe hypersensitivity reactions that may be fatal have been reported following appearance of rash. Although, in some patients with rash, allopurinol may be reinstated at a lower dosage without untoward incident, the drug should not be reinstituted in patients who have had a severe reaction.

Allopurinol may increase the frequency of acute gouty attacks during the first 6-12 months of therapy; therefore, prophylactic doses of colchicine should generally be administered concurrently during the first 3-6 months of allopurinol therapy. (See Uses: Gout.)

Patients should be warned that drowsiness may occur during allopurinol therapy and may impair their ability to perform activities requiring mental alertness. Patients should also be warned to discontinue the drug and consult their physician immediately at the first sign of rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth.

Liver function tests (particularly in patients with preexisting liver disease), renal function tests (particularly in patients with impaired renal function or concurrent illness that can affect renal function such as hypertension or diabetes mellitus), and complete blood cell counts should be performed before initiating allopurinol and periodically during therapy, especially during the first few months. If patients receiving allopurinol develop anorexia, weight loss, or pruritus, assessment of liver function should be part of the diagnostic evaluation.

Patients with impaired renal function must be carefully observed while receiving allopurinol (particularly during the early stages of therapy) and the dosage decreased or the drug discontinued if evidence of deterioration in renal function occurs and persists. Patients with impaired renal function require lower dosages of allopurinol than those with normal renal function. (See Dosage and Administration: Dosage in Renal Impairment.) The usual initial dosage of allopurinol should be reduced in patients with impaired renal function. Since concomitant therapy with allopurinol and a thiazide diuretic in patients with decreased renal function may increase the risk of allopurinol-induced hypersensitivity reactions, concomitant therapy with the drugs should be used with caution in such patients and the patients should be observed closely.(See Drug Interactions: Uricosuric Agents and Diuretics.)

Pediatric Precautions

Pending further accumulation of data, the manufacturers state that allopurinol is rarely indicated in children except in those with hyperuricemia secondary to neoplastic disease, cancer chemotherapy, or genetic disorders of purine metabolism. Clinical experience in about 200 pediatric patients suggests that safety and efficacy of allopurinol sodium for injection are similar to those in adults.

Geriatric Precautions

The manufacturer of allopurinol sodium for injection states that clinical studies of parenteral allopurinol sodium did not include a sufficient number of patients 65 years of age or older to determine whether such patients respond differently than younger individuals, but that other reported clinical experience has not identified differences in response between geriatric and younger patients. In a pharmacokinetic study, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of oxypurinol (active metabolite of allopurinol) were about 50-60% higher in geriatric individuals than in younger individuals following single oral allopurinol dosing.(See Pharmacokinetics: Absorption.) Since these differences appear to be related to changes in renal function in geriatric patients, some clinicians state that adjustments in allopurinol dosage may be necessary in geriatric patients based on the degree of renal impairment.(See Dosage and Administration: Dosage in Renal Impairment.) In addition, appropriate dosage of allopurinol in geriatric patients should be selected with caution because of the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease and drug therapy in these patients.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date using allopurinol in pregnant women, the drug has been shown to be teratogenic in mice using intraperitoneal allopurinol doses of 50 or 100 mg/kg (0.3 or 0.75 times the recommended human dose on a mg/m basis) on gestation days 10 or 13. Allopurinol should be used during pregnancy only when clearly needed.

Fertility

Reproduction studies in rats and rabbits using dosages up to 20 times the usual human dosage have not revealed evidence of impaired fertility. Infertility in human males and impotence have occurred rarely during allopurinol therapy, but a causal relationship to the drug has not been established.

Lactation

Since allopurinol and oxypurinol are distributed into milk, allopurinol should be used with caution in nursing women.

Drug Interactions

The following drug interactions were observed in patients receiving oral allopurinol therapy. Although many patients received long-term oral administration of allopurinol (e.g., those with gout or renal calculi), these interactions may be relevant to allopurinol sodium for injection therapy as well.

Antineoplastic Agents

In dosages of 300-600 mg daily, allopurinol inhibits the oxidative metabolism of azathioprine and mercaptopurine by xanthine oxidase, thus increasing the possibility of toxic effects from these drugs, particularly bone marrow depression. When allopurinol is administered concomitantly with mercaptopurine or azathioprine, the doses of the antineoplastic agents should initially be reduced to 25-33% of the usual dose and subsequent dosage adjusted according to the patient response and toxic effects. Substitution of thioguanine for mercaptopurine has also been suggested.

Concomitant administration of allopurinol with cyclophosphamide may increase the incidence of bone marrow depression as compared with cyclophosphamide alone, but the mechanism for this interaction is not known. However, results of a well-controlled study in patients with lymphoma have shown that concomitant use of allopurinol with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine did not increase the incidence of bone marrow depression in these patients.

Drugs that Increase Serum Urate Concentration

Many drugs may increase serum urate concentrations, including most diuretics, pyrazinamide, diazoxide, alcohol, and mecamylamine. If these drugs are administered during allopurinol therapy, dosage of allopurinol may need to be increased.

Anticoagulants

Allopurinol inhibits the hepatic microsomal drug metabolism of dicumarol. In one study, the half-life of dicumarol was increased from 51 to 152 hours when the anticoagulant was taken concurrently with allopurinol. Although the clinical importance of this effect may vary, patients taking allopurinol with dicumarol should be observed for increased anticoagulant effects and prothrombin time should be monitored periodically in these patients. Allopurinol has not been shown to substantially potentiate the anticoagulant effect of warfarin except in one case when warfarin, allopurinol, and indomethacin were administered concurrently.

Ampicillin and Amoxicillin

An increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant ampicillin or amoxicillin as compared with those receiving allopurinol, ampicillin, or amoxicillin alone. Some clinicians suggest that either allopurinol or hyperuricemia may potentiate aminopenicillin allergenicity. However, other clinicians state that the rash reported in patients receiving allopurinol and aminopenicillins concomitantly is generally the delayed aminopenicillin rash that appears to be nonimmunologic. The clinical importance of this effect has not been determined; however, some clinicians suggest that concomitant use of the drugs should be avoided if possible.

Uricosuric Agents and Diuretics

Uricosurics promote urinary excretion of oxypurinol (which also inhibits xanthine oxidase) and may thereby reduce the inhibition of xanthine oxidase produced by allopurinol therapy; however, the effects of allopurinol and a uricosuric are generally additive, and the combination is usually used to therapeutic advantage. Renal precipitation of oxypurines has not occurred to date in patients receiving allopurinol alone or in combination with a uricosuric, but the possibility should be kept in mind.

Diuretics such as thiazides and ethacrynic acid, when given with allopurinol, may increase serum oxypurinol concentrations and may thereby increase the risk of serious allopurinol toxicity, including hypersensitivity reactions (particularly in patients with decreased renal function); however, allopurinol has been used safely with thiazides to reduce hyperuricemia induced by the diuretics. A review of reports of allopurinol toxicity in patients who were receiving concomitant therapy with allopurinol and a thiazide indicated that patients were principally receiving a thiazide for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed; however, in patients in whom renal insufficiency was documented, dosage of allopurinol was not appropriately reduced. Although a causal mechanism and relationship have not been definitely established, the evidence suggests that renal function should be monitored (even in the absence of renal failure) in patients receiving allopurinol and a thiazide concomitantly and that dosage of allopurinol in such patients should be adjusted even more conservatively than usual if decreased renal function is detected.

Chlorpropamide

Allopurinol and chlorpropamide cause adverse hepatorenal reactions. Although the combination does not enhance the occurrence of these reactions, caution is indicated if these 2 drugs are administered concomitantly. Because allopurinol or its metabolites may compete with chlorpropamide for renal tubular secretion, patients who receive these drugs concomitantly (especially those with renal insufficiency) should be observed for signs of excessive hypoglycemia.

Other Drugs

Concurrent use of co-trimoxazole with allopurinol has been associated with thrombocytopenia in a few patients.

Increased blood concentrations of cyclosporine have been reported in patients receiving allopurinol and cyclosporine concomitantly. Therefore, blood cyclosporine concentrations should be monitored and dosage adjustments of cyclosporine should be considered when these drugs are used concomitantly.

Pharmacokinetics

Absorption

Following oral administration, approximately 80-90% of a dose of allopurinol is absorbed from the GI tract. Peak plasma concentrations of allopurinol are reached 2-6 hours after a usual dose.

Following oral administration of single 100- or 300-mg dose of allopurinol in healthy adult males in one study, peak plasma allopurinol concentrations of about 0.5 or 1.4 µg/mL, respectively, occurred in about 1-2 hours, while peak oxypurinol (the active metabolite of allopurinol) concentrations of about 2.4 and 6.4µg/mL, respectively, were reached within about 3-4 hours. In the same study, following IV infusion over 30 minutes of a single 100- or 300-mg dose of allopurinol (as allopurinol sodium), peak plasma concentrations of about 1.6 and 5.1 µg/mL, respectively, occurred in about 30 minutes, while peak oxypurinol concentrations of about 2.2 and 6.2 µg/mL, respectively, were reached within about 4 hours.

Peak plasma concentrations and the area under the plasma concentration-time curve (AUC) of oxypurinol following oral administration of allopurinol 200 mg as a single dose have been reported to be about 50-60% higher in geriatric patients (71-93 years of age) than in younger adults (24-35 years of age); these differences appear to be related to changes in renal function in geriatric patients. Some clinicians state that adjustments in allopurinol dosage may be necessary in geriatric patients based on the degree of renal impairment. (See Dosage and Administration: Dosage in Renal Impairment.)

Because allopurinol concentrations are difficult to determine and because serum concentrations may not adequately reflect the amount of drug bound to xanthine oxidase in the tissues, serum urate concentrations should be used to monitor therapy. After beginning allopurinol therapy, serum urate concentrations begin to decrease slowly within 24-48 hours and reach a nadir after 1-3 weeks of therapy. During allopurinol therapy, serum urate concentrations remain relatively constant; however, serum urate concentrations usually return to pretreatment levels within 1-2 weeks after discontinuing the drug. Because of the continued mobilization of urate deposits, substantial reduction of uric acid may be delayed 6-12 months or may not occur in some patients, particularly in those with tophaceous gout and in those who are underexcretors of uric acid.

Allopurinol is absorbed poorly following rectal administration of the drug as suppositories (in a cocoa butter or polyethylene glycol base). Plasma allopurinol or oxipurinol concentrations have been minimal or undetectable following such rectal administration.

Distribution

Allopurinol is uniformly distributed in total tissue water with the exception of the brain, where concentrations of the drug are approximately 50% those of other tissues. Small amounts of oxypurinol and allopurinol crystals have been found in muscle. Allopurinol and oxypurinol are not bound to plasma proteins. Allopurinol and oxypurinol are distributed into milk.

Elimination

Allopurinol and allopurinol sodium are rapidly metabolized by xanthine oxidase to oxypurinol, which is pharmacologically active. Rapid metabolism of allopurinol to oxypurinol does not seem to be affected substantially during multiple dosing. Pharmacokinetic parameters (e.g., AUC, plasma elimination half-lives) of oxypurinol appear to be similar following oral administration of allopurinol and IV administration of allopurinol sodium. The half-lives of allopurinol and oxypurinol are about 1-3 hours and 18-30 hours, respectively, in patients with normal renal function and are increased in patients with renal impairment. Patients genetically deficient in xanthine oxidase are unable to convert allopurinol to oxypurinol. Both allopurinol and oxypurinol are conjugated and form their respective ribonucleosides.

About 5-7% of an oral allopurinol dose is excreted in urine unchanged within 6 hours after ingestion and about 12% of an IV dose of the drug is excreted unchanged 5 hours after administration. After this time, the drug is excreted by the kidneys as oxypurinol and in small amounts as allopurinol and oxypurinol ribonucleosides. Unlike allopurinol, a large part of oxypurinol is reabsorbed by the renal tubules; therefore, its renal clearance is much lower than that of allopurinol. About 70% of the administered daily dose is excreted in urine as oxypurinol and an additional 20% appears in feces as unchanged drug within 48-72 hours.

Allopurinol and oxypurinol are dialyzable.

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