VA Class:MS400
ATC Class:M04AA01
Allopurinol, a structural isomer of hypoxanthine, is a xanthine oxidase inhibitor.
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.152, 153, 156 For patients unable to tolerate oral therapy, allopurinol sodium for injection may be used.152 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.156
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.152 However, because of study design, clinical outcome associated with IV allopurinol sodium therapy could not be assessed.152
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.157, 158, 159, 160, 161 (See Uses: Chemotherapy-induced Hyperuricemia, in Rasburicase 44:00.) At the time of this study, IV allopurinol was unavailable.158 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.160 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).158
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.151 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.
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†.
Allopurinol is administered orally. Allopurinol also has been administered rectally†. Allopurinol sodium is administered by IV infusion.152, 156 IV therapy with the drug generally is used in patients who do not tolerate oral therapy.152
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.
Because of a strong association between the presence of the variant human leukocyte antigen (HLA)-B*5801 allele and risk of developing allopurinol-induced severe hypersensitivity reactions,164, 166, 170, 171, 172 pharmacogenetic testing for HLA-B*5801 should be considered prior to initiation of allopurinol therapy in certain high-risk populations in which this allele is known to be highly prevalent.165, 167, 168, 169, 172, 181 The American College of Rheumatology (ACR) and some clinicians state that screening for HLA-B*5801 should be considered prior to initiation of allopurinol therapy in populations in which both the HLA-B*5801 allele frequency is increased and HLA-B*5801-positive patients have a very high risk of experiencing severe hypersensitivity reactions (e.g., individuals of Korean ancestry with stage 3 or worse chronic kidney disease, individuals of Han Chinese or Thai ancestry irrespective of renal function).165, 181 Genotyping results are considered positive if 1 or 2 copies of HLA-B*5801 are detected and negative if no copies of the variant allele are detected.164, 166 Experts state that allopurinol therapy should be avoided in patients who have tested positive for HLA-B*5801.163, 164, 165, 167 If use of allopurinol cannot be avoided and the benefits are considered to outweigh the risks, more intensive monitoring for manifestations of hypersensitivity reactions is required.172 (See Pharmacogenomics of Allopurinol-induced Serious Hypersensitivity Reactions under Cautions: Dermatologic and Sensitivity Reactions.)
Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management.163, 164 Many HLA-B*5801-positive patients who are treated with allopurinol will never develop severe cutaneous reactions,164 and such reactions may develop in HLA-B*5801-negative patients.164, 166, 172 (See Cautions: Dermatologic and Sensitivity Reactions.) For additional information and guidance on how to interpret and apply the results of HLA-B*5801 testing, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for HLA genotype and allopurinol dosing should be consulted.163, 164
Oral allopurinol usually is administered in a single daily dose. The manufacturers recommend that oral doses greater than 300 mg be administered in divided doses. Administration of the drug after meals may minimize adverse GI effects.156
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.152 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 mL152 Allopurinol solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit.152 The injection should be discarded if discoloration or particulate matter is present.152
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 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.152, 156
In patients with gout, allopurinol therapy should be initiated at a low dosage to reduce the possibility of early flare-up of acute gouty attacks and also because some data suggest that higher initial dosages may be associated with increased risk of severe hypersensitivity reactions.165, 168 Dosage should be gradually increased to achieve target serum urate concentrations (less than 6 mg/dL), or until the maximum recommended dosage is reached.165, 168
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. The manufacturers state that the usual dosage may range from 200-300 mg daily in adults with mild gout and from 400-600 mg daily in those with moderately severe tophaceous gout. 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 dosa the manufacturers state that 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.
Some experts recommend that allopurinol therapy be initiated at a dosage of 100 mg daily or less in adults with gout and that dosage be increased every 2-5 weeks in increments of 100 mg daily to achieve target serum urate concentrations or until a maximum recommended dosage of 800-900 mg daily is reached.156, 165, 167, 168, 169 Although a dosage of 300 mg daily is commonly used, up to one-half of patients with normal renal function will not achieve target serum urate concentrations at this dosage.165, 168, 169 In some studies utilizing dosages up to 600-800 mg daily, target serum urate concentrations were achieved in 75-80% of patients.168, 191
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
For the prevention of acute uric acid nephropathy in patients with leukemia, lymphoma, and solid tumor malignancies who are undergoing chemotherapy that is 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.
Dosage of allopurinol sodium is expressed in terms of allopurinol.152
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/m2 daily and children 10 years and younger receive an initial dosage of 200 mg/m2 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.152, 162 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.152, 162
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.
Various approaches to dosing allopurinol in patients with renal impairment have been recommended in an attempt to minimize the risk of allopurinol-induced hypersensitivity reactions.165, 167 Use of a low initial dosage has been recommended to reduce the risk of such reactions;165, 167, 168, 186 the relationship between hypersensitivity reactions and the maintenance dosage used in renal impairment is more controversial.186 This uncertainty is reflected in the lack of consensus on allopurinol dosage in patients with renal impairment.186 (See Cautions: Dermatologic and Sensitivity Reactions.)
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.
The manufacturers and some experts recommend that maximum dosages of allopurinol be adjusted according to creatinine clearance.156, 168 For oral dosing, the manufacturers recommend 200 mg of allopurinol daily when creatinine clearance is 10-20 mL/minute and state that dosage should not exceed 100 mg daily in patients with creatinine clearances less than 10 mL/minute. In patients with severely impaired renal function (i.e., creatinine clearance less than 3 mL/minute), the manufacturers state that use of longer dosing intervals also may be required.
Some clinicians have recommended alternative maintenance dosages of allopurinol based on the patient's creatinine clearance (see Table 1).150 Although such creatinine clearance-based dosing was widely adopted,165, 184 this dosing strategy frequently fails to reduce serum urate concentrations to target levels, and evidence that this strategy reduces the risk of allopurinol-induced hypersensitivity reactions in patients who tolerate low initial dosages of the drug is lacking.167, 183, 184 More recent data suggest that dosage can be increased safely beyond these creatinine clearance-based maintenance dosages, with greater reduction of serum urate concentrations.183, 184
Creatinine Clearance (mL/minute) | Maintenance Dosage |
|---|---|
0 | 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 |
Based on data suggesting that initial dosage is a risk factor for allopurinol-induced hypersensitivity reactions, the American College of Rheumatology (ACR) and some clinicians recommend that allopurinol therapy be initiated at a reduced dosage of 50 mg daily in patients with stage 4 or worse chronic kidney disease (creatinine clearance less than 30 mL/minute).165, 183 Dosage may be adjusted in increments of 50-100 mg every 2-5 weeks to achieve target serum urate concentrations.183 The ACR and some other clinicians state that dosage may be increased to levels exceeding 300 mg daily, even in patients with renal impairment,165, 169 provided patients receive appropriate education and are monitored regularly for evidence of hypersensitivity reactions or other adverse effects.165
Other experts and clinicians recommend use of even lower initial dosages (based on estimated glomerular filtration rate [eGFR]) in patients with renal impairment (see Table 2), followed by a gradual increase in dosage (e.g., in 50-mg increments at intervals of approximately every 4 weeks);167, 173 although these experts state that maximum dosage in patients with renal impairment should be lower than in patients without renal impairment, target serum urate concentrations should be the same.167
Estimated GFR (mL/minute per 1.73 m2) | Initial Dosage |
|---|---|
Less than 5 | 50 mg weekly |
5-15 | 50 mg twice weekly |
16-30 | 50 mg every 2 days |
31-45 | 50 mg daily |
46-60 | 50 and 100 mg on alternating days |
61-90 | 100 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.152
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: Dermatologic and Sensitivity 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.152
Dermatologic and Sensitivity Reactions
Serious and sometimes fatal hypersensitivity reactions have been reported in approximately 0.1-0.4% of patients receiving allopurinol.164, 165, 166, 167, 187 The reactions include a spectrum of cutaneous reactions and systemic manifestations, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and allopurinol hypersensitivity syndrome; systemic manifestations may include fever, leukocytosis, atypical circulating lymphocytes, eosinophilia, lymphadenopathy, vasculitis, and organ system involvement such as hepatitis and acute renal failure.152, 164, 165, 166, 167, 172, 187 The reactions also have been referred to as severe cutaneous adverse reactions (SCARs).164, 166, 186 These reactions have similar clinical presentations, and some of the terms have been used interchangeably in published literature to describe the clinical syndromes.171, 177, 186, 187 Onset typically occurs within weeks or months following initiation of allopurinol therapy, but may occur later.164, 165, 172, 187 The mortality rate of severe allopurinol-induced hypersensitivity reactions is up to 20-30%.164, 165, 166, 168, 187 If such reactions occur, allopurinol should be discontinued immediately, since early diagnosis and drug discontinuance may improve prognosis.172
Serious and fatal cases of hypersensitivity angiitis and allergic vasculitis involving erythematous maculopapular rash with desquamation, severe exfoliative dermatitis, vesicular bullous dermatitis, arterial nephrosclerosis, oliguria, congestive heart failure, and acute onset of permanent deafness have been reported during therapy with the drug. Allopurinol-induced hepatotoxicity may also be a hypersensitivity reaction to the drug. (See Cautions: Hepatic Effects.) A generalized hypersensitivity vasculitis has rarely led to irreversible hepatotoxicity and death.
Presence of human leukocyte antigen (HLA)-B*5801, an inherited allelic variant of the HLA-B gene, is strongly associated with severe hypersensitivity reactions to allopurinol, particularly in certain Asian populations.164, 166, 170, 171, 172 (See Pharmacogenomics of Allopurinol-induced Serious Hypersensitivity Reactions under Cautions: Dermatologic and Sensitivity Reactions.) However, other genetic or nongenetic factors (e.g., renal impairment, thiazide diuretic use, recent initiation of allopurinol therapy, high initial allopurinol dosage) also have been associated with an increased risk of such reactions.163, 164, 165, 170, 172, 183, 184, 186, 187 The magnitude of risk associated with these factors is uncertain because of the low incidence of severe allopurinol-associated hypersensitivity reactions.164 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 see Drug Interactions: Diuretics.)
Some of the reported nongenetic risk factors (e.g., renal impairment, diuretic therapy, higher allopurinol dosage) are associated with increased plasma concentrations of oxypurinol, the active metabolite of allopurinol.163, 170, 186 Oxypurinol has been shown to bind to the peptide-binding groove of HLA-B*5801 and activate T cells in a dose-dependent manner,163 and some reports suggest that increased oxypurinol concentrations may be associated with poorer prognosis in patients who experience hypersensitivity reactions.163, 170, 186 However, evidence of a clear relationship between oxypurinol concentration and development of allopurinol-induced hypersensitivity is lacking.173, 186
There are conflicting data regarding allopurinol dosage.184, 187 Some data suggest that high initial dosages are associated with increased risk of hypersensitivity reactions and that initiating allopurinol therapy at a low dosage adjusted for renal function may reduce the risk of such reactions.164, 167, 173, 186 However, the relationship between allopurinol maintenance dosage, particularly in individuals with renal impairment, and hypersensitivity is more controversial,186 and this uncertainty is reflected in the lack of consensus on allopurinol dosage in renal impairment.186 (See Dosage and Administration: Dosage in Renal Impairment.)
Allopurinol should 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.)
Pharmacogenomics of Allopurinol-induced Serious Hypersensitivity Reactions
Studies have demonstrated a strong association, particularly in certain Asian populations, between the risk of developing allopurinol-induced severe hypersensitivity reactions (SJS, TEN, DRESS, allopurinol hypersensitivity syndrome) and the presence of HLA-B*5801, an inherited allelic variant of the HLA-B gene.164, 166, 170, 171, 172 The HLA-B*5801 allele is found most commonly in individuals of Han Chinese, Korean, or Thai ancestry, with some estimates indicating that up to 20%, approximately 12%, or 6-15% of individuals in these respective ethnic groups may be HLA-B*5801-positive.164, 166, 172 Studies conducted in Japan and Europe suggest that 1-2% of these populations may be HLA-B*5801-positive.166, 172 In the US, the allele reportedly is present in approximately 7% of individuals of Asian ancestry, 3-6% of African-Americans, and less than 2% of Caucasians and Hispanics.170, 176, 178 The strength of the association between HLA-B*5801 and hypersensitivity reactions appears to vary among ethnic groups according to the frequency of HLA-B*5801 expression.164, 166, 170, 171, 187 In one study in Taiwan, HLA-B*5801 was present in 100% of Han Chinese patients with allopurinol-induced hypersensitivity syndrome, SJS, or TEN, compared with 15% of allopurinol-tolerant patients and 20% of population controls.164, 166, 175 Strong associations also have been reported in Thai and Korean populations.164, 189, 190 More modest associations have been observed in Japanese and European Caucasian populations, with HLA-B*5801 present in approximately 36-56 and 55-64%, respectively, of patients with severe hypersensitivity reactions to allopurinol.164, 166, 170
Presence of the HLA-B*5801 allele has not been found to be predictive of less severe dermatologic reactions (e.g., simple or mild rash, maculopapular eruption) associated with allopurinol.163, 164
Pharmacogenetic testing for HLA-B*5801 should be considered prior to initiation of allopurinol therapy in certain high-risk populations in which this allele is known to be highly prevalent.165, 167, 168, 169, 172, 181 The American College of Rheumatology (ACR) and some clinicians state that screening for HLA-B*5801 should be considered prior to initiation of allopurinol therapy in populations in which both the HLA-B*5801 allele frequency is increased and HLA-B*5801-positive patients have a very high risk of experiencing severe hypersensitivity reactions (e.g., individuals of Korean ancestry with stage 3 or worse chronic kidney disease, individuals of Han Chinese or Thai ancestry irrespective of renal function).165, 181 Experts state that allopurinol therapy should be avoided in patients who have tested positive for HLA-B*5801.163, 164, 165, 167 If use of allopurinol cannot be avoided and the benefits of allopurinol are considered to outweigh the risks, more intensive monitoring for manifestations of hypersensitivity reactions is required.172
Severe hypersensitivity reactions can occur in allopurinol-treated patients who are negative for HLA-B*5801 regardless of their ethnicity,164, 166, 172 and a substantial number of patients with the variant allele will not develop severe hypersensitivity reactions if they receive allopurinol therapy.164 Results of cost-effectiveness analyses conducted for some populations (mostly in Asia) suggest that screening for HLA-B*5801 prior to initiation of allopurinol therapy would be cost-effective in certain populations (e.g., Taiwanese and Thai populations, Korean patients with chronic renal insufficiency),168, 177, 179, 180 and prospective studies evaluating HLA-B*5801 screening in Taiwanese individuals of Han Chinese ancestry and in Korean patients with chronic renal insufficiency suggest that screening these populations for HLA-B*5801 reduces the incidence of allopurinol-induced severe adverse cutaneous reactions below historically predicted rates.181, 182 Additional studies are needed to assess the role of screening in other populations with lower or ill-defined frequencies of the allele.168, 181 Based on estimated allele frequency and health-care costs in the US, some clinicians suggest that screening of African-Americans prior to initiation of allopurinol therapy also may be cost-effective.178
Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management.163, 164 Regardless of genotyping results, patients receiving allopurinol should be monitored closely.164
Alterations in liver function test results, including transient elevations of serum alkaline phosphatase, urinary urobilinogen, AST, and ALT, 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.
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.152 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.
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.
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 reported adverse effects of allopurinol include fever, diaphoresis, myopathy, arthralgias, and epistaxis. Renal failure, decreased renal function, hematuria, increased creatinine, oliguria, hyperuricemia, and urinary tract infection also have been reported. Patients receiving allopurinol also have developed lactic 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.152, 156 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.152, 156
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. Patients initiating allopurinol therapy should be informed of the potential for severe hypersensitivity reactions to occur and should be advised to immediately discontinue the drug and seek medical attention at the first appearance of any signs or symptoms of hypersensitivity (e.g., rash, pruritus).156, 172, 186 Pharmacogenetic testing should be considered prior to initiation of therapy in certain high-risk patients who may have a genetic predisposition to severe allopurinol-induced hypersensitivity reactions.165, 167, 168, 169, 172, 181 (See Pharmacogenetic Testing under Dosage and Administration: Administration.)
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: Diuretics.)
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.152
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.152 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.154 (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.154 (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.152
Pregnancy, Fertility, and Lactation
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/m2 basis) on gestation days 10 or 13.152, 156 Allopurinol should be used during pregnancy only when clearly needed.156
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.
Since allopurinol and oxypurinol are distributed into milk, allopurinol should be used with caution in nursing women.
The following drug interactions were observed in patients receiving oral allopurinol therapy.152 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.152
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.
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.
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.
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.152, 156
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.
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.152
In 2 patients with renal impairment, concomitant use of allopurinol (300 mg daily) and buffered didanosine (single 200-mg dose) increased peak plasma concentrations and area under the concentration-time curve (AUC) of didanosine by 232 and 312%, respectively.174 In 14 healthy individuals who received allopurinol (300 mg daily) and buffered didanosine (single 400-mg dose), peak plasma concentrations and AUC of didanosine were increased by 69 and 113%, respectively.174 The manufacturer of didanosine states that concomitant use of allopurinol and didanosine is contraindicated since increased didanosine exposure may result in increased didanosine-associated toxicity.174
Diuretics such as thiazides, furosemide, 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. Consideration should be given to the indication for concomitant diuretic use and whether alternative agents (e.g., other antihypertensive agents) might appropriately be used.186 When diuretics (particularly thiazides) and allopurinol are used concomitantly, especially in patients with chronic renal impairment, more intensive monitoring for manifestations of hypersensitivity reactions is required.172 (See Cautions: Dermatologic and Sensitivity Reactions.)
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.
Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Oxypurinol, a metabolite of allopurinol, also inhibits xanthine oxidase. By inhibiting xanthine oxidase, allopurinol and its metabolite block conversion of the oxypurines (hypoxanthine and xanthine) to uric acid, thus decreasing serum and urine concentrations of uric acid. The drug differs, therefore, from uricosuric agents which lower serum urate concentrations by promoting urinary excretion of uric acid. Xanthine oxidase concentrations are not altered by long-term administration of the drug.
Allopurinol does not directly interfere with purine nucleotide or nucleic acid synthesis. The drug, however, indirectly increases oxypurine and allopurinol ribonucleotide concentrations and decreases phosphoribosylpyrophosphate concentrations, thus decreasing de novo purine biosynthesis by pseudofeedback inhibition. In addition, allopurinol increases the incorporation of hypoxanthine and xanthine into DNA and RNA, thereby further decreasing serum urate concentrations. Allopurinol may produce a deficit of total purines (uric acid and oxypurines) amounting to several hundred mg daily.
Accompanying the decrease in uric acid produced by allopurinol is an increase in serum and urine concentrations of hypoxanthine and xanthine. Plasma concentrations of these oxypurines do not, however, rise commensurately with the fall in serum urate concentrations and are often 20-30% less than would be expected in view of urate concentrations prior to allopurinol therapy. This discrepancy occurs because renal clearance of the oxypurines is at least 10 times greater than that of uric acid. In addition, normal urinary purine output is almost exclusively uric acid, but after treatment with allopurinol, it is composed of uric acid, xanthine, and hypoxanthine, each having independent solubility. Thus, the risk of crystalluria is reduced. Alkalinization of the urine increases the solubility of the purines, further minimizing the risk of crystalluria. Decreased tubular transport of uric acid also results in increased renal reabsorption of calcium and decreased calcium excretion.
Allopurinol also interferes with de novo pyrimidine nucleotide synthesis by inhibiting orotidine 5'-phosphate decarboxylase. Secondary orotic aciduria and orotidinuria result. Orotic acid is highly insoluble and could form a heavy sediment of urinary crystals; however, the increased excretion of orotic acid and orotidine rarely exceeds 10% of the total pyrimidines synthesized by the body. In addition, enhanced conversion of uridine to uridine 5'-monophosphate usually occurs and, therefore, this partial inhibition of pyrimidine synthesis is considered innocuous.
In rats, allopurinol reportedly increases liver storage of iron by inhibiting the ferritin-xanthine oxidase system responsible for mobilization of iron from the liver; however, this effect has not been demonstrated clinically.
Allopurinol may also inhibit hepatic microsomal enzymes. Allopurinol is not cytotoxic and has no effect on transplantable tumors. The drug has no analgesic, anti-inflammatory, or uricosuric activity.
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 6.4 µg/mL, respectively, were reached within about 3-4 hours.152 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.152
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.154 Some clinicians state that adjustments in allopurinol dosage may be necessary in geriatric patients based on the degree of renal impairment.154 (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 oxypurinol concentrations have been minimal or undetectable following such rectal administration.
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.
Allopurinol and allopurinol sodium are rapidly metabolized by xanthine oxidase to oxypurinol, which is pharmacologically active.152 Rapid metabolism of allopurinol to oxypurinol does not seem to be affected substantially during multiple dosing.152 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.152, 153 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.152 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.
Allopurinol, a structural isomer of hypoxanthine, is a xanthine oxidase inhibitor used in the treatment of gout and selected hyperuricemias. The drug occurs as a fluffy white to off-white powder having a slight odor and is very slightly soluble in water and in alcohol. The apparent pKa of allopurinol is 9.4 and its active oxidative metabolite, oxypurinol (alloxanthine), has an apparent pKa of 7.7.
Allopurinol sodium occurs as a white amorphous mass and has a pKa of 9.31.152 Following reconstitution of the commercially available allopurinol sodium lyophilized powder with sterile water for injection to a concentration of 20 mg/mL, the solution is clear and almost colorless with no more than a slight opalescence and has a pH of 11.1-11.8.152
Allopurinol tablets should be stored in well-closed containers at 15-30°C. Commercially available allopurinol sodium lyophilized powder for injection should be stored at a controlled room temperature of 20-25°C.152 Following reconstitution of allopurinol sodium for injection with sterile water for injection, the solutions contain approximately 20 mg/mL and should be further diluted with 0.9% sodium chloride injection or 5% dextrose injection.152 These further diluted allopurinol sodium solutions, containing no more than 6 mg/mL, should be stored at 20-25°C and should be used within 10 hours of reconstitution.152 Reconstituted and/or diluted solutions should not be refrigerated.152
Allopurinol sodium injection has been reported to be incompatible with various drugs (e.g., sodium bicarbonate),152 but the compatibility depends on several factors (e.g., concentrations of the drugs, resulting pH, temperature).155 Specialized references should be consulted for specific compatibility information.155
An oral suspension of allopurinol containing 20 mg/mL has been prepared extemporaneously from the commercially available tablets. The tablets were crushed, mixed with a volume of suspending agent (Cologel®) equal to one-third the final volume, and then the suspension was brought to the final volume with a 2:1 mixture of simple syrup and wild cherry syrup. The resulting suspension was stable for at least 14 days when stored in an amber glass bottle at room temperature or 5°C.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 100 mg* | Allopurinol Tablets | |
Zyloprim® (scored) | ||||
300 mg* | Allopurinol Tablets | |||
Zyloprim® (scored) | Prometheus |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion only | 500 mg (of allopurinol)* | Allopurinol Sodium for Injection | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
150. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency. Am J Med . 1984; 76:47-56. [PubMed 6691361]
151. Ettinger B, Tang A, Citron JT et al. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med . 1986; 315:1386-9. [PubMed 3534570]
152. Mylan. Aloprim® (allopurinol sodium) for injection prescribing information. Rockford, IL; 2018 May.
153. Smalley RV, Guaspari A, Haase-Statz S et al. Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol . 2000; 18:1758-63. [PubMed 10764437]
154. Turnheim K, Krivanek P, Oberbauer R. Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects. Br J Clin Pharmacol . 1999; 48:501-9. [PubMedCentral][PubMed 10583019]
155. Newton DW. Introduction: physicochemical determinants of incompatibility and instability of drugs for injection and infusion. In: Trissel LA. Handbook of injectable drugs. 3rd ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc., Inc.; 1983:xi-xxi.
156. Prometheus. Zyloprim® (allopurinol) tablets prescribing information. San Diego, CA; 2003 Oct.
157. Sanofi-Synthelabo Inc. Elitek® (rasburicase) injection for intravenous use prescribing information. New York, NY; 2002 Jul 22.
158. Goldman SC, Holcenberg JS, Finklestein JZ et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood . 2001; 97:2998-3003. [PubMed 11342423]
159. Easton J, Noble S, Jarvis B. Rasburicase. Pediatr Drugs. 2001; 3:433-9
160. Anon. Rasburicase (Elitek®) for hyperuricemia. Med Letter Drug Ther . 2002; 44:96-7.
161. Lohr LK. Rasburicase, a new, recombinate form of urate oxidase, treats hyperuricemia in tumor lysis syndrome. Hem/Onc Today. October 2002. From the Hem/Onc Today website ([Web]) Accessed 2003 Jan 23.
162. Nabi. Boca Raton, FL: Personal communication.
163. Saito Y, Stamp LK, Caudle KE et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther . 2016; 99:36-7. [PubMed 26094938]
164. Hershfield MS, Callaghan JT, Tassaneeyakul W et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther . 2013; 93:153-8. [PubMed 23232549]
165. Khanna D, Fitzgerald JD, Khanna PP et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) . 2012; 64:1431-46. [PubMed 23024028]
166. Dean L. Allopurinol therapy and HLA-B*58:01 genotype. 2013 Mar 26 [Updated 2016 Mar 16]. In: Pratt V, McLeod H, Rubinstein W et al., eds. Medical genetics summaries [Internet]. Bethesda, MD: National Center for Biotechnology Information.
167. Hui M, Carr A, Cameron S et al. The British Society for Rheumatology Guideline for the Management of Gout. Rheumatology (Oxford) . 2017; 56:e1-e20. [PubMed 28549177]
168. Richette P, Doherty M, Pascual E et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis . 2017; 76:29-42. [PubMed 27457514]
169. . Drugs for gout. Med Lett Drugs Ther . 2019; 61:33-37. [PubMed 30845096]
170. Gonçalo M. HLA-B*58:01 is not the only risk factor associated with allopurinol-induced severe cutaneous adverse drug reactions. Ann Transl Med . 2018; 6:S7. [PubMed 30613583]
171. Wu R, Cheng YJ, Zhu LL et al. Impact of HLA-B*58:01 allele and allopurinol-induced cutaneous adverse drug reactions: evidence from 21 pharmacogenetic studies. Oncotarget . 2016; 7:81870-81879. [PubMed 27835909]
172. Accord-UK. Allopurinol 100 mg tablets summary of product characteristics. Barnstaple, Devon, UK; 2019 May 20.
173. Stamp LK, Taylor WJ, Jones PB et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum . 2012; 64:2529-36. [PubMed 22488501]
174. Bristol-Myers Squibb Company. Videx® (didanosine powder for solution) prescribing information. Princeton, NJ; 2018 Dec.
175. Hung SI, Chung WH, Liou LB et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A . 2005; 102:4134-9. [PubMed 15743917]
176. Lu N, Rai SK, Terkeltaub R et al. Racial disparities in the risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States. Semin Arthritis Rheum . 2016; 46:253-258. [PubMed 27217070]
177. Park DJ, Kang JH, Lee JW et al. Cost-effectiveness analysis of HLA-B5801 genotyping in the treatment of gout patients with chronic renal insufficiency in Korea. Arthritis Care Res (Hoboken) . 2015; 67:280-7. [PubMed 25047754]
178. Jutkowitz E, Dubreuil M, Lu N et al. The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the United States. Semin Arthritis Rheum . 2017; 46:594-600. [PubMed 27916277]
179. Ke CH, Chung WH, Wen YH et al. Cost-effectiveness Analysis for Genotyping before Allopurinol Treatment to Prevent Severe Cutaneous Adverse Drug Reactions. J Rheumatol . 2017; 44:835-843. [PubMed 28365572]
180. Saokaew S, Tassaneeyakul W, Maenthaisong R et al. Cost-effectiveness analysis of HLA-B*5801 testing in preventing allopurinol-induced SJS/TEN in Thai population. PLoS One . 2014; 9:e94294. [PubMed 24732692]
181. Ko TM, Tsai CY, Chen SY et al. Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. BMJ . 2015; 351:h4848. [PubMed 26399967]
182. Jung JW, Kim DK, Park HW et al. An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing. Genet Med . 2015; 17:807-14. [PubMed 25634024]
183. Vargas-Santos AB, Neogi T. Management of Gout and Hyperuricemia in CKD. Am J Kidney Dis . 2017; 70:422-439. [PubMed 28456346]
184. Stamp LK, O'Donnell JL, Zhang M et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum . 2011; 63:412-21. [PubMed 21279998]
186. Stamp LK, Barclay ML. How to prevent allopurinol hypersensitivity reactions?. Rheumatology (Oxford) . 2018; 57:i35-i41. [PubMed 29272508]
187. Ramasamy SN, Korb-Wells CS, Kannangara DR et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Drug Saf . 2013; 36:953-80. [PubMed 23873481]
188. Stamp LK, Barclay ML, O'Donnell JL et al. Furosemide increases plasma oxypurinol without lowering serum urate--a complex drug interaction: implications for clinical practice. Rheumatology (Oxford) . 2012; 51:1670-6. [PubMed 22539486]
189. Tassaneeyakul W, Jantararoungtong T, Chen P et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics . 2009; 19:704-9. [PubMed 19696695]
190. Kang HR, Jee YK, Kim YS et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics . 2011; 21:303-7. [PubMed 21301380]
191. Reinders MK, Haagsma C, Jansen TL et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout. Ann Rheum Dis . 2009; 68:892-7. [PubMed 18633127]