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© 2000 American Society for Clinical Oncology Allopurinol: Intravenous Use for Prevention and Treatment of HyperuricemiaByFrom SynertronInc; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI; and Glaxo Wellcome Inc, Research Triangle Park, NC. Address reprint requests to Richard V. Smalley, MD, Synertron, Inc, PO Box 5360, Madison, WI 53705-0630; email rvsmalley{at}aol.com
PURPOSE: To tabulate data obtained over a 21-year period to determine the efficacy and safety of an intravenous (IV) allopurinol preparation. PATIENTS AND METHODS: IV allopurinol was provided on a compassionate plea basis to patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven investigators at multiple hospitals in the United States treated 1,172 patients with IV allopurinol. The vast majority of these patients had a malignancy and were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable to the time period of IV allopurinol administration were collected, collated, and analyzed retrospectively. There was no randomization. RESULTS: In patients initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or improved in 87% of adult patients and normalized or improved in 95% of pediatric patients. IV allopurinol, administered prophylactically to patients at high risk of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93% of adults and 92% of children. Toxicities caused by IV allopurinol were minimal and consisted of 10 instances of mild to moderate skin or allergic reactions. CONCLUSION: IV allopurinol is as efficacious and safe as oral allopurinol and will be of significant benefit to patients at risk of TLS and AUAN and unable to take oral medication.
ALLOPURINOL, A STRUCTURAL analog of the natural purine base, hypoxanthine, is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in humans. Allopurinol, itself, is metabolized to the corresponding xanthine analog, oxypurinol, which is also an inhibitor of xanthine oxidase. Since 1966, the oral formulation of allopurinol (Zyloprim; Glaxo Wellcome Inc, Research Triangle Park, NC) has been approved in the United States for the treatment of hyperuricemia. Its efficacy and safety in the management of hyperuricemia associated with malignancies and with the use of cytotoxic chemotherapy have been confirmed with widespread use. In 1968, the use of intravenous (IV) allopurinol as treatment for hyperuricemia associated with malignancy was first reported.1 Because some patients are unable to tolerate or receive oral therapy, Burroughs Wellcome Co. began providing IV allopurinol on a compassionate plea basis to requesting physicians in 1969.2,3 In 1977, the compassionate use was formalized with a written protocol and case report form. In this article, we report the summary results of this compassionate plea use of IV allopurinol in 1,172 patients.
The objectives of this program were to serve physicians who requested IV allopurinol for patients unable to take oral allopurinol, to provide data that would document the efficacy of IV allopurinol in the treatment or prevention of hyperuricemia, and to provide data on the safety of IV allopurinol. After 1977, when a formal protocol was established, eligibility requirements included informed consent from the patient and an inability to take oral medications. The only exclusion criterion was a known or suspected idiosyncratic or allergic reaction to allopurinol. Therefore, all patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted were eligible. There were no patient exclusions for performance status. The use of IV allopurinol was to be approved by the institution’s investigational review board. When a patient was identified as needing IV medication, the physician placed a call to Burroughs Wellcome Co. and allopurinol was shipped immediately by air or overnight express. IV allopurinol was provided as the lyophilized sterile sodium salt equivalent to 500 mg of allopurinol packaged in individual 30-mL vials. The drug was reconstituted on site by adding 25 mL of sterile water for injection, providing a concentrated solution of 20 mg/mL with a pH of 10.5 to 11. The solution was further diluted to a desired concentration with sterile saline or 5% dextrose in water with a recommended final concentration of no greater than 1.2 mg/mL. According to protocol, patients were to receive IV allopurinol daily at a dose of 40 to 150 mg/m2 IV every 8 hours. In actuality, however, the dose and schedule received by each patient was selected by the treating physician based on their clinical judgment. The weight of approximately 80% of the patients was recorded, but height was recorded far less frequently. Therefore, in the analysis of dose per patient, milligrams per kilograms was used. Patients with severely impaired renal function or decreased urate clearance were to receive proportionately less allopurinol because the half-life of oxypurinol, the chief metabolite of allopurinol, has been shown to be greatly prolonged in such patients.4,5 Therapy was to be changed to oral allopurinol as soon as oral intake was practical. A complete blood cell count, serum uric acid (SUA), urinalysis, blood urea nitrogen, and serum creatinine were to be obtained in patients at baseline and daily during the time they were receiving IV allopurinol. All adverse patient experiences were to be recorded whether or not they were felt to be drug related. The use of other concurrent medications was not curtailed. Investigators were to use their best clinical judgment and were warned by the protocol of the following possibilities: (1) allopurinol might prolong the half-life of the anticoagulant, dicumarol; (2) severe hypersensitivity reactions to allopurinol might occur more frequently when allopurinol is given in conjunction with a thiazide diuretic; (3) there might be a high frequency of rashes among patients receiving ampicillin concurrently with allopurinol; (4) the concomitant administration of a uricosuric agent with allopurinol might result in a decrease in the urinary secretion of oxypurines; and (5) allopurinol inhibits the oxidation of 6-mercaptopurine by xanthine oxidase, thereby potentiating its efficacy and toxicity when administered concurrently.
Data were retrieved either from copies of hospital charts (before 1977) or case report forms (after 1977). Data were retrospectively reviewed, extracted, entered, and analyzed by Synertron, Inc, a data management and consulting firm in Madison, WI. This review retrospectively classified patients into six major groups: adult therapeutic, prophylactic, or unknown, and pediatric therapeutic, prophylactic, or unknown. Patients were arbitrarily classified as adults if they were For purposes of analysis, patients with a baseline SUA of more than 7.0 mg/dL (therapeutic group) were retrospectively considered assessable for response if they received at least 2 days of allopurinol treatment and had a repeat SUA determination at least 48 hours thereafter. Patients receiving IV allopurinol prophylactically were considered assessable for efficacy if there was an SUA level reported at baseline (within 48 hours) and on any two of days 2 to 4 after initiation of chemotherapy and they received at least 3 days of treatment concurrently with cytotoxic treatment. Patients lacking a baseline SUA (unknown group) were not assessable for response. Within the therapeutic groups, allopurinol was considered completely effective (a complete response) if the SUA became and remained normal while on treatment, and patients were considered improved (a partial response) if the SUA level decreased by at least 1 mg/dL but did not return to normal. In the prophylactic groups, allopurinol therapy was considered completely effective if the SUA level remained below 7.0 mg/dL during treatment. The 231 patients treated before the availability of case report forms were evaluated for safety and tolerability only. Because data were not collected in a standardized fashion before 1977, data from patients treated during this period were considered inadequate for evaluation of efficacy. The 941 patients from whom data were collected on case report forms were evaluated for efficacy, safety, and tolerability. Retrospective criteria for assessability for efficacy were applied, and a response rate with 95% confidence limits was determined for the group as a whole and for various subsets.
Between 1969 and 1990, 1,172 patients received IV allopurinol for compassionate plea use. Case report form data were available for 941 patients treated between 1977 and 1990. Data on the remaining 231 patients treated before 1977 are only included in the safety and tolerability database. The 941 patients treated between 1977 and 1990 were categorized in this review by diagnosis and placed in one of the following five disease categories: non-Hodgkin’s lymphoma (NHL), acute leukemia (AL), other hematologic disorders, solid tumors, and nonmalignant disorders. Approximately one half of patients (n = 460) were considered assessable by previously described criteria. Table 1 lists the number of assessable patients within each disease category. As expected, the majority of patients in each age group had either AL or NHL. Within the adult therapeutic subset, the most common type of NHL was Burkitt’s lymphoma, whereas in the adult prophylactic group, the most common histologic subtype was diffuse histiocytic lymphoma. In the adult AL subset, the types of AL were approximately evenly divided between acute lymphocytic and acute nonlymphocytic leukemia. In the pediatric age group, approximately one half of the NHL patients in both the therapeutic and the prophylactic group had Burkitt’s lymphoma, and approximately 60% of the patients with AL had acute lymphocytic leukemia.
There were 453 patients in the therapeutic group, of whom 204 adult and 137 pediatric patients were assessable for efficacy. Of the 327 patients in the prophylactic group, 46 adult and 73 pediatric patients were considered assessable for response. Thus, 78 adult and 34 pediatric patients in the therapeutic group and 107 adult and 101 pediatric patients in the prophylactic group were not assessable. The reasons for the large number of unassessable patients were too few SUA determinations, the course of IV allopurinol therapy was too short, or both. Fifty-four pediatric and 107 adult patients lacked a baseline SUA and were classified as unknown (ie, neither therapeutic nor prophylactic). In the therapeutic subset, the SUA normalized in 57% of adult patients and in 88% of pediatric patients evaluated for efficacy (Table 2). Also in the therapeutic subset, there was no association between the likelihood to respond and diagnosis, but there did seem to be a dose-response effect in the adult population (Table 2). Of the 91 adult patients receiving a total dose of 301 mg daily or greater, the SUA normalized in 65 (71%; 95% confidence interval [CI], 61% to 80%); whereas of the 113 adult patients receiving a total dose of 300 mg or less per day, the SUA normalized in 52 (46%; 95% CI, 37% to 56%). In the adult therapeutic group, 181 patients had sufficient data recorded to provide an estimate of mean and median dose (mg/d) administered. Those achieving a complete response received a higher dose of IV allopurinol than did those obtaining a partial response and a still higher dose than those not obtaining any response (Table 3). The normalization rate was so high in the pediatric age group that no discernible association with either disease or dose was detected.
For all assessable adult patients who achieved at least a 1.0 mg/dL reduction in SUA from baseline, mean time to response was 5 days (95% CI, 4 to 13 days). For patients whose SUA level normalized (< 7.0 mg/dL), the mean number of days of allopurinol treatment required was 2 (95% CI, 0 to 3 days). The mean time to response (  1.0 mg/dL reduction of SUA from baseline) was 1 day (95% CI, 1 to 2 days) for all assessable pediatric therapeutic patients and was also 1 day (95% CI, 0 to 2 days) for those achieving SUA normalization. Logistic regression was used to examine the relationship of selected prognostic factors (age, sex, baseline SUA level, and diagnosis) to SUA normalization in the therapeutic group (adult and pediatric). Of these factors, age as a continuous variable was the strongest predictor of SUA normalization. Increased age reduced the chance of normalization. Baseline SUA was also a significant predictor of the likelihood to normalize, both alone and in a model including age; the higher the SUA level, the less likely the chance to normalize. The addition of sex and diagnosis did not significantly improve prediction over the model with only age and baseline SUA as prognostic factors. The SUA remained normal in 93% of assessable adult prophylactic patients and in 92% of assessable pediatric prophylactic patients (Table 4). In seven of the nine assessable patients whose SUA increased despite prophylactic IV allopurinol, the SUA increased transiently (24 hours) 2 days after initiating cytotoxic chemotherapy. In the other two patients, the SUA increased later (days 5 to 6) and may have been a clerical error. Because the response rate was greater than 90% in each age group, neither a prognostic factor analysis nor a dose response effect was performed.
Both the adult therapeutic and prophylactic groups received IV allopurinol for an average of 5.7 days. The pediatric therapeutic and prophylactic groups received IV allopurinol for an average of 6.4 and 6.3 days, respectively. The average daily dose received by the adult therapeutic group was 373.4 mg (median, 300 mg; range, 16 to 1,750 mg), and the average daily dose received by the adult prophylactic group was 361.8 mg (median, 300 mg; range, 83 to 1,100 mg) (Table 5). The average daily doses received for the pediatric therapeutic and prophylactic groups were 183.1 mg (median, 175 mg; range, 3 to 514 mg) and 193.6 mg (median, 180 mg; range, 15 to 700 mg), respectively. Average total cumulative doses received for the adult therapeutic and prophylactic groups were 2,037 mg and 2,030 mg, respectively. Similar figures for the pediatric therapeutic and prophylactic groups were 1,158 mg and 1,305 mg, respectively. The average daily doses per kilogram in the adult and pediatric groups ranged from 4.2 to 6.1 mg/kg and from 5.2 to 10.7 mg/kg, respectively (Table 6).
An evaluation of renal function as measured by serum creatinine was performed in the adult and pediatric patients treated prophylactically (assessable and unassessable). Two hundred fifty-eight of these 327 patients had a normal baseline creatinine at the time of initiating IV allopurinol therapy, 29 had an elevated baseline serum creatinine, and 40 had no baseline creatinine data. Of those patients initiating IV allopurinol therapy with a normal baseline serum creatinine, the serum creatinine became elevated on therapy in 13 (5%). In 10 of these patients, this seemed to be directly related to cell lysis secondary to cytotoxic chemotherapy and occurred despite IV allopurinol therapy. Five of these 10 patients fully recovered after an adequate antitumor response to the cytotoxic chemotherapy, whereas the other five either did not respond to their cytotoxic chemotherapy or there was inadequate follow-up. There were no unusual clinical difficulties noted in the 29 patients initiating treatment with an elevated baseline serum creatinine. In the therapeutic group, 207 of the 423 patients for whom serum creatinine data were available had elevated serum creatinine levels at baseline. In 29% of these patients, serum creatinine levels returned to normal on therapy and remained elevated in 71%. Among the 216 patients initiating therapy with a normal serum creatinine level, the level increased and remained elevated while on therapy in 24 patients (13%). There was no clinical evidence of renal complications reported in these patients. A full analysis of potential dose and creatinine relationship is underway. There were only 10 instances of toxicity directly related to allopurinol therapy. These were all allergic in nature, primarily cutaneous reactions, and were mild to moderate in severity. Seven of the reactions were rashes (usually generalized and maculopapular), one patient developed eosinophilia, and two had local vesicular reactions. Serious (grade 3 to 4) adverse events were reported in a total of 167 patients. All were thought to be compatible with the underlying disease or associated (non-allopurinol) treatment. Clearly, in this generally critically ill population, such events may have been under reported.
Acute uric acid nephropathy (AUAN), resulting from a secondary overproduction of uric acid, is a potentially disastrous sequela of the tumor lysis syndrome (TLS) and can exacerbate the TLS through impairment of renal excretory function. TLS most commonly occurs in cancer patients with rapidly proliferating, large-burden tumors that undergo rapid cell lysis.6 In the late 1950s and early 1960s, Elion and Hitchings synthesized a number of xanthine oxidase inhibitors that had potential benefit for patients at risk for TLS and AUAN.5,7 Pioneering clinical investigation of one of these compounds, allopurinol, was performed by Rundles et al8 and somewhat later by Krakoff and Meyer.9 Subsequently, the near-standard inclusion of allopurinol in prophylactic regimens has almost certainly resulted in a significant attenuation of the incidence of AUAN. Allopurinol is rapidly absorbed after oral administration (assuming normal gastrointestinal function), peak levels being reached within 2 hours of administration, and is rapidly converted after oral or IV administration to its major active metabolite, oxypurinol.7,10-13 Nearly all traces of allopurinol in the plasma are gone within 6 hours of either IV or oral administration, and plasma disappearance curves after either mode of administration are comparable. Oxypurinol is also an inhibitor of xanthine oxidase.5 Systemic exposure to oxypurinol, as determined by its plasma area under the curve, was similar after either route of administration, and recent studies have demonstrated a half-life for oxypurinol in the range of 12 to 20 hours after either IV or oral administration of allopurinol.10-13 The significantly longer plasma half-life and greater plasma concentration of oxypurinol compared with the parent drug indicate that it is the compound primarily responsible for the reduction of circulating uric acid concentrations. In summary, the pharmacokinetics of oxypurinol, the major metabolite of allopurinol, do not seem to be influenced by the route of allopurinol administration. Based on pharmacokinetic information, the daily IV dosage of allopurinol should be the same as the currently recommended oral dose. Over the past 25 years, the use of oral allopurinol has been shown to be efficacious and safe. Very few toxicities have been reported that are attributable to oral allopurinol. In this series of 1,172 patients receiving IV allopurinol, only 10 had an adverse event directly attributable to IV allopurinol, an incidence of less than 1%. In each case, the adverse event was of mild to moderate severity and allergic in nature. This incidence is comparable with the extensive experience with oral allopurinol. However, a rare but more profound reaction has been previously noted with oral allopurinol, consisting of a syndrome of fever, hepatitis (manifested by a rising transaminase), skin rash (described as diffuse, erythematous, and desquamative), and eosinophilia, and seems to occur most commonly in patients with compromised renal function. Young et al14 initially described two patients with such a reaction. Ten years later, Hande et al4 identified a total of 78 patients from both their experience and the literature confirming an inverse relationship between the incidence of this syndrome and the serum creatinine level of the patient receiving allopurinol. They noted that most, if not all, patients developing this syndrome had received allopurinol for a prolonged (> 14 days) period. In the present series of 1,172 patients, there was no indication of such a syndrome in the 15% or more patients who had an elevated serum creatinine, perhaps because most received IV allopurinol for a relatively short time (< 14 days). Nevertheless, one should be aware of the possible development of a serious allopurinol reaction in patients on long-term therapy with compromised renal function. Approximately 15% of patients developed elevated creatinine levels while on IV allopurinol therapy in our series. There was no indication that this increase in serum creatinine level was in any way caused by IV allopurinol, and in many of the patients, the serum creatinine reverted to normal before the discontinuation of allopurinol therapy. Other patients initiated IV allopurinol therapy with an elevated serum creatinine level, and in more than half the patients, the serum creatinine became normal while receiving IV allopurinol. There were between 200 and 250 patients in this series who received IV allopurinol at a time when their serum creatinine level was abnormal and none developed serious allopurinol toxicity. When attempting to prevent AUAN in a patient likely to develop TLS with treatment, such therapy administered over a short period of time (< 7 days) should be between 90% and 100% effective in preventing AUAN, as demonstrated in this series. There was the suggestion of a dose response effect in the present series in the adult therapeutic group. An average daily dose of greater than 300 mg seemed to be more effective than a lesser dose. This relationship could be confirmed statistically, but because of the observational nature of this study and the lack of randomization of dose levels, conclusions cannot be made as to whether or not initial or average daily dose influences the likelihood of normalizing the SUA level. Allopurinol administered IV to nearly 1,200 patients over a 22-year period has been shown to be safe and as well-tolerated as oral allopurinol. Data available from 460 of these patients in this retrospective review indicate IV allopurinol is efficacious in treating or preventing hyperuricemia associated with malignancy. The addition of IV allopurinol to the therapeutic armamentarium of physicians treating critically or potentially seriously ill patients at risk of developing either TLS or AUAN should make the administration of cytotoxic chemotherapy to such patients significantly safer.
For her efforts over the years on this project, we are indebted to Donna Cederberg, who died of breast cancer at a relatively young age. We also thank Dorothy Binning for her assistance in the preparation of this manuscript.
Synertron, Inc received a grant from Burroughs Wellcome Co. to independently tabulate and analyze data provided.
1. Kann HE, Wells JH, Gallelli JF, et al: The development and use of an intravenous preparation of allopurinol. Am J Med Sci 256:53-59, 1968[Medline] 2. Brown CH III, Stashick E, Carbone PP: Clinical efficacy and lack of toxicity of allopurinol (NSC-1390) given intravenously. Cancer Chemother Rep 54:125-129, 1970[Medline] 3. Donnenberg A, Holton CP, Mayer CMH, et al: Evaluation of intravenous allopurinol (NSC-1390) in pediatric neoplasia. Cancer Chemother Rep 58:737-739, 1974[Medline] 4. Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency. Am J Med 76:47-56, 1984 5. Elion GB, Yu T-F, Gutman AB, et al: Renal clearance of oxypurinol, the chief metabolite of allopurinol. Am J Med 45:69-77, 1968[Medline] 6. Silverman P, Distelhorst CW: Metabolic emergencies in clinical oncology. Semin Onc 16:504-515, 1989 7. Elion GB, Kovensky A, Hitchings GH, et al: Metabolic studies of allopurinol, an inhibitor of xanthine oxidase. Biochem Pharm 15:863-880, 1966[Medline] 8. Rundles RW, Wyngaarden JB, Hitchings GH, et al: Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia and gout. Trans Assoc Am Physicians 76:126-140, 1963 9. Krakoff IH, Meyer RL: Prevention of hyperuricemia in leukemia and lymphoma: Use of allopurinol, a xanthine oxidase inhibitor. JAMA 193:89-94, 1965 10. Breithaupt H, Tittel M: Kinetics of allopurinol after single intravenous and oral doses: Noninteraction with benzbromarone and hydrochlorothiazide. Eur J Clin Pharmacol 22:77-84, 1982[Medline] 11. Hande K, Reed E, Chabner B: Allopurinol kinetics. Clin Pharmacol Ther 23:598-605, 1978[Medline] 12. Appelbaum SJ, Mayersohn M, Dorr RT, et al: Allopurinol kinetics and bioavailability: Intravenous, oral and rectal administration. Cancer Chemother Pharmacol 8:93-98, 1982[Medline] 13. Murrell GAC, Rapeport WG: Clinical pharmacokinetics of allopurinol. Clin Pharmacokinetics 11:343-353, 1986[Medline] 14. Young JL, Boswell RB, Nies AS: Severe allopurinol hypersensitivity: Association with thiazides and prior renal compromise. Arch Intern Med 134:553-558, 1974[Medline] Submitted July 30, 1999; accepted December 29, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
7.0 mg/dL), and unknown (no baseline SUA) groups. Within these major groupings, patients were subgrouped by disease and dose. Assessability for efficacy was determined using stringent criteria retrospectively established for this analysis. 
