504740
research-article2013
AOPXXX10.1177/1060028013504740Annals of PharmacotherapyThurston et al
Review Article
Safety and Efficacy of Allopurinol in Chronic Kidney Disease
Annals of Pharmacotherapy 47(11) 1507–1516 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504740 aop.sagepub.com
Maria Miller Thurston, PharmD, BCPS1, Beth Bryles Phillips, PharmD, FCCP, BCPS2, and Catherine A. Bourg, PharmD, BCPS, BCACP2
Abstract Objective: To review the evidence surrounding the use of allopurinol in chronic kidney disease (CKD) and discuss safety and efficacy considerations of such use. Data Sources: A literature search was conducted through MEDLINE (1950-July 2013), PubMed (1965-July 2013), and International Pharmaceutical Abstracts (1970-July 2013) using the search terms allopurinol and kidney or renal. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: All articles in English identified from the data sources were evaluated for inclusion. Data Synthesis: Gout management with allopurinol in patients with CKD can be challenging because of the risk of adverse events and uncertain efficacy. Not all gout treatment guidelines provide recommendations for allopurinol use specifically in patients with CKD. Literature regarding the safety and efficacy of dosing allopurinol in CKD has shown inconsistent results and is based primarily on retrospective, case cohort or observational data. Some trials have demonstrated an increased risk of allopurinol-induced adverse reactions in patients with CKD, whereas others have not confirmed renal insufficiency as a risk factor. More CKD patients achieved a target uric acid level in studies where the allopurinol dose was titrated to effect as compared with those studies in which patients were given renally adjusted or untitrated allopurinol doses. Conclusions: Studies evaluating allopurinol use in patients with CKD have reported inconsistent findings relative to safety and efficacy. Providers should be aware of the potential risk of allopurinol hypersensitivity syndrome as well as the need for reducing the initiation dose and gradual titration of allopurinol to safely achieve a target serum urate level in this population. Keywords allopurinol, safety, efficacy, renal, chronic kidney disease, allopurinol hypersensitivity syndrome, adverse effects Received 8 August 2013; accepted 21 August 2013
Request What is the urate lowering efficacy and risk of adverse events when dosing allopurinol in patients with chronic kidney disease (CKD)?
Response Background Gout is a type of painful, inflammatory arthritis that affects approximately 8.3 million adults in the United States.1 Hyperuricemia, or excess systemic levels of uric acid (UA), is the primary cause of gout and may lead to gout flares that can be prevented with allopurinol, a xanthine oxidase inhibitor.2 Allopurinol was first introduced in the United States in the 1960s and has an extensive history of use in patients with normal and impaired renal function.3 Common adverse
effects include gastrointestinal effects and mild rash.4 Historically, there has been concern over the use of allopurinol in patients with CKD. This is an especially relevant concern today because approximately 40% to 50% of patients with gout have co-occurring CKD.5,6 In addition, chronically elevated UA levels may be a risk factor for the development of CKD and may cause disease progression.5,7 Although allopurinol is widely used as first-line urate lowering therapy (ULT), it is often not prescribed or 1
Mercer University College of Pharmacy, Atlanta, GA, USA University of Georgia College of Pharmacy, Athens, GA, USA
2
Corresponding Author: Maria Miller Thurston, PharmD, BCPS, Mercer University College of Pharmacy, DuVall Building, Room #161, 3001 Mercer University Drive, Atlanta, GA 30341-4415, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on January 2, 2014
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Annals of Pharmacotherapy 47(11)
monitored according to clinical practice guidelines and/or best evidence, which may lead to suboptimal efficacy and risk of adverse events, such as allopurinol hypersensitivity syndrome (AHS).8 Whereas treatment guidelines are fairly explicit regarding the use and dosing of allopurinol in patients with normal renal function, there is a concern regarding the lack of guidance in patients with CKD, given the potential risks. A widely accepted renal dosing textbook recommends a percentage reduction in the standard allopurinol maintenance dose in patients based on varying degrees of renal impairment.9 Other recommendations for dosing in CKD are based on pharmacokinetic studies, not safety data, and will be discussed in more detail within the literature review section below.10 A comparison of dosing guidelines and recommendations in patients with CKD has been summarized in Table 1.4,11-14 When managing concurrent gout and CKD, clinicians should be aware of adverse effects that may occur with increasing doses of allopurinol and accumulation of allopurinol’s active metabolite, oxypurinol, because of inadequate renal clearance. At the same time, there is also a need to adequately treat frequent attacks and to lower the serum UA (SUA) level to the goal of 4 hyperuricemia CKD: 50 mg/d
European League Against Rheumatism12
American College of Rheumatology13
SUA every 2 to 5 weeks during titration then every 6 months thereafter
SUA during titration with no specified interval
SUA: Normal levels are usually achieved in 1 to 3 weeks
Monitoring
40 mg/dL
Definition of Renal Impairment
Table 2. Select Studies Evaluating the Safety and Efficacy of Allopurinol in CKD.
AVG ALO dose = 279 mg, range (100-450 mg) ×2.3 ± 3.3 years in group A and ×3.7 ± 4.8 years in group B; NS difference between groups in dose or duration
• Cases: Initial dose ALO 123 ± 54 mg daily; final dose ALO 212 ± 116 mg daily • Controls: Initial dose ALO 117 ± 65 mg daily; final dose ALO 212 ± 122 mg daily Duration not specified
ALO 300 to 600 mg ×1 dose given prior measurement of creatinine and oxypurinol in 18 patients
Intervention: ALO Dose and Duration)
5 Patients (4%) developed ALO related ADRs: 2 patients in nondose-adjusted group and 3 in doseadjusted group (1 case of AHS); P = NS
Those who developed ALO-induced ADRs (ie, cases) had more CKD (46% vs 30%) at baseline than those who did not (ie, controls), P = .005, but no difference in mean baseline CrCl, P = .389
Determined direct linear relationship between CrCl and renal Cl of oxypurinol: Oxypurinol Cl in mL/min = 0.22 × CrCl − 2.87; r = 0.93; P < .001
Results
(continued)
Included 71 pediatric cases and those with asymptomatic hyperuricemia; renal dysfunction not confirmed as a risk factor for adverse events using multivariate analysis; NS difference in concomitant diuretic use between groups, P = .676; regression analysis found use of colchicine (P = .012) and statins (P = .041) were associated with ALO-induced adverse events Mean age and duration of disease significantly lower in group B; P = .002 and P = .05, respectively; no increase in ADRs in those who received higher than recommended maintenance doses
High percentage of patients with renal impairment in AHS cases described; proposed algorithm for doses to be adjusted based on CrCl
Comments
1511
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on January 2, 2014
Studies evaluating safety and efficacy Prospective, OL; n = Stamp et al. 83 total; n = 45 dose (2011)19 escalation; n = 38 no dose escalation
Study evaluating efficacy Retrospective; n = Fuldeore et al 3929 total; n = 1536 (2011)6 CKD (67% stage 2, 23% stage 3, 10% stage 4); n = 2393 no CKD
Reference
Study Design; Number of Patients and Groups
Table 2. (continued)
• Dose escalation: 93.3% men; mean age: 59.5 years, range = 27-83 years; mean CrCl: 62.2 mL/min, range = 19-130 mL/ min • No dose escalation: 81.6% men; mean age: 57.8 years, range = 36-79 years; mean CrCl: 72.2 mL/min, range = 33-116 mL/ min Renal impairment not defined
1. CKD eGFR < 90 mL/ • Stage 2: 89% men; min age: 13% ≤ 44 years; eGFR: 76.9 ± 8.3 mL/ min • Stage 3: 84 % men; age: 11% ≤ 44 years; eGFR: 47.8 ± 8.5 mL/ min • Stage 4: 82% men; age: 22% ≤ 44 years; eGFR: 19.1 ± 6.9 mL/ min • 2. No CKD • 88.6% Men; age: 35.9% ≤ 44 years; eGFR: 109.6 ± 12.6 mL/min
Patient Population
Definition of Renal Impairment ALO use in 3122 patients 1. CKD • Stage 2: Initial dose, 249 ± 107 mg daily; last dose, 262 ± 102 mg daily • Stage 3: Initial dose, 234 ± 104 mg daily; last dose, 248 ± 94 mg daily • Stage 4: Initial dose, 218 ± 105 mg daily; last dose, 242 ± 127 mg daily 2. No CKD • Initial dose 248 ± 107 mg daily; last dose 269 ± 106 mg daily • NS difference in length of follow-up: 897-937 days
Intervention: ALO Dose and Duration) 25.6% Without CKD and 22.2% with CKD achieved SUA < 6 mg/dL, P = .0409; dose titration without CKD (14.6%) and with CKD (15.6%), P = .45
Results
ALO ineffective in lowering SUA levels; less effective in CKD
Comments
(continued)
Determine • Baseline ALO dose: 10/45 (22.2%) Did All patients were efficacy and Dose escalation: not complete tolerating stable safety of 221.4 (100-400) titration; 35/45 doses of ALO at least increasing the mg daily; no dose (77.8%) completed 1 month prior to ALO dose escalation: 278.95 titration; of those enrollment. Author above proposed (50-400) mg daily (P 35 patients, 31 were conclusions: Titrating CrCl-based = .003) successfully titrated ALO to target SUA dose in patient • ALO dose increased to SUA 1 year • Group 3: ALO 331 (100-750) mg daily, with 71% taking >1 year
ALO use in 227 patients: AVG ALO dose 214 ± 95 mg/d; ×≥3 months
Intervention: ALO Dose and Duration)
Comments
70.9% Taking Higher than recommended recommended doses dose and 19.4% based on CrCl taking higher than were more effective recommended in lowering SUA doses; proportion levels; no cutaneous of patients achieving hypersensitivity SUA 1.5 mg/ association of definite mL/min/1.73 m2 or definite or possible ADRs and exposure to ALO maintenance doses 1-1.5 or >1.5 times the limits of Hande et al10; mean SUA was lower (P = .001) and proportion achieving SUA
research-article2013
AOPXXX10.1177/1060028013504740Annals of PharmacotherapyThurston et al
Review Article
Safety and Efficacy of Allopurinol in Chronic Kidney Disease
Annals of Pharmacotherapy 47(11) 1507–1516 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504740 aop.sagepub.com
Maria Miller Thurston, PharmD, BCPS1, Beth Bryles Phillips, PharmD, FCCP, BCPS2, and Catherine A. Bourg, PharmD, BCPS, BCACP2
Abstract Objective: To review the evidence surrounding the use of allopurinol in chronic kidney disease (CKD) and discuss safety and efficacy considerations of such use. Data Sources: A literature search was conducted through MEDLINE (1950-July 2013), PubMed (1965-July 2013), and International Pharmaceutical Abstracts (1970-July 2013) using the search terms allopurinol and kidney or renal. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: All articles in English identified from the data sources were evaluated for inclusion. Data Synthesis: Gout management with allopurinol in patients with CKD can be challenging because of the risk of adverse events and uncertain efficacy. Not all gout treatment guidelines provide recommendations for allopurinol use specifically in patients with CKD. Literature regarding the safety and efficacy of dosing allopurinol in CKD has shown inconsistent results and is based primarily on retrospective, case cohort or observational data. Some trials have demonstrated an increased risk of allopurinol-induced adverse reactions in patients with CKD, whereas others have not confirmed renal insufficiency as a risk factor. More CKD patients achieved a target uric acid level in studies where the allopurinol dose was titrated to effect as compared with those studies in which patients were given renally adjusted or untitrated allopurinol doses. Conclusions: Studies evaluating allopurinol use in patients with CKD have reported inconsistent findings relative to safety and efficacy. Providers should be aware of the potential risk of allopurinol hypersensitivity syndrome as well as the need for reducing the initiation dose and gradual titration of allopurinol to safely achieve a target serum urate level in this population. Keywords allopurinol, safety, efficacy, renal, chronic kidney disease, allopurinol hypersensitivity syndrome, adverse effects Received 8 August 2013; accepted 21 August 2013
Request What is the urate lowering efficacy and risk of adverse events when dosing allopurinol in patients with chronic kidney disease (CKD)?
Response Background Gout is a type of painful, inflammatory arthritis that affects approximately 8.3 million adults in the United States.1 Hyperuricemia, or excess systemic levels of uric acid (UA), is the primary cause of gout and may lead to gout flares that can be prevented with allopurinol, a xanthine oxidase inhibitor.2 Allopurinol was first introduced in the United States in the 1960s and has an extensive history of use in patients with normal and impaired renal function.3 Common adverse
effects include gastrointestinal effects and mild rash.4 Historically, there has been concern over the use of allopurinol in patients with CKD. This is an especially relevant concern today because approximately 40% to 50% of patients with gout have co-occurring CKD.5,6 In addition, chronically elevated UA levels may be a risk factor for the development of CKD and may cause disease progression.5,7 Although allopurinol is widely used as first-line urate lowering therapy (ULT), it is often not prescribed or 1
Mercer University College of Pharmacy, Atlanta, GA, USA University of Georgia College of Pharmacy, Athens, GA, USA
2
Corresponding Author: Maria Miller Thurston, PharmD, BCPS, Mercer University College of Pharmacy, DuVall Building, Room #161, 3001 Mercer University Drive, Atlanta, GA 30341-4415, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on January 2, 2014
1508
Annals of Pharmacotherapy 47(11)
monitored according to clinical practice guidelines and/or best evidence, which may lead to suboptimal efficacy and risk of adverse events, such as allopurinol hypersensitivity syndrome (AHS).8 Whereas treatment guidelines are fairly explicit regarding the use and dosing of allopurinol in patients with normal renal function, there is a concern regarding the lack of guidance in patients with CKD, given the potential risks. A widely accepted renal dosing textbook recommends a percentage reduction in the standard allopurinol maintenance dose in patients based on varying degrees of renal impairment.9 Other recommendations for dosing in CKD are based on pharmacokinetic studies, not safety data, and will be discussed in more detail within the literature review section below.10 A comparison of dosing guidelines and recommendations in patients with CKD has been summarized in Table 1.4,11-14 When managing concurrent gout and CKD, clinicians should be aware of adverse effects that may occur with increasing doses of allopurinol and accumulation of allopurinol’s active metabolite, oxypurinol, because of inadequate renal clearance. At the same time, there is also a need to adequately treat frequent attacks and to lower the serum UA (SUA) level to the goal of 4 hyperuricemia CKD: 50 mg/d
European League Against Rheumatism12
American College of Rheumatology13
SUA every 2 to 5 weeks during titration then every 6 months thereafter
SUA during titration with no specified interval
SUA: Normal levels are usually achieved in 1 to 3 weeks
Monitoring
40 mg/dL
Definition of Renal Impairment
Table 2. Select Studies Evaluating the Safety and Efficacy of Allopurinol in CKD.
AVG ALO dose = 279 mg, range (100-450 mg) ×2.3 ± 3.3 years in group A and ×3.7 ± 4.8 years in group B; NS difference between groups in dose or duration
• Cases: Initial dose ALO 123 ± 54 mg daily; final dose ALO 212 ± 116 mg daily • Controls: Initial dose ALO 117 ± 65 mg daily; final dose ALO 212 ± 122 mg daily Duration not specified
ALO 300 to 600 mg ×1 dose given prior measurement of creatinine and oxypurinol in 18 patients
Intervention: ALO Dose and Duration)
5 Patients (4%) developed ALO related ADRs: 2 patients in nondose-adjusted group and 3 in doseadjusted group (1 case of AHS); P = NS
Those who developed ALO-induced ADRs (ie, cases) had more CKD (46% vs 30%) at baseline than those who did not (ie, controls), P = .005, but no difference in mean baseline CrCl, P = .389
Determined direct linear relationship between CrCl and renal Cl of oxypurinol: Oxypurinol Cl in mL/min = 0.22 × CrCl − 2.87; r = 0.93; P < .001
Results
(continued)
Included 71 pediatric cases and those with asymptomatic hyperuricemia; renal dysfunction not confirmed as a risk factor for adverse events using multivariate analysis; NS difference in concomitant diuretic use between groups, P = .676; regression analysis found use of colchicine (P = .012) and statins (P = .041) were associated with ALO-induced adverse events Mean age and duration of disease significantly lower in group B; P = .002 and P = .05, respectively; no increase in ADRs in those who received higher than recommended maintenance doses
High percentage of patients with renal impairment in AHS cases described; proposed algorithm for doses to be adjusted based on CrCl
Comments
1511
Downloaded from aop.sagepub.com at Universitats-Landesbibliothek on January 2, 2014
Studies evaluating safety and efficacy Prospective, OL; n = Stamp et al. 83 total; n = 45 dose (2011)19 escalation; n = 38 no dose escalation
Study evaluating efficacy Retrospective; n = Fuldeore et al 3929 total; n = 1536 (2011)6 CKD (67% stage 2, 23% stage 3, 10% stage 4); n = 2393 no CKD
Reference
Study Design; Number of Patients and Groups
Table 2. (continued)
• Dose escalation: 93.3% men; mean age: 59.5 years, range = 27-83 years; mean CrCl: 62.2 mL/min, range = 19-130 mL/ min • No dose escalation: 81.6% men; mean age: 57.8 years, range = 36-79 years; mean CrCl: 72.2 mL/min, range = 33-116 mL/ min Renal impairment not defined
1. CKD eGFR < 90 mL/ • Stage 2: 89% men; min age: 13% ≤ 44 years; eGFR: 76.9 ± 8.3 mL/ min • Stage 3: 84 % men; age: 11% ≤ 44 years; eGFR: 47.8 ± 8.5 mL/ min • Stage 4: 82% men; age: 22% ≤ 44 years; eGFR: 19.1 ± 6.9 mL/ min • 2. No CKD • 88.6% Men; age: 35.9% ≤ 44 years; eGFR: 109.6 ± 12.6 mL/min
Patient Population
Definition of Renal Impairment ALO use in 3122 patients 1. CKD • Stage 2: Initial dose, 249 ± 107 mg daily; last dose, 262 ± 102 mg daily • Stage 3: Initial dose, 234 ± 104 mg daily; last dose, 248 ± 94 mg daily • Stage 4: Initial dose, 218 ± 105 mg daily; last dose, 242 ± 127 mg daily 2. No CKD • Initial dose 248 ± 107 mg daily; last dose 269 ± 106 mg daily • NS difference in length of follow-up: 897-937 days
Intervention: ALO Dose and Duration) 25.6% Without CKD and 22.2% with CKD achieved SUA < 6 mg/dL, P = .0409; dose titration without CKD (14.6%) and with CKD (15.6%), P = .45
Results
ALO ineffective in lowering SUA levels; less effective in CKD
Comments
(continued)
Determine • Baseline ALO dose: 10/45 (22.2%) Did All patients were efficacy and Dose escalation: not complete tolerating stable safety of 221.4 (100-400) titration; 35/45 doses of ALO at least increasing the mg daily; no dose (77.8%) completed 1 month prior to ALO dose escalation: 278.95 titration; of those enrollment. Author above proposed (50-400) mg daily (P 35 patients, 31 were conclusions: Titrating CrCl-based = .003) successfully titrated ALO to target SUA dose in patient • ALO dose increased to SUA 1 year • Group 3: ALO 331 (100-750) mg daily, with 71% taking >1 year
ALO use in 227 patients: AVG ALO dose 214 ± 95 mg/d; ×≥3 months
Intervention: ALO Dose and Duration)
Comments
70.9% Taking Higher than recommended recommended doses dose and 19.4% based on CrCl taking higher than were more effective recommended in lowering SUA doses; proportion levels; no cutaneous of patients achieving hypersensitivity SUA 1.5 mg/ association of definite mL/min/1.73 m2 or definite or possible ADRs and exposure to ALO maintenance doses 1-1.5 or >1.5 times the limits of Hande et al10; mean SUA was lower (P = .001) and proportion achieving SUA
