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Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis

  • Review Article - Safety and Pharmacovigillance
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An Erratum to this article was published on 21 April 2015

Abstract

Allopurinol is the most widely used urate-lowering drug (ULD). Together with efficacy and cost, safety is an aspect that helps taking clinical decisions. This systematic review analyzes allopurinol safety. The literature search was performed in MEDLINE, EMBASE, and the Cochrane Library (January 2014). Selection criteria: (a) patients >18, (b) gout by the ACR criteria or evidence of urate crystal in synovial fluid, (c) comparator (placebo or other ULD), and (d) RCTs, cohorts, or meta-analysis. Primary outcomes: rate of adverse events and death. The quality was assessed with the Jadad’s scale. A meta-analysis with fixed effects was performed. From 544 studies, seven met the eligibility criteria and were included. All RCT presented a low power for safety. All RCTs included a mixed population of patients with gout and hyperuricemia. Allopurinol (300 mg) was compared to febuxostat (40–240 mg) in five RCTs, to benzbromarone and probenecid in two RCTs, and to placebo in one. In the RCTs comparing allopurinol with benzbromarone and probenecid, the highest discontinuation rate was with probenecid (26 %), followed by allopurinol (11 %) and benzbromarone (4 %). The incidence of adverse events was similar between allopurinol (range 38.6–85) and febuxostat (range 41.8–80). Six patients on febuxostat and three on allopurinol died during the studies; no deaths were judged related to drug. The combined risk of adverse events was RR = 1.04 (95 % CI 0.98, 1.11). Allopurinol is a safe option, slightly better than other ULDs. The grade of evidence is high, but further research is needed to evaluate higher doses and long-term safety.

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Acknowledgments

This work was supported by the Spanish Society of Rheumatology and Menarini. Menarini had no role in the study design, literature search, data collection, data analysis, data interpretation, or writing of this report.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Rush University Medical Center, 1611 West Harrison Street, Suite 510, Chicago, IL, 60612, USA

    Isabel Castrejon

  2. Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain

    Esther Toledano

  3. Research Unit, Spanish Society of Rheumatology, Madrid, Spain

    María Piedad Rosario

  4. Institute for Musculoskeletal Health, Madrid, Spain

    Estíbaliz Loza & Loreto Carmona

  5. Department of Rheumatology, Hospital Universitario Cruces, Baracaldo, Spain

    Fernando Pérez-Ruiz

Authors
  1. Isabel Castrejon
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  2. Esther Toledano
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  3. María Piedad Rosario
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  4. Estíbaliz Loza
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  5. Fernando Pérez-Ruiz
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  6. Loreto Carmona
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Corresponding author

Correspondence to Isabel Castrejon.

Appendices

Appendix 1: MEDLINE search

P (patients)

Search ((“Gout”[Mesh]) OR Gouts OR “Arthritis, Gouty”[Mesh] OR Gouty Arthritis OR Arthritides, Gouty OR Gouty Arthritides) OR (“Juvenile gout”[Supplementary Concept] OR Gouty nephropathy, familial juvenile OR Nephropathy, familial, with gout OR Familial juvenile hyperuricaemic nephropathy) OR (acute gout) OR (gouty) OR (gouty arthritis) OR (acute gouty arthritis) OR (tophaceous gout) OR (chronic tophaceous gout) OR (chronic tophaceous gout) OR (gout hyperuricemia) OR (gout renal) OR (hyperuricemia gout) OR (gout arthritis) OR (chronic gout) OR (“Hyperuricemia”[Mesh]) OR (“Uric Acid”[Mesh] OR Acid, Uric OR Trioxopurine OR 2,6,8-Trihydroxypurine OR Potassium Urate OR Urate, Potassium OR Urate OR Ammonium Acid Urate OR Acid Urate, Ammonium OR Urate, Ammonium Acid OR Sodium Urate Monohydrate OR Monohydrate, Sodium Urate OR Urate Monohydrate, Sodium OR Monosodium Urate Monohydrate OR Monohydrate, Monosodium Urate OR Urate Monohydrate, Monosodium OR Sodium Acid Urate Monohydrate OR Sodium Urate OR Urate, Sodium OR Monosodium Urate OR Urate, Monosodium OR Sodium Acid Urate OR Acid Urate, Sodium OR Urate, Sodium Acid) OR (intercritical gout) OR (monohydrate crystals) OR (primary gout) OR (secondary gout)

I (intervention)

Search “Allopurinol”[Mesh] OR Zyloprim OR Wellcome Brand of Allopurinol OR Allopurinol Wellcome Brand OR Zyloric OR Glaxo Wellcome Brand of Allopurinol OR Allopurinol OR Bicther Brand of Allopurinol OR Allopurinol Bicther Brand OR Allorin OR Douglas Brand of Allopurinol OR Allopurinol Douglas Brand OR Allpargin OR Merz Brand of Allopurinol OR Allopurinol Merz Brand OR Allural OR Pan Quimica OR Quimica, Pan OR Apulonga OR Dorsch Brand of Allopurinol OR Allopurinol Dorsch Brand OR Apurin OR Multipharma Brand of Allopurinol OR Allopurinol Multipharma Brand OR Atisuril OR Byk Gulden Brand of Allopurinol OR Bleminol OR gepepharm Brand of Allopurinol OR Allopurinol gepepharm Brand OR Caplenal OR Rhône-Poulenc Rorer Brand of Allopurinol OR Rhône-Poulenc Rorer Brand of Allopurinol OR APS Brand of Allopurinol OR Allopurinol APS Brand OR Capurate OR Fawns

0 (outcome)

Search ((((((((((((((((((((((“adverse effects “[Subheading] OR side effects OR undesirable effects OR injurious effects)) OR (“Safety”[Mesh] OR Safeties)) OR (“Drug Toxicity”[Mesh] OR Drug Toxicities OR Toxicities, Drug OR Toxicity, Drug OR Drug Safety OR Safety, Drug OR Adverse Drug Reaction OR Adverse Drug Reactions OR Drug Reaction, Adverse OR Drug Reactions, Adverse OR Reaction, Adverse Drug OR Reactions, Adverse Drug OR Adverse Drug Event OR Adverse Drug Events OR Drug Event, Adverse OR Drug Events, Adverse OR Event, Adverse Drug OR Events, Adverse Drug)) OR (“toxicity “[Subheading] OR toxic potential OR margin of safety)) OR (drug fatality)) OR (‘drug mortality’ OR ‘fatal adverse drug reaction’ OR ‘fatal adverse reaction’ OR ‘fatal side effect’)) OR (drug mortality OR fatal adverse drug reaction OR fatal adverse reaction OR fatal side effect)) OR (“poisoning “[Subheading] OR poisonous effects)) OR (“Drug Hypersensitivity”[Mesh] OR Drug Hypersensitivities OR Hypersensitivities, Drug OR Drug Allergy OR Allergies, Drug OR Drug Allergies OR Hypersensitivity, Drug OR Allergy, Drug)) OR (‘drug sensitivity’ OR ‘drug sensitivity test’ OR ‘drug subsensitivity’ OR ‘drug susceptibility’ OR ‘parasitic sensitivity tests’ OR ‘susceptibility, drug’)) OR (drug sensitivity OR drug sensitivity test OR drug subsensitivity OR drug susceptibility OR parasitic sensitivity tests OR susceptibility, drug)) OR (sensitivity drug)) OR (“Drug Interactions”[Mesh] OR Drug Interaction OR Interaction, Drug OR Interactions, Drug)) OR (“drug effects “[Subheading] OR pharmacologic effects OR effect of drugs)) OR (“Adverse Drug Reaction Reporting Systems”[Mesh] OR Drug Reaction Reporting Systems, Adverse)) OR (‘adverse drug reaction’ OR ‘adverse drug effect’ OR ‘adverse drug eventor adverse effect’ OR ‘adverse reaction’ OR ‘adverse reaction, drug’ OR ‘drug adverse effect’ OR ‘drug adverse reaction’ OR ‘drug reaction, adverse’ OR ‘drug side effect’)) OR (‘adverse drug reaction’ OR ‘adverse drug effect’ OR “adverse drug eventor” OR “adverse effect” OR ‘adverse reaction’ OR ‘adverse reaction, drug’ OR ‘drug adverse effect’ OR ‘drug adverse reaction’ OR ‘drug reaction, adverse’ OR ‘drug side effect’)) OR (adverse drug reaction OR adverse drug effect OR “adverse drug eventor” OR “adverse effect” OR adverse reaction OR adverse reaction, drug OR drug adverse effect OR drug adverse reaction OR drug reaction, adverse OR drug side effect)) OR (“drug carcinogenicity” OR ‘carcinogenicity, drug induced’)) OR (“drug carcinogenicity” OR carcinogenicity, drug induced)) OR (“drug cytotoxicity” OR “cytotoxicity, drug”)) OR (“Treatment Outcome”[Mesh] OR Outcome, Treatment OR Rehabilitation Outcome OR Outcome, Rehabilitation OR Treatment Effectiveness OR Effectiveness, Treatment OR Treatment Efficacy OR Efficacy, Treatment) OR “Hypersensitivity”[Mesh] OR Hypersensitivities OR Allergy OR Allergies OR Allergic Reaction OR Allergic Reactions OR Reaction, Allergic OR Reactions, Allergic OR Search “Stevens-Johnson Syndrome”[Mesh] OR Stevens Johnson Syndrome OR Search (((“Allopurinol/adverse effects”[Mesh]) OR ( “Gout Suppressants/adverse effects”[Mesh] OR “Gout Suppressants/toxicity”[Mesh])) OR ( “Drug Eruptions/chemically induced”[Mesh] OR “Drug Eruptions/complications”[Mesh] ))OR(“Eosinophilia/chemically induced”[Mesh]OR”Eosinophilia/complications”[Mesh]) OR DRESS OR “drug related eosinophilia with systemic symptoms”

Study

Search ((((((((((((((“Review”[Publication Type] OR Review, Systematic OR Review, Multicase OR Review Literature OR Review, Academic OR Review of Reported Cases OR Review)) OR (((“Clinical Trial”[Publication Type]) OR “Validation Studies”[Publication Type]) OR “Evaluation Studies”[Publication Type])) OR (“Clinical Trial, Phase I”[Publication Type] OR Clinical Trial, Phase 1)) OR (“Clinical Trial, Phase II”[Publication Type] OR Clinical Trial, Phase 2 OR Clinical Trial, Phase II)) OR (“Clinical Trial, Phase III”[Publication Type] OR Clinical Trial, Phase 3 OR Clinical Trial, Phase III)) OR (“Clinical Trial, Phase IV”[Publication Type] OR Clinical Trial, Phase 4 OR Clinical Trial, Phase IV)) OR (“Controlled Clinical Trial”[Publication Type])) OR (“Multicenter Study”[Publication Type] OR Multicenter Studies OR Multicenter Study)) OR (“Randomized Controlled Trial”[Publication Type] OR Randomized Controlled Trial)) OR (“Cohort Studies”[Mesh] OR Cohort Study OR Studies, Cohort OR Study, Cohort OR Concurrent Studies OR Studies, Concurrent OR Concurrent Study OR Study, Concurrent OR Historical Cohort Studies OR Studies, Historical Cohort OR Cohort Studies, Historical OR Cohort Study, Historical OR Historical Cohort Study OR Study, Historical Cohort OR Analysis, Cohort OR Analyses, Cohort OR Cohort Analyses OR Cohort Analysis OR Closed Cohort Studies OR Cohort Studies, Closed OR Closed Cohort Study OR Cohort Study, Closed OR Study, Closed Cohort OR Studies, Closed Cohort OR Incidence Studies OR Incidence Study OR Studies, Incidence OR Study, Incidence OR Cohort Studies)) OR (“Cohort Studies”[Mesh] OR cohort study OR studies, cohort OR study, cohort OR concurrent studies OR studies, concurrent OR concurrent study OR study, concurrent OR historical cohort studies OR studies, historical cohort OR cohort studies, historical OR cohort study, historical OR historical cohort study OR study, historical cohort OR analysis, cohort OR analysis, cohort OR cohort analyses OR cohort analysis OR closed cohort studies OR cohort studies, closed OR closed cohort study OR cohort study, closed OR study, closed cohort OR studies, closed cohort OR incidence studies OR incidence study OR studies, incidence OR study, incidence OR cohort studies)) OR (“Longitudinal Studies”[Mesh] OR Longitudinal Study OR Studies, Longitudinal OR Study, Longitudinal OR Longitudinal Survey OR Longitudinal Surveys OR Survey, Longitudinal OR Surveys, Longitudinal OR Longitudinal Studies)) OR (“Follow-Up Studies”[Mesh] OR Follow-Up Studies OR Follow-Up Study OR Studies, Follow-Up OR Study, Follow-Up OR Follow-up Studies OR Follow-up Study OR Studies, Follow-up OR Study, Follow-up OR Follow-Up Studies))

Limits

Humans, English, French, Spanish

Appendix 2: Excluded studies and reason for exclusion

Article

Reason for exclusion

Kim (2013)

Incidence of cutaneous adverse reactions in allopurinol users

White (2012)

Gout patients at high risk of CV events

Wells (2012)

Secondary analysis of the CONFIRMS trial comparing Afro-Americans with Caucasian

Tayar (2012)

Febuxostat review and meta-analysis

Chohan (2012)

Comparison of female versus male gout patients

Schumacher (2012)

Rilonacept and allopurinol versus placebo

Becker (2011)

Side effects depending on patient age not treatment

Suarez-Almazor (2010)

Protocol to review febuxostat use in gout

Saito (2010), Hanvivadhanakul (2002), Stolbach (1982)

No gout patients

Poon (2009), Luk (2009), Sundy (2007), Perez-Ruiz (1998), Gibson (1982)

No data about allopurinol safety

Reinders (2007)

Allopurinol versus allopurinol and probenecid

Keenan (2012), Kim (2006), Wortmann (2005), Pascual (2000), Pascual (2007)

Narrative reviews

Catton (2006)

Protocol to review allopurinol use in gout

Pohar (2006)

Canadian recommendation to use febuxostat

Takahashi (2003)

Allopurinol was not included as treatment arm

Vazquez-Mellado (2001)

Prevalence study of side effect of allopurinol in patients with gout

Perez-Ruiz (1999)

Patients with gout and renal function impairment

Delbarre (1966), Kuzell (1966)

Case reports

Appendix 3: Characteristics of the included reviews and meta-analysis

Review and meta-analysis

Stevenson (2011)

Evidence Review Group(ERG)

NICE recommendations

Includes:

Becker (2005)

Schumacher ACR-1837 (2005)

Singh (2010)

Meta-analysis of allopurinol and febuxostat safety

Includes:

Becker (2010)

Schumacher (2008)

Becker (2005)

Stevenson (2009)

Evidence Review Group(ERG)

NICE recommendations

Includes:

Becker (2005)

Schumacher ACR-1837 (2005)

Yu (2007)

Review about Febuxostat efficacy

Includes:

Becker (2005)

Schumacher ACR-1837 (2005)

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Castrejon, I., Toledano, E., Rosario, M.P. et al. Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis. Rheumatol Int 35, 1127–1137 (2015). https://doi.org/10.1007/s00296-014-3189-6

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