Narrative Review: Efficacy and Safety Influencing the Trends of Febuxostat Use

Abdul Malik; Muhammad Arief; Nurlia; Ariska Wigatiningtyas; Niken Indriyanti

doi:10.30872/

Authors

Abdul Malik Mulawarman University Author
Muhammad Arief Mulawarman University Author
Nurlia Mulawarman University Author
Ariska Wigatiningtyas Sekolah Tinggi Ilmu Kesehatan Samarinda Author
Niken Indriyanti Mulawarman University Author

DOI:

https://doi.org/10.30872/

Keywords:

Febuxostat, comparison, efficacy, security, allopurinol

Abstract

Febuxostat is a xanthine oxidase inhibitor used to reduce serum uric acid levels and is new in Indonesia. This study to examine trends in the comparative efficacy and safety of febuxostat versus allopurinol in patients with gout. The study was conducted review of relevant articles obtained from the PubMed and Google Scholar databases published between 2015 and 2025. Drug efficacy was evaluated by monitoring changes in serum uric acid levels from baseline following treatment initiation. Both febuxostat and allopurinol demonstrated good efficacy in lowering serum uric acid levels; however, febuxostat showed a more favorable renal safety profile. But, findings regarding cardiovascular outcomes remain controversial. The CARES study reported a higher risk of cardiovascular mortality associated with febuxostat use. This review summarizes evidence on the efficacy, safety, and usage trends of febuxostat. Febuxostat has the potential to be more widely used in the future and represents a highly effective and cost-efficient long-term therapeutic alternative, particularly for patients who are intolerant to allopurinol or have renal comorbidities. However, long-term cardiovascular safety monitoring remains necessary.

Author Biographies

Abdul Malik, Mulawarman University

Pharmacy Professional Study Program, Faculty of Pharmacy, Mulawarman University, Samarinda, Indonesia.
Muhammad Arief, Mulawarman University

Pharmacy Professional Study Program, Faculty of Pharmacy, Mulawarman University, Samarinda, Indonesia.
Nurlia, Mulawarman University

Pharmacy Professional Study Program, Faculty of Pharmacy, Mulawarman University, Samarinda, Indonesia.
Ariska Wigatiningtyas, Sekolah Tinggi Ilmu Kesehatan Samarinda

Pharmacist Professional Education Study Program, Sekolah Tinggi Ilmu Kesehatan Samarinda, Indonesia.
Niken Indriyanti, Mulawarman University

Pharmaceutical Research and Development Laboratory “Farmaka Tropis”, Faculty of Pharmacy, Mulawarman University, Samarinda, Indonesia.

References

[1] A. K. So and F. Martinon, “Inflammation in gout: mechanisms and therapeutic targets,” Nature Reviews Rheumatology, vol. 13, no. 11, pp. 639–647, 2017, doi: 10.1038/nrrheum.2017.155.

[2] L. Du, Y. Zong, H. Li, Q. Wang, L. Xie, B. Yang, Y. Pang, C. Zhang, Z. Zhong, and J. Gao, “Hyperuricemia and its related diseases: mechanisms and advances in therapy,” Signal Transduction and Targeted Therapy, vol. 9, no. 1, p. 212, 2024, doi: 10.1038/s41392-024-01916-y.

[3] N. Parisa, M. T. Kamaluddin, M. I. Saleh, and E. Sinaga, “The inflammation process of gout arthritis and its treatment,” Journal of Advanced Pharmaceutical Technology & Research, vol. 14, no. 3, pp. 166–170, 2023, doi: 10.4103/japtr.japtr_144_23.

[4] S. Zukhri and D. Permatasari, “Hubungan pola makan dan pola aktivitas dengan pengendalian kadar asam urat penderita hiperurisemia,” TRIAGE Jurnal Ilmu Keperawatan, vol. 9, no. 2, pp. 1–5, 2022.

[5] J. W. Kim, S. G. Kwak, and S. H. Park, “Prescription pattern of urate-lowering therapy in Korean gout patients: Data from the national health claims database,” The Korean Journal of Internal Medicine, vol. 33, no. 1, pp. 228–229, 2018, doi: 10.3904/kjim.2016.429.

[6] C. F. Kuo, M. J. Grainge, L. C. See, K. H. Yu, S. F. Luo, W. Zhang, and M. Doherty, “Epidemiology and management of gout in Taiwan: A nationwide population study,” Arthritis Research & Therapy, vol. 17, no. 1, p. 13, 2015, doi: 10.1186/s13075-015-0522-8.

[7] C. F. Kuo, M. J. Grainge, C. Mallen, W. Zhang, and M. Doherty, “Rising burden of gout in the UK but continuing suboptimal management: A nationwide population study,” Annals of the Rheumatic Diseases, vol. 74, no. 4, pp. 661–667, 2015, doi: 10.1136/annrheumdis-2013-204463.

[8] A. Daffa, K. Kurniawan, A. Fadholah, M. C. Dewi, and T. Nasywa, “Analisis efektivitas biaya pengobatan allopurinol dan colchicine pada pasien asam urat rawat jalan di RSUD Sragen,” Jurnal Ilmiah Global Farmasi (JIGF), vol. 3, no. 1, 2025, doi: 10.21111/jigf.v3i1.87.

[9] Y. Lee, J. Hwang, S. H. Desai, X. Li, C. Jenkins, J. B. Kopp, C. A. Winkler, and S. K. Cho, “Efficacy of xanthine oxidase inhibitors in lowering serum uric acid in chronic kidney disease: A systematic review and meta-analysis,” Journal of Clinical Medicine, vol. 11, no. 9, p. 2468, 2022, doi: 10.3390/jcm11092468.

[10] A. Rey, B. Batteux, S. M. Laville, J. Marienne, K. Masmoudi, V. Gras-Champel, and S. Liabeuf, “Acute kidney injury associated with febuxostat and allopurinol: A post-marketing study,” Arthritis Research & Therapy, vol. 21, no. 1, p. 229, 2019, doi: 10.1186/s13075-019-2011-y.

[11] Y. O. Hsu, I. W. Wu, S. H. Chang, C. C. Lee, C. Y. Tsai, C. Y. Lin, W. T. Lin, Y. T. Huang, C. Y. Wu, G. Kuo, C. Y. Hsiao, H. L. Lin, C. C. Yang, T. H. Yen, Y. C. Chen, C. C. Hung, Y. C. Tian, C. F. Kuo, C. W. Yang, G. F. Anderson, and H. Y. Yang, “Comparative renoprotective effect of febuxostat and allopurinol in predialysis stage 5 chronic kidney disease patients: A nationwide database analysis,” Clinical Pharmacology & Therapeutics, vol. 107, no. 5, pp. 1159–1169, 2020, doi: 10.1002/cpt.1697.

[12] J. R. O’Dell, M. T. Brophy, M. H. Pillinger, T. Neogi, P. M. Palevsky, H. Wu, A. Davis-Karim, J. A. Newcomb, R. Ferguson, D. Pittman, G. W. Cannon, T. Taylor, R. Terkeltaub, A. C. Cannella, B. R. England, L. N. Helget, and T. R. Mikuls, “Comparative effectiveness of allopurinol and febuxostat in gout management,” NEJM Evidence, vol. 1, no. 3, p. EVIDoa2100028, 2022, doi: 10.1056/evidoa2100028.

[13] X. Liu, K. Liu, Q. Sun, Y. Wang, J. Meng, Z. Xu, and Z. Shi, “Efficacy and safety of febuxostat for treating hyperuricemia in patients with chronic kidney disease and in renal transplant recipients: A systematic review and meta-analysis,” Experimental and Therapeutic Medicine, vol. 16, no. 3, pp. 1859–1865, 2018, doi: 10.3892/etm.2018.6367.

[14] I. S. Mackenzie, I. Ford, G. Nuki, J. Hallas, C. J. Hawkey, J. Webster, S. H. Ralston, M. Walters, M. Robertson, R. De Caterina, E. Findlay, F. Perez-Ruiz, J. J. V. McMurray, and T. M. MacDonald, “Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): A multicentre, prospective, randomised, open-label, non-inferiority trial,” The Lancet, vol. 396, no. 10264, pp. 1745–1757, 2020, doi: 10.1016/S0140-6736(20)32234-0.

[15] P. Khanna, R. J. Johnson, B. Marder, B. LaMoreaux, and A. Kumar, “Systemic urate deposition: An unrecognized complication of gout?,” Journal of Clinical Medicine, vol. 9, no. 10, p. 3204, 2020, doi: 10.3390/jcm9103204.

[16] A. Barry, L. N. Helget, M. Androsenko, H. Wu, B. Kramer, J. A. Newcomb, M. T. Brophy, A. Davis-Karim, B. R. England, R. Ferguson, M. H. Pillinger, T. Neogi, M. H. Pillinger, T. R. Merriman, J. R. O’Dell, and T. R. Mikuls, “Comparison of gout flares with the initiation of treat-to-target allopurinol and febuxostat: A post-hoc analysis of a randomized multicenter trial,” Arthritis & Rheumatology, vol. 76, no. 10, pp. 1552–1559, 2024, doi: 10.1002/art.42927.

[17] E. Jia, Y. Zhang, W. Ma, B. Li, H. Geng, L. Zhong, X. Yao, J. Xie, Y. Xiao, Y. Jiang, X. Qiu, M. Xiao, X. Cui, J. Wei, and J. Zhang, “Initiation of febuxostat for acute gout flare does not prolong the current episode: A randomized clinical trial,” Rheumatology, vol. 60, no. 9, pp. 4199–4204, 2021, doi: 10.1093/rheumatology/keaa908.

[18] J. Lee, J. Kim, B. Ghang, and W. Jeong, “A retrospective observational study of the appropriate starting dose of febuxostat in patients with gout,” The Korean Journal of Internal Medicine, vol. 38, no. 3, pp. 427–433, 2023, doi: 10.3904/kjim.2022.190.

[19] R. Sun, J. Lu, H. Li, X. Cheng, Y. Xin, and C. Li, “Evaluation of febuxostat initiation during an acute gout attack: A prospective, randomized clinical trial,” Joint Bone Spine, vol. 87, no. 5, pp. 461–466, 2020, doi: 10.1016/j.jbspin.2020.03.017.

[20] T. Uhlig, L. F. Karoliussen, J. Sexton, T. K. Kvien, E. A. Haavardsholm, F. Perez-Ruiz, and H. B. Hammer, “One- and 2-year flare rates after treat-to-target and tight-control therapy of gout: Results from the NOR-Gout study,” Arthritis Research & Therapy, vol. 24, no. 1, p. 88, 2022, doi: 10.1186/s13075-022-02772-3.

[21] S. Ito, Y. Morita, M. Nitami, R. Iwama, A. Nakajima, H. Yamanaka, and M. Honda, “Efficacy and safety of febuxostat in Japanese paediatric patients with hyperuricaemia including gout: Phase 2, single arm, open-label, multicentre studies,” Modern Rheumatology, vol. 35, no. 1, pp. 194–202, 2025, doi: 10.1093/mr/roae056.

[22] M. Turab, S. S. Hasan, S. A. Zaidi, S. Khalid, F. Shaikh, and D. Zehra, “The allopurinol and febuxostat in the treatment of hyperuricemic patients and their impact on lipid fractions (cholesterol, LDL, HDL),” Journal of Hunan University Natural Sciences, vol. 49, no. 1, pp. 282–289, 2022, doi: 10.55463/issn.1674-2974.49.1.34.

[23] A. Kim, Y. Kim, G. T. Kim, E. Ahn, M. W. So, and S. G. Lee, “Comparison of persistence rates between allopurinol and febuxostat as first-line urate-lowering therapy in patients with gout: An 8-year retrospective cohort study,” Clinical Rheumatology, vol. 39, no. 12, pp. 3769–3776, 2020, doi: 10.1007/s10067-020-05161-w.

[24] A. Waller and K. M. Jordan, “Use of febuxostat in the management of gout in the United Kingdom,” Therapeutic Advances in Musculoskeletal Disease, vol. 9, no. 2, pp. 55–64, 2017, doi: 10.1177/1759720X16682010.

[25] R. Koto, A. Nakajima, H. Horiuchi, and H. Yamanaka, “Real-world treatment of gout and asymptomatic hyperuricemia: A cross-sectional study of Japanese health insurance claims data,” Modern Rheumatology, vol. 31, no. 1, pp. 261–269, 2021, doi: 10.1080/14397595.2020.1784556.

[26] N. Liu, H. Xu, Q. Sun, X. Yu, W. Chen, H. Wei, J. Jiang, Y. Xu, and W. Lu, “The role of oxidative stress in hyperuricemia and xanthine oxidoreductase (XOR) inhibitors,” Oxidative Medicine and Cellular Longevity, vol. 2021, p. 1470380, 2021, doi: 10.1155/2021/1470380.

[27] R. Sarvepalli, V. Penabaka, Y. Bhargavi, B. Nithin, G. Sai Sarath, Y. Nagalakshmaiah, and K. Sai Sreya, “A review on febuxostat as uric acid lowering agent,” Asian Journal of Medical and Pharmaceutical Sciences, vol. 13, no. 1, pp. 17–20, 2025, doi: 10.30904/j.ajmps.2025.4761.

[28] S. P. Chinchilla, I. Urionaguena, and F. Perez-Ruiz, “Febuxostat for the chronic management of hyperuricemia in patients with gout,” Expert Review of Clinical Pharmacology, vol. 9, no. 5, pp. 665–673, 2016, doi: 10.1586/17512433.2016.1162094.

[29] A. Z. Sosinsky, Y. Song, L. Gunawardhana, S. Phillips, and M. Page, “The impact of label changes (boxed warning) on real-world febuxostat utilization in patients with gout: A cross-sectional drug utilization study,” Rheumatology and Therapy, vol. 10, no. 5, pp. 1277–1295, 2023, doi: 10.1007/s40744-023-00581-x.

[30] L. K. Stamp, T. R. Merriman, M. L. Barclay, J. A. Singh, R. L. Roberts, D. F. Wright, and N. Dalbeth, “Impaired response or insufficient dosage? Examining the potential causes of ‘inadequate response’ to allopurinol in the treatment of gout,” Seminars in Arthritis and Rheumatism, vol. 44, no. 2, pp. 170–174, 2014, doi: 10.1016/j.semarthrit.2014.05.007.

[31] P. Richette, P. Clerson, L. Périssin, R. M. Flipo, and T. Bardin, “Revisiting comorbidities in gout: A cluster analysis,” Annals of the Rheumatic Diseases, vol. 74, no. 1, pp. 142–147, 2015, doi: 10.1136/annrheumdis-2013-203779.

[32] M. Bevis, M. Blagojevic-Bucknall, C. Mallen, S. Hider, and E. Roddy, “Comorbidity clusters in people with gout: An observational cohort study with linked medical record review,” Rheumatology, vol. 57, no. 8, pp. 1358–1363, 2018, doi: 10.1093/rheumatology/key096.

[33] K. Kimura, T. Hosoya, S. Uchida, M. Inaba, H. Makino, S. Maruyama, S. Ito, T. Yamamoto, Y. Tomino, I. Ohno, Y. Shibagaki, S. Iimuro, N. Imai, M. Kuwabara, H. Hayakawa, H. Ohtsu, and Y. Ohashi, “Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: A randomized trial,” American Journal of Kidney Diseases, vol. 72, no. 6, pp. 798–810, 2018, doi: 10.1053/j.ajkd.2018.06.028.

[34] K. G. Saag, M. A. Becker, W. B. White, A. Whelton, J. S. Borer, P. B. Gorelick, B. Hunt, M. Castillo, and L. Gunawardhana, “Evaluation of the relationship between serum urate levels, clinical manifestations of gout, and death from cardiovascular causes in patients receiving febuxostat or allopurinol in an outcomes trial,” Arthritis & Rheumatology, vol. 74, no. 9, pp. 1593–1601, 2022, doi: 10.1002/art.42160.

[35] M. Konishi, S. Kojima, K. Uchiyama, N. Yokota, E. Tokutake, Y. Wakasa, et al., “Effect of febuxostat on clinical outcomes in patients with hyperuricemia and cardiovascular disease,” International Journal of Cardiology, vol. 349, pp. 127–133, 2022.

[36] Y. Kawachi, Y. Fujishima, H. Nishizawa, A. Tanaka, H. Yoshida, S. Niwano, M. Suzuki, I. Shimomura, and K. Node, “Effect of the xanthine oxidase inhibitor febuxostat on the cardio-ankle vascular index in asymptomatic patients with hyperuricemia and liver dysfunction: A sub-analysis of the PRIZE study,” Journal of Atherosclerosis and Thrombosis, vol. 32, no. 4, pp. 474–490, 2025, doi: 10.5551/jat.65087.

[37] M. Dong, Z. Cui, Y. Liu, Y. Bu, K. An, and L. Mao, “Effects of febuxostat therapy on circulating adipokine profiles in patients with overweight or obesity and asymptomatic hyperuricemia: A randomized controlled study,” Obesity Facts, vol. 17, no. 5, pp. 524–534, 2024, doi: 10.1159/000540701.

[38] Y. Saito, A. Tanaka, H. Yoshida, H. Nakashima, N. Ban, M. Matsuhisa, Y. Kobayashi, K. Node, and PRIZE Study Investigators, “Effects of xanthine oxidase inhibition by febuxostat on lipid profiles of patients with hyperuricemia: Insights from randomized PRIZE study,” Nutrients, vol. 16, no. 14, p. 2324, 2024, doi: 10.3390/nu16142324.

[39] T. Yokota, S. Kinugawa, A. Fukushima, T. Okumura, T. Murohara, H. Tsutsui, and LEAF-CHF Investigators, “Efficacy and safety of the urate-lowering agent febuxostat in chronic heart failure patients with hyperuricemia: Results from the LEAF-CHF study,” Heart and Vessels, vol. 40, no. 2, pp. 111–122, 2025.

[40] J. H. Deng, P. H. Lai, L. S. Xie, S. S. Qiu, D. S. Qiu, and J. X. Zhang, “Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: A systematic review and meta-analysis,” Clinical and Translational Science, vol. 17, no. 3, p. e13757, 2024, doi: 10.1111/cts.13757.

[41] W. B. White, K. G. Saag, M. A. Becker, J. S. Borer, P. B. Gorelick, A. Whelton, B. Hunt, M. Castillo, and L. Gunawardhana, “Cardiovascular safety of febuxostat or allopurinol in patients with gout,” New England Journal of Medicine, vol. 378, no. 13, pp. 1200–1210, 2018, doi: 10.1056/NEJMoa1710895.

[42] W. Sun, L. Cui, R. Terkeltaub, Y. Chen, X. Li, X. Cheng, T. Liu, N. Dalbeth, and C. Li, “Risk of hepatotoxicity in patients with gout treated with febuxostat or benzbromarone: A propensity score-matched cohort study,” Arthritis Care & Research, vol. 77, no. 9, pp. 1149–1156, 2025, doi: 10.1002/acr.25547.

[43] N. Dalbeth, K. G. Saag, W. E. Palmer, H. K. Choi, B. Hunt, P. A. MacDonald, L. S. Hunt, and L. Gunawardhana, “Effects of febuxostat in early gout: A randomized, double-blind, placebo-controlled study,” Arthritis & Rheumatology, vol. 69, no. 12, pp. 2386–2395, 2017, doi: 10.1002/art.40297.

[44] I. I. Sarhan, Y. A. Abdellatif, R. E. Saad, and N. M. Teama, “Renoprotective effect of febuxostat on contrast-induced acute kidney injury in chronic kidney disease patients stage 3: Randomized controlled trial,” BMC Nephrology, vol. 24, no. 1, p. 65, 2023, doi: 10.1186/s12882-023-03114-4.

[45] X. H. Yang, B. L. Zhang, Y. Cheng, S. K. Fu, and H. M. Jin, “Febuxostat provides renoprotection in patients with hyperuricemia or gout: A systematic review and meta-analysis of randomized controlled trials,” Annals of Medicine, vol. 56, no. 1, p. 2332956, 2024, doi: 10.1080/07853890.2024.2332956.

[46] A. Chewcharat, Y. Chen, C. Thongprayoon, A. M. Harrison, M. A. Mao, and W. Cheungpasitporn, “Febuxostat as a renoprotective agent for treatment of hyperuricaemia: A meta-analysis of randomised controlled trials,” Internal Medicine Journal, vol. 51, no. 5, pp. 752–762, 2021, doi: 10.1111/imj.14814.

[47] C. Y. Yang, C. H. Chen, S. T. Deng, C. S. Huang, Y. J. Lin, Y. J. Chen, C. Y. Wu, S. I. Hung, and W. H. Chung, “Allopurinol use and risk of fatal hypersensitivity reactions: A nationwide population-based study in Taiwan,” JAMA Internal Medicine, vol. 175, no. 9, pp. 1550–1557, 2015, doi: 10.1001/jamainternmed.2015.3536.

[48] J. A. Singh and J. D. Cleveland, “Hypersensitivity reactions with allopurinol and febuxostat: A study using the Medicare claims data,” Annals of the Rheumatic Diseases, vol. 79, no. 4, pp. 529–535, 2020, doi: 10.1136/annrheumdis-2019-216917.

[49] T. Alotaibi, J. Bjazevic, R. Kim, S. Gryn, N. Sultan, G. Dresser, and H. Razvi, “Allopurinol hypersensitivity syndrome: Raising awareness of an uncommon but potentially serious adverse event among kidney stone patients,” Canadian Urological Association Journal, vol. 18, no. 5, p. E167, 2024.

[50] H. Jeong, E. Choi, A. Suh, M. Yoo, and B. Kim, “Risk of cardiovascular disease associated with febuxostat versus allopurinol use in patients with gout: A retrospective cohort study in Korea,” Rheumatology International, vol. 43, no. 2, pp. 265–281, 2023, doi: 10.1007/s00296-022-05222-0.

[51] S. Sawada, K. Kajiyama, H. Shida, R. Kimura, Y. Nakazato, T. Iguchi, Y. Oniyama, C. Ishiguro, and Y. Uyama, “Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan,” Clinical and Translational Science, vol. 16, no. 2, pp. 206–215, 2023, doi: 10.1111/cts.13439.

[52] M. J. Kim, J. Y. Pyo, S. R. Choi, A. Shin, H. Choung, Y. J. Ha, Y. J. Lee, E. B. Lee, and E. H. Kang, “Comparative risk of retinal microvascular disorders in patients with gout initiating febuxostat versus allopurinol: A population-based cohort study,” Scientific Reports, vol. 15, no. 1, p. 28939, 2025, doi: 10.1038/s41598-025-00551-z.

[53] Y. Bai, B. Wu, L. Gou, Z. Fang, T. Xu, T. Zhang, and Y. Li, “Cardiovascular safety evaluation of febuxostat and allopurinol: Findings from the FDA adverse event reporting system,” Journal of Clinical Medicine, vol. 12, no. 18, p. 6089, 2023, doi: 10.3390/jcm12186089.

[54] A. Rezapour, S. Alidoost, A. Asgharzadeh, Z. Farhadi, N. Khodadadi, R. M. Bakhsh, R. Sepehrian, M. Salemi, M. Taheri Mirghaed, M. Behzadifar, and R. Sohrabi, “Cost-effectiveness of allopurinol versus febuxostat in the treatment of gout patients: A systematic review,” Medical Journal of the Islamic Republic of Iran, vol. 34, p. 41, 2020, doi: 10.34171/mjiri.34.41.

[55] M. Dehlin, L. Jacobsson, and E. Roddy, “Global epidemiology of gout: Prevalence, incidence, treatment patterns and risk factors,” Nature Reviews Rheumatology, vol. 16, no. 7, pp. 380–390, 2020, doi: 10.1038/s41584-020-0441-1.