Allopurinol is a commonly prescribed medication for the treatment of gout, a form of arthritis characterized by severe pain, redness, and tenderness in joints. Despite its efficacy, allopurinol can cause allergic reactions in some individuals. This blog will explore the types of people who may have an allergic reaction to allopurinol and discuss alternative medications that can be used to manage gout.
Who is at Risk for Allergic Reactions to Allopurinol?
1. Genetically Susceptible Populations
Certain genetic factors can predispose individuals to allergic reactions to allopurinol. One of the most significant genetic markers is the presence of the HLA-B*5801 allele. This allele is particularly prevalent in specific ethnic groups, including Han Chinese, Thai, and Korean populations. Individuals with this genetic marker are at a higher risk of developing severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when taking allopurinol (Greenberger, 2012, pp. 103–107; Stamp & Barclay, 2018, pp. i35–i41).
2. Patients with Chronic Kidney Disease
Chronic kidney disease (CKD) can increase the risk of allopurinol hypersensitivity syndrome (AHS). The impaired renal function in CKD patients can lead to the accumulation of allopurinol and its metabolites, increasing the likelihood of adverse reactions. Therefore, patients with CKD should be closely monitored when prescribed allopurinol, and alternative treatments should be considered if necessary (Stamp & Barclay, 2018, pp. i35–i41).
3. Individuals with a History of Drug Allergies
Patients with a history of allergic reactions to other medications are more likely to experience an allergic reaction to allopurinol. This includes individuals who have had previous reactions to drugs such as antibiotics, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs). A thorough medical history should be taken to identify any potential risks before prescribing allopurinol (Greenberger, 2012, pp. 103–107, 2019, pp. 474–479).
4. Patients with Specific Comorbidities
Certain comorbidities can increase the risk of allergic reactions to allopurinol. For example, individuals with human immunodeficiency virus (HIV) infection, chronic lymphocytic leukemia, and other immunocompromised states are at a higher risk of drug hypersensitivity reactions. These patients should be carefully evaluated before initiating allopurinol therapy (Greenberger, 2012, pp. 103–107, 2019, pp. 474–479).
5. Elderly Patients
Elderly patients are generally more susceptible to adverse drug reactions due to age-related changes in drug metabolism and excretion. The risk of allopurinol hypersensitivity may be higher in this population, necessitating careful dose adjustments and monitoring (Mumoli et al., 2011, pp. 709–710).
Alternative Medications for Gout Management
For individuals who cannot tolerate allopurinol due to allergic reactions, several alternative medications can be used to manage gout effectively. These alternatives include febuxostat, probenecid, and pegloticase, among others.
1. Febuxostat
Febuxostat is a xanthine oxidase inhibitor, similar to allopurinol, but with a different chemical structure. It is an effective alternative for patients who are allergic to allopurinol or have not achieved adequate uric acid control with allopurinol. Febuxostat has been shown to be effective in reducing serum uric acid levels and preventing gout flares. It is particularly useful for patients with renal impairment, as it does not require dose adjustments based on renal function (Bardin et al., 2016, pp. 314–317; Ильиных et al., 2017, pp. 83–88).
Efficacy and Safety
Clinical trials have demonstrated that febuxostat is as effective, if not more so, than allopurinol in lowering serum uric acid levels. It has also been associated with a lower risk of severe cutaneous adverse reactions compared to allopurinol. However, febuxostat should be used with caution in patients with cardiovascular disease, as some studies have suggested an increased risk of cardiovascular events with its use (Bardin et al., 2016, pp. 314–317; Ильиных et al., 2017, pp. 83–88).
2. Probenecid
Probenecid is a uricosuric agent that increases the excretion of uric acid in the urine. It is an effective alternative for patients who cannot tolerate xanthine oxidase inhibitors like allopurinol and febuxostat. Probenecid is particularly useful for patients with normal renal function and those who do not have a history of kidney stones (Sivordova et al., 2021).
Efficacy and Safety
Probenecid has been shown to be effective in reducing serum uric acid levels and preventing gout flares. However, it is not suitable for patients with renal impairment or a history of uric acid kidney stones, as it can increase the risk of stone formation. Additionally, probenecid can interact with other medications, so a thorough review of the patient’s medication list is necessary before initiating therapy(Sivordova et al., 2021).
3. Pegloticase
Pegloticase is a recombinant uricase enzyme that converts uric acid to allantoin, a more soluble and easily excreted compound. It is used for the treatment of chronic gout in patients who have not responded to conventional therapies. Pegloticase is administered intravenously and is typically reserved for patients with severe, refractory gout (Sivordova et al., 2021).
Efficacy and Safety
Pegloticase has been shown to be highly effective in reducing serum uric acid levels and resolving tophi in patients with chronic gout. However, it is associated with a risk of infusion reactions and the development of anti-pegloticase antibodies, which can reduce its efficacy over time. Patients receiving pegloticase should be closely monitored for signs of infusion reactions and antibody development (Sivordova et al., 2021).
4. Lesinurad
Lesinurad is a selective uric acid reabsorption inhibitor that works by inhibiting the URAT1 transporter in the kidneys, thereby increasing the excretion of uric acid. It is used in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout. Lesinurad is an option for patients who require additional uric acid-lowering therapy beyond what can be achieved with a xanthine oxidase inhibitor alone (Sivordova et al., 2021).
Efficacy and Safety
Lesinurad has been shown to be effective in combination with allopurinol or febuxostat in reducing serum uric acid levels. However, it is associated with a risk of renal adverse events, including acute renal failure, particularly when used as monotherapy. Therefore, lesinurad should always be used in combination with a xanthine oxidase inhibitor and with close monitoring of renal function(Sivordova et al., 2021).
5. Colchicine
Colchicine is an anti-inflammatory medication that is used to treat acute gout flares and to prevent recurrent flares. While it does not lower serum uric acid levels, it is an important adjunctive therapy for managing the inflammatory component of gout. Colchicine can be used in combination with uric acid-lowering therapies to provide comprehensive gout management(Sivordova et al., 2021).
Efficacy and Safety
Colchicine is effective in reducing the pain and inflammation associated with acute gout flares. It is also used at low doses for flare prophylaxis. However, colchicine can cause gastrointestinal side effects, such as diarrhea and abdominal pain, and should be used with caution in patients with renal or hepatic impairment. Drug interactions should also be considered, as colchicine can interact with several other medications (Sivordova et al., 2021).
Conclusion
Allopurinol is a widely used and effective medication for the management of gout, but it can cause allergic reactions in certain individuals. Populations at higher risk for allergic reactions to allopurinol include those with specific genetic markers, chronic kidney disease, a history of drug allergies, certain comorbidities, and elderly patients. For these individuals, alternative medications such as febuxostat, probenecid, pegloticase, lesinurad, and colchicine can be used to manage gout effectively.
It is essential for healthcare providers to carefully evaluate each patient’s risk factors and medical history before prescribing allopurinol or its alternatives. Close monitoring and patient education are crucial to ensure the safe and effective management of gout. By understanding the risks and benefits of each treatment option, healthcare providers can tailor therapy to meet the individual needs of their patients, improving outcomes and quality of life for those living with gout.
References
Abdurrahman, Z., Kastner, M., Wurman, C., Harada, L., Bantock, L., Cruickshank, H., & Waserman, S. (2011). Experiencing a first food allergic reaction: a survey of parent and caregiver perspectives. Allergy, Asthma & Clinical Immunology, 9, 18–18.
Adamcová, M., Šturdík, I., Koller, T., & Payer, J. (2016). [DRESS syndrome]. Vnitrni Lekarstvi, 62 4, 334–337.
Al-kuraishy, H., Al-Gareeb, A., Al-Niemi, M., Aljowaie, R. M., Almutairi, S., Alexiou, A., & Batiha, G. (2022). The Prospective Effect of Allopurinol on the Oxidative Stress Index and Endothelial Dysfunction in Covid-19. Inflammation, 45, 1651–1667.
Anonymous. (2021). Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine — United States, December 21, 2020–January 10, 2021. MMWR. Morbidity and Mortality Weekly Report, 70, 125–129.
Árnadóttir, M. (2014). Febuxostat in adenosine phosphoribosyltransferase deficiency. American Journal of Kidney Diseases, 64 2, 316.
Balakirski, G., & Merk, H. (2017). Cutaneous allergic drug reactions: update on pathophysiology, diagnostic procedures and differential diagnosic. Cutaneous and Ocular Toxicology, 36, 307–316.
Bardin, T., Chalès, G., Pascart, T., Flipo, R., Ea, H. K., Roujeau, J., Delayen, A., & Clerson, P. (2016). Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment. Joint, Bone, Spine : Revue Du Rhumatisme, 83 3, 314–317.
Bian, S., Li, L., Wang, Z., Cui, L., Xu, Y., Guan, K., & Zhao, B. (2022). Allergic Reactions After the Administration of COVID-19 Vaccines. Frontiers in Public Health, 10.
Blumenthal, K., Robinson, L., Camargo, C., Shenoy, E., Banerji, A., Landman, A., & Wickner, P. G. (2021). Acute Allergic Reactions to mRNA COVID-19 Vaccines. Journal of the American Medical Association (JAMA).
Brinker, A. (2009). Allopurinol and the role of uric acid in hypertension. Journal of the American Medical Association (JAMA), 301 3, 270; author reply 270-1.
Careta, M. F., Delgado, L., & Patriota, R. (2015). Report of Allergic Reaction After Application of Botulinum Toxin. Aesthetic Surgery Journal, 35 5, NP102-5.
Cash, J. C., & Bradbury-Golas, K. (2019). Allergic Rhinitis. Canadian Family Practice Guidelines.
Chu, D., Abrams, E., Golden, D., Blumenthal, K., Wolfson, A. R., Stone, C., Krantz, M., Shaker, M., & Greenhawt, M. (2022). Risk of Second Allergic Reaction to SARS-CoV-2 Vaccines: A Systematic Review and Meta-analysis. JAMA Internal Medicine.
Copaescu, A., & Trublano, J. A. (2022). The assessment of severe cutaneous adverse drug reactions. Australian Prescriber, 45, 43–48.
Earll, J., & Saavedra, M. (1983). Oxipurinol therapy in allopurinol-allergic patients. American Family Physician, 28 5, 147–148.
Fam, A. (2001). Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient. Current Rheumatology Reports, 3, 29–35.
Fine, P., Savrinski, B., & Millodot, M. (2003). Contact lens management of a case of Stevens-Johnson syndrome: a case report. Optometry, 74 10, 659–664.
Fontana, R., Li, Y.-J., Phillips, E., Saeed, N., Barnhart, H., Kleiner, D., & Hoofnagle, J. (2021). Allopurinol hepatotoxicity is associated with human leukocyte antigen Class I alleles. Liver International (Print), 41, 1884–1893.
Gb, E. (2020). The Role of Uric Acid Metabolism in Anaphylaxis: the Effect of Allopurinol on Allergic Reactions to Peanut in Peanut Allergic Adults.
Gede, N., Putra, J., Ganesha, R., Ngurah, G., & Dermawan, P. (2023). Identification and treatment of identification and treatment of erythema multiforme induced by allopurinol. Interdental Jurnal Kedokteran Gigi (IJKG).
Godinho, M., Aguinaga, F., Grynszpan, R., Lima, V. M., Azulay, D., Cuzzi, T., Ramos‐e‐Silva, M., & Manela‐Azulay, M. (2015). Granulomatous reaction to red tattoo pigment treated with allopurinol. Journal of Cosmetic Dermatology, 14.
Greenberger, P. (2012). Chapter 30: Drug allergy. Allergy and Asthma Proceedings, 33 Suppl 1, 103–107.
Greenberger, P. (2019). Drug allergy. Allergy and Asthma Proceedings, 40 6, 474–479.
Han, S., Sun, L., He, F., & Che, H. (2017). Anti-allergic activity of glycyrrhizic acid on IgE-mediated allergic reaction by regulation of allergy-related immune cells. Scientific Reports, 7.
Hui-Chen, & Zhang, Q. (2010). The Possible Pathogenesis and Clinic Treatment of Heavy Drug Eruption Caused by Allopurinol. International Medicine and Health Guidance News, 16, 2248–2250.
Kim, M. S., Youn, S., Na, C., & Shin, B. (2015). Allergic reaction to hyaluronidase use after hyaluronic acid filler injection. Journal of Cosmetic & Laser Therapy, 17, 283–285.
Kim, Y.-Y., Je, I., Kim, M. J., Kang, B., Choi, Y.-A., Baek, M., Lee, B., Choi, J. K., Park, H.-R., Shin, T., Lee, S., Yoon, S.-B., Lee, S.-R., Khang, D., & Kim, S.-H. (2016). 2-Hydroxy-3-methoxybenzoic acid attenuates mast cell-mediated allergic reaction in mice via modulation of the FcεRI signaling pathway. Acta Pharmacologica Sinica, 38, 90–99.
Klimek, L., Novak, N., Hamelmann, E., Werfel, T., Wagenmann, M., Taube, C., Bauer, A., Merk, H., Rabe, U., Jung, K., Schlenter, W., Ring, J., Chaker, A., Wehrmann, W., Becker, S., Mülleneisen, N., Nemat, K., Czech, W., Wrede, H., … Worm, M. (2021). Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and USA. Allergo Journal International, 30, 51–55.
Kounis, N., Koniari, I., Gregorio, C., Velissaris, D., Petalas, K., Brinia, A., Assimakopoulos, S., Gogos, C., Kouni, S., Kounis, G., Calogiuri, G., & Hung, M.-Y. (2021). Allergic Reactions to Current Available COVID-19 Vaccinations: Pathophysiology, Causality, and Therapeutic Considerations. Vaccines, 9.
Kumar, A., & Azmi, W. (2014). Phytomedicine: A novel alternative for treatment of gout.
Kumar, M., Duraisamy, K., & Chow, B. (2021). Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2). Cells, 10.
Kyung, S., Cho, Y., Kim, Y. J., Park, J.-W., Jeong, S., Jae-Lee, Sung, Y. M., & Lee, S. (2011). A Paragonimiasis Patient with Allergic Reaction to Praziquantel and Resistance to Triclabendazole: Successful Treatment after Desensitization to Praziquantel. Korean Journal of Parasitology, 49, 73–77.
Latalski, M., Walczyk, A., Fatyga, M., Rutz, E., Szponder, T., Bielecki, T., & Danielewicz, A. (2019). Allergic reaction to platelet-rich plasma (PRP). Medicine, 98.
Lockard, O., Harmon, C., Nolph, K., & Irvin, W. (1976). Allergic reaction to allopurinol with cross-reactivity to oxypurinol. Annals of Internal Medicine, 85 3, 333–335.
Luxi, N., Giovanazzi, A., Arcolaci, A., Bonadonna, P., Crivellaro, M., Cutroneo, P., Ferrajolo, C., Furci, F., Guidolin, L., Moretti, U., Olivieri, E., Petrelli, G., Zanoni, G., Senna, G., & Trifirò, G. (2022). Allergic Reactions to COVID-19 Vaccines: Risk Factors, Frequency, Mechanisms and Management. BioDrugs, 36, 443–458.
Macaulay, S., Bayliff, C., & Mehta, S. (2002). Fluoroquinolone-Induced Acute Interstitial Nephritis: Two Case Reports. The Canadian Journal of Hospital Pharmacy, 55.
Mahase, E. (2020). Covid-19: People with history of significant allergic reactions should not receive Pfizer vaccine, says regulator. British Medical Journal, 371.
Mahipathy, S. R. V., Durairaj, A. R., Sundaramurthy, N., Ramachandran, M., & Natarajan, P. G. (2019). Lyell’s syndrome: a rare case report. International Surgery Journal.
Martínez-Aranguren, R., Gamboa, P., García-Lirio, E., Alonso, A., & Sanz, M. (2012). In vitro cytokine production after in vivo desensitization in an allopurinol-induced delayed allergic reaction. Annals of Allergy, Asthma & Immunology, 108 4, 280–281.
Mathews, H. G., & Tancil, C. G. (1996). Extrapyramidal Reaction caused by Ondansetron. The Annals of Pharmacotherapy, 30, 196–196.
Monti, G., Viola, S., Tarasco, Lupica, M., Cosentino, & Castagno, E. (2011). A case of severe allergic reaction to cooked potato. Acta Paediatrica, 100.
Mumoli, N., Cei, M., Luschi, R., Carmignani, G., & Camaiti, A. (2011). Allergic reaction to Croscarmellose sodium used as excipient of a generic drug. QJM : Monthly Journal of the Association of Physicians, 104 8, 709–710.
Nakao, A., Nakao, A., Nakamura, Y., & Shibata, S. (2015). The circadian clock functions as a potent regulator of allergic reaction. Allergy. European Journal of Allergy and Clinical Immunology, 70, 467–473.
Neki, N., Kumar, J., Jain, A., Bajaj, R., Manav, M., Kumar, H., & Chavan, V. (2016). Allopurinol Induced Stevens – Johnson Syndrome: A Rare Case Report. Kerala Medical Journal, 9, 40–42.
Sampath, V., Rabinowitz, G., Shah, M. M., Jain, S., Diamant, Z., Jeseňák, M., Rabin, R., Vieths, S., Agache, I., Akdiş, M., Barber, D., Breiteneder, H., Chinthrajah, S., Chivato, T., Collins, W., Eiwegger, T., Fast, K., Fokkens, W., O’Hehir, R., … Nadeau, K. (2021). Vaccines and allergic reactions: The past, the current COVID‐19 pandemic, and future perspectives. Allergy. European Journal of Allergy and Clinical Immunology, 76, 1640–1660.
Scavone, C., Mauro, C. D., Ruggiero, R., Bernardi, F., Trama, U., Aiezza, M., Rafaniello, C., & Capuano, A. (2019). Severe Cutaneous Adverse Drug Reactions Associated with Allopurinol: An Analysis of Spontaneous Reporting System in Southern Italy. Drugs – Real World Outcomes, 7, 41–51.
Sharma, P., Gupta, N., Hasan, N., Krishnamurthy, B., & Singh, S. (2016). Hypersensitivity with Inhalational Budesonide: An Under Recognised Entity. Journal of Clinical and Diagnostic Research : JCDR, 10 10, FD01–FD02.
Shavit, R., Maoz-Segal, R., Iancovici-Kidon, M., Offengenden, I., Yahia, S. H., Maayan, D. M., Lifshitz-Tunitsky, Y., Niznik, S., Frizinsky, S., Deutch, M., Elbaz, E., Genaim, H., Rahav, G., Levy, I., Belkin, A., Regev-Yochay, G., Afek, A., & Agmon-Levin, N. (2021). Prevalence of Allergic Reactions After Pfizer-BioNTech COVID-19 Vaccination Among Adults With High Allergy Risk. JAMA Network Open, 4.
Shimabukuro, T., & Team, C. C.-R. (2021). Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020. MMWR. Morbidity and Mortality Weekly Report, 70, 46–51.
Shittu, M., Shah, P., Elkhalili, W., Suleiman, A., Shaaban, H., Shah, P. A., & Shamoon, F. (2015). A Rare Case of Recurrent Pacemaker Allergic Reaction. Heart Views, 16, 59–61.
Sivordova, L., Polyakova, Y., Papichev, E., Akhverdyan, Y., & Zavodovskii, B. V. (2021). Modern facilities of pharmacological correction of hyperuricemia in rheumatic diseases: management of difficult clinical cases. Meditsinskiy Sovet Medical Council.
Skypala, I., Bartra, J., Ebo, D., Faber, M., Fernández-Rivas, M., Gomez, F., Luengo, O., Till, S., Asero, R., Barber, D., Cecchi, L., Perales, A. D., Hoffmann‐Sommergruber, K., Pastorello, E., Swoboda, I., Konstantinopoulos, A., Ree, R., & Scala, E. (2021). The diagnosis and management of allergic reactions in patients sensitized to non‐specific lipid transfer proteins. Allergy. European Journal of Allergy and Clinical Immunology, 76.
Smith, C. (2023). Allergic Contact Dermatitis. Springer Berlin Heidelberg.
Sokolowska, M., Eiwegger, T., Ollert, M., Torres, M., Barber, D., Giacco, S. D. D., Jutel, M., Nadeau, K., Palomares, Ó., Rabin, R., Riggioni, C., Vieths, S., Agache, I., & Shamji, M. (2021). EAACI statement on the diagnosis, management and prevention of severe allergic reactions to COVID‐19 vaccines. Allergy. European Journal of Allergy and Clinical Immunology, 76, 1629–1639.
Sprung, J., Weingarten, T., & Schwartz, L. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122 3, 713–714.
Stamp, L., & Barclay, M. (2018). How to prevent allopurinol hypersensitivity reactions? Rheumatology, 57 suppl_1, i35–i41.
Tohyama, M., & Hashimoto, K. (2001). [Hypersensitivity syndrome and HHV-6]. Nihon Rinsho. Japanese Journal of Clinical Medicine, 59 11, 2285–2292.
Tournikioti, K., Douzenis, A., Antoniadou, A., Papazahos, K., Moschos, C., Papageorgiou, C., & Rizos, E. (2016). Eosinophilia Associated With Olanzapine. Journal of Clinical Psychopharmacology, 36 2, 180–181.
Wang, H., Wang, H., & Liu, Z. P. (2011). Agents that induce pseudo-allergic reaction. Drug Discoveries & Therapeutics, 5 5, 211–219.
Warren, C., Snow, T., Lee, A. S., Shah, M. M., Heider, A., Blomkalns, A., Betts, B., Buzzanco, A., Gonzalez, J. C., Chinthrajah, R., Do, E., Chang, I., Dunham, D., Lee, G. M., O’Hara, R., Park, H. K., Shamji, M., Schilling, L., Sindher, S., … Nadeau, K. (2021). Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System. JAMA Network Open, 4.
Winter, R., Bent, S. V. D., Esch, M., Wolkerstorfer, A., & Rustemeyer, T. (2019). Allergic Reaction to Red Cosmetic Lip Tattoo Treated With Hydroxychloroquine. Dermatitis.
Ильиных, Е. В., Владимиров, С. А., & Елисеев, М. С. (2017). Фебуксостат в терапии подагры: от теории к практике. Modern Rheumatology Journal, 11, 83–88.