Hydroxychloroquine: From Pharmacological Profile to Neglected Adverse Reactions

Year 2020, Volume: 4 Issue: 3, 205 - 211, 01.09.2020

Sevgi Akarsu

Abstract

The effectiveness of hydroxychloroquine (HCQ) has been increasingly recognized in nearly all major fields of medicine. This ancient but
still indispensable drug has a high bioavailability and a very long half-life due to its large volume of distribution. Although HCQ is generally
considered a safe and well-tolerated drug, it can sometimes cause mild and reversible reactions that do not require treatment interruption
such as gastrointestinal discomfort, photosensitivity and cutaneous findings. However, long-term treatment and high cumulative doses of HCQ
may rarely lead to severe adverse reactions (including retinal, neuromuscular, cardiac and auditory toxicities) which are considered serious
and require drug discontinuation but unfortunately not always reversible. The interaction of HCQ with other drugs (and vice versa) is also
an important clinical issue. It has been emphasized that caution should be used in prescribing medications concurrently with HCQ, such as
drugs that prolong QT interval and other arrhythmogenic drugs, drugs known to induce retinal toxicity, insulin or other antidiabetics, digoxin,
cyclosporine, drugs used to treat myasthenia gravis and drugs known to lower the convulsive threshold. In this article, the pharmacological
properties, clinically significant drug interactions as well as frequent and rare adverse reactions of HCQ have been reviewed in detail.
Keywords: hydroxychloroquine, antimalarial, pharmacokinetic, drug interaction, adverse reaction

Keywords

hydroxychloroquine, antimalarial, pharmacokinetic, drug interaction, adverse reaction

References

• 1. Van Beek MJ, Piette WW. Antimalarials. Dermatol Clin 2001;19:147– 160. [CrossRef]
• 2. Jancinová V, Nosál R, Petríková M. On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb Res 1994;74:495– 504. [CrossRef]
• 3. Hage MP, Al-Badri MR, Azar ST. A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti-inflammatory role. Ther Adv Endocrinol Metab 2014;5:77–85. [CrossRef]
• 4. Li R, Lin H, Ye Y, et al. Attenuation of antimalarial agent hydroxychloroquine on TNF-α-induced endothelial inflammation. Int Immunopharmacol 2018;63:261–269. [CrossRef]
• 5. Xu R, Ji Z, Xu C, Zhu J. The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: A systematic review and meta-analysis. Medicine (Baltimore) 2018;97:e12912. [CrossRef]
• 6. Shukla AM, Shukla AW. Expanding horizons for clinical applications of chloroquine, hydroxychloroquine, and related structural analogues. Drugs Context 2019;8. pii:2019–9–1. [CrossRef]
• 7. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020;16:155–166. [CrossRef]
• 8. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother 2020;75:1667–1670. [CrossRef]
• 9. Al-Bari AA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015;70:1608– 1621. [CrossRef ] 10. Haładyj E, Sikora M, Felis-Giemza A, Olesińska M. Antimalarialsare they effective and safe in rheumatic diseases? Reumatologia 2018;56:164–173. [CrossRef]
• 11. Fiehn C, Ness T, Weseloh C, et al. Safety management in treatment with antimalarials in rheumatology. Interdisciplinary recommendations on the basis of a systematic literature review. Z Rheumatol 2020. [CrossRef]
• 12. Graham Dukes MN. Chloroquine and hydroxychloroquine. In: Aranson JK, Meyler L, editors. Meyler’s side effects of drugs. The International Encyclopedia of Adverse Drug Reactions and Interactions, 15th ed. Amsterdam: Elsevier Science; 2016. p.253–267. [CrossRef]
• 13. Kalia S, Dutz JP. New concepts in antimalarial use and mode of action in dermatology. Dermatol Ther 2007;20:160–174. [CrossRef]
• J Basic Clin Health Sci 2020; 4:205-211 Akarsu S. Hydroxychloroquine-related adverse reactions 211 14. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf 2018;41:919–931. [CrossRef]
• 15. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmol 2016;123:1386–1394. [CrossRef]
• 16. Ezra N, Jorizzo J. Hydroxychloroquine and smoking in patients with cutaneous lupus erythematosus. Clin Exp Dermatol 2012;37:327– 334. [CrossRef]
• 17. Lee JY, Lee J, Kwok SK, Ju JH, Park KS, Park SH. Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2017;69:536–542. [CrossRef]
• 18. Spinelli FR, Moscarelli E, Ceccarelli F, et al. Treating lupus patients with antimalarials: analysis of safety profile in a single-center cohort. Lupus 2018;27:1616–1623. [CrossRef]
• 19. Bethel M, Yang FM, Li S, et al. Hydroxychloroquine in patients with systemic lupus erythematosus with end- stage renal disease. J Investig Med 2016;64:908–910. [CrossRef]
• 20. Borden MB, Parke AL. Antimalarial drugs in systemic lupus erythematosus: use in pregnancy. Drug Saf 2001;24:1055–1063. [CrossRef]
• 21. Costedoat-Chalumeau N, Amoura Z, Huong DLT, Lechat P, Piette JC. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature. Autoimmun Rev 2005;4:111– 115. [CrossRef]
• 22. Peng W, Liu R, Zhang L, Fu Q, Mei D, Du X. Breast milk concentration of hydroxychloroquine in Chinese lactating women with connective tissue diseases. Eur J Clin Pharmacol 2019;75:1547–1553. [CrossRef]
• 23. Andreoli L, Bertsias GK, Agmon-Levin N, et al. EULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017;76:476–485. [CrossRef]
• 24. Guillotin V, Bouhet A, Barnetche T, et al. Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: A systematic review and meta-analysis. Joint Bone Spine 2018;85:663–668. [CrossRef]
• 25. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti- SSA/Ro- antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012;126:76–82. [CrossRef]
• 26. Kaplan YC, Ozsarfati J, Nickel C, Koren G. Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis. Br J Clin Pharmacol 2016;81:835–848. [CrossRef]
• 27. Chew CY, Mar A, Nikpour M, Saracino AM. Hydroxychloroquine in dermatology: New perspectives on an old drug. Australas J Dermatol 2020;61:e150–e157. [CrossRef]
• 28. Tal Y, Maoz Segal R, Langevitz P, Kivity S, Darnizki Z, Agmon-Levin N. Hydroxychloroquine desensitization, an effective method to overcome hypersensitivity-a multicenter experience. Lupus 2018;27:703–707. [CrossRef]
• 29. Sharma AN, Mesinkovska NA, Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review. J Am Acad Dermatol 2020;83:563–578. [CrossRef]
• 30. Matsuda T, My Ly NT, Kambe N, et al. Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A case report and review of the published work. J Dermatol 2018;45:344– 348. [CrossRef]
• 31. Bahloul E, Jallouli M, Garbaa S, et al. Hydroxychloroquine-induced hyperpigmentation in systemic diseases: prevalence, clinical features and risk factors: a cross-sectional study of 41 cases. Lupus 2017;26:1304–1308. [CrossRef]
• 32. Coulombe J, Boccara O. Hydroxychloroquine-related skin discoloration. CMAJ 2017;189:E212. [CrossRef]
• 33. Sawalha AH. Hydroxychloroquine-induced hyperpigmentation of the skin. J Rheumatol 2015;42:135–136. [CrossRef]
• 34. Pai SB, Sudershan B, Kuruvilla M, Kamath A, Suresh PK. Hydroxychloroquine-induced erythroderma. Indian J Pharmacol 2017;49:132–134. [CrossRef]
• 35. Schwartz RA, Janniger CK. Generalized pustular figurate erythema: a newly delineated severe cutaneous drug reaction linked with hydroxychloroquine. Dermatol Ther 2020;33:e13380. [CrossRef] 36. Mohammad S, Clowse MEB, Eudy AM, Criscione-Schreiber LG. Examination of hydroxychloroquine use and hemolytic anemia in G6PDH-deficient patients. Arthritis Care Res (Hoboken) 2018;70:481– 485. [CrossRef]
• 37. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132:1453–1460. [CrossRef]
• 38. Jorge A, Ung C, Young LH, Melles RB, Choi HK. Hydroxychloroquine retinopathy --implications of research advances for rheumatology care. Nat Rev Rheumatol 2018;14:693–703. [CrossRef]
• 39. Mititelu M, Wong BJ, Brenner M, Bryar PJ, Jampol LM, Fawzi AA. Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging. JAMA Ophthalmol 2013;131:1187–97. [CrossRef]
• 40. Geamănu Pancă A, Popa-Cherecheanu A, Marinescu B, Geamănu CD, Voinea LM. Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. J Med Life 2014;7:322– 326. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233433/
• 41. Espandar G, Moghimi J, Ghorbani R, Pourazizi M, Seiri MA, Khosravi S. Retinal toxicity in patients treated with hydroxychloroquine: a cross-sectional study. Med Hypothesis Discov Innov Ophthalmol 2016;5:41–46. https://europepmc.org/backend/ptpmcrender. fcgi?accid=PMC5347188&blobtype=pdf
• 42. Demir D, Öcal F, Abanoz M, Dermenci H. A case of thrombocytopenia associated with the use of hydroxychloroquine following open heart surgery. Int J Surg Case Rep 2014;5:1282–1284. [CrossRef]
• 43. Radke JB, Kingery JM, Maakestad J, Krasowski MD. Diagnostic pitfalls and laboratory test interference after hydroxychloroquine intoxication: A case report. Toxicol Rep 2019;6:1040–1046. [CrossRef]
• 44. Yogasundaram H, Putko BN, Tien J, et al. Hydroxychloroquineinduced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment. Can J Cardiol 2014;30:1706–1715. [CrossRef]
• 45. Kwon JB, Kleiner A, Ishida K, Godown J, Ciafaloni E, Looney RJ Jr. Hydroxychloroquine-induced myopathy. J Clin Rheumatol 2010;16:28–31. [CrossRef]
• 46. Tselios K, Gladman DD, Su J, Urowitz MB. Antimalarials as a risk factor for elevated muscle enzymes in systemic lupus erythematosus. Lupus 2016;25:532–535. [CrossRef]
• 47. de Novaes Fernandes MR, Rosa Soares DB, Thien CI, Carneiro S. Hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus. An Bras Dermatol 2018;93:469–470. [CrossRef]
• 48. Jourde-Chiche N, Mancini J, Dagher N, et al. Antimalarial ototoxicity: an underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network. Ann Rheum Dis 2012;71:1586. [CrossRef]
• 49. Karasic TB, O’Hara MH, Loaiza-Bonilla A, et al. Effect of gemcitabine and nab-Paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol 2019;5:993–998. [CrossRef]
• 50. Mao IC, Lin CY, Wu CL, Kor CT, Chang CC. Hydroxychloroquine and risk of development of cancers: a nationwide population-based cohort study. Ther Clin Risk Manag 2018;14:1435–1443. [CrossRef]