Hydroxychloroquine: From Pharmacological Profile to Neglected Adverse Reactions
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
___
- 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]