What are the adverse effects of hydroxychloroquine?

Hydroxychloroquine Side Effects

Hydroxychloroquine causes a spectrum of adverse effects ranging from common gastrointestinal symptoms to serious, potentially irreversible retinal and cardiac toxicity that require systematic monitoring.

Most Common Side Effects

Gastrointestinal disturbances—including nausea, vomiting, diarrhea, and stomach discomfort—are the most frequently reported side effects and account for most treatment intolerances. 1, 2

• Headache occurs commonly with oral hydroxychloroquine therapy 1, 3
• Pruritus and urticaria (itching and hives) are frequently reported 1, 4
• Dizziness may occur as a side effect 1
• Visual disturbances, including blurred vision and diplopia, may develop but typically reverse with discontinuation 1

Critical Dose-Limiting Toxicity: Retinopathy

Irreversible retinal damage represents the most serious dose-limiting adverse effect of hydroxychloroquine, caused by drug binding to melanin in the retinal pigment epithelium. 1, 5

Risk Factors and Prevalence

• The overall prevalence of hydroxychloroquine retinopathy is 7.5%, but this varies dramatically with dosage and duration 6
• Risk remains less than 2% within the first 10 years when daily doses stay at 4.0-5.0 mg/kg actual body weight, but rises to almost 20% after 20 years of use 6
• Daily doses exceeding 5 mg/kg of actual body weight significantly increase risk (odds ratio 5.67) 1, 6
• Renal impairment increases risk due to decreased drug excretion (odds ratio 2.08) 1, 6
• Concomitant tamoxifen therapy substantially increases risk (odds ratio 4.59) 1, 6
• Asian patients typically show extramacular damage near the arcades, while European-descent patients show parafoveal involvement 7

Monitoring Requirements

• Baseline ophthalmologic examination within the first year is mandatory, including best corrected distance visual acuity, automated threshold visual field testing of the central 10 degrees, and spectral domain optical coherence tomography. 5
• Annual ophthalmologic examinations are required for all patients on antimalarial therapy, though can be deferred until 5 years in patients without significant risk factors 1, 5
• For Asian patients, visual field testing should be performed in the central 24 degrees instead of the central 10 degrees 5
• Retinopathy can progress even after drug discontinuation, making early detection critical. 7

Dosing to Minimize Risk

• Daily doses should not exceed 5 mg/kg of actual body weight 1
• Corneal deposits (verticillata/vortex keratopathy) can occur but are reversible and not associated with vision loss 1, 7

Cardiovascular Toxicity

Hydroxychloroquine causes multiple cardiac complications including conduction abnormalities, QT prolongation, cardiomyopathy, and heart failure—not vasovagal syncope. 8, 5

Acute Cardiac Effects

• QT/QTc prolongation is a significant concern, particularly when combined with azithromycin 5, 2
• The magnitude of QT prolongation increases with increasing drug concentrations 5
• Ventricular arrhythmias including torsades de pointes have been reported 5
• Cardiovascular effects may progress through vasodilation, hypotension, suppressed myocardial function, cardiac arrhythmia, and cardiac arrest, particularly with parenteral administration or overdose 1

Chronic Cardiac Effects

• Conduction disorders are the predominant cardiac complication, affecting 85% of patients with hydroxychloroquine cardiotoxicity 8
• ECG abnormalities include widening of QRS interval, T-wave changes, bundle branch blocks, and atrioventricular blocks 8, 7, 2
• Cardiomyopathy and heart failure can develop with long-term use 8, 2
• Patients may present with ventricular hypertrophy, pulmonary hypertension, and sick sinus syndrome 5

Contraindications and Monitoring

• Avoid hydroxychloroquine in patients with congenital or acquired QT prolongation, cardiac disease (heart failure, myocardial infarction), proarrhythmic conditions (bradycardia <50 bpm), history of ventricular dysrhythmias, or uncorrected hypokalemia/hypomagnesemia. 5
• Concomitant use of ondansetron >8mg, domperidone, and citalopram is contraindicated due to torsades de pointes risk 1, 7
• Many tyrosine kinase inhibitors (cabozantinib, ceritinib, crizotinib, nilotinib, osimertinib, vandetanib, vemurafenib) and other medications increase QT interval and require caution 7
• Correct electrolyte imbalances prior to use and monitor cardiac function as clinically indicated 5
• Some clinicians perform yearly ECGs in asymptomatic patients, especially those on long-term therapy 1
• Discontinue hydroxychloroquine immediately if any cardiac manifestations are present, as conduction disorders may represent initial manifestations of potentially irreversible toxicity. 8

Serious Dermatologic Reactions

Serious skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, and acute generalized exanthematous pustulosis have been reported. 5, 2, 3

• Drug eruption or rash is the most common dermatologic adverse effect, occurring in 358 of 689 reported cases, typically within 4 weeks of initiating therapy and resolving within weeks of discontinuation 3, 4
• Cutaneous hyperpigmentation occurs in 116 reported cases 4
• Skin hyperpigmentation, discoloration of nail beds and mucous membranes can develop 7
• Hair bleaching occurs in blonde and red-haired individuals 7, 9
• Hair loss has been reported in 12 cases 4
• Stomatitis occurred in 11 cases 4
• Discontinue hydroxychloroquine if severe skin reactions occur. 5

Psoriasis Exacerbation

• Hydroxychloroquine may precipitate a severe flare-up of psoriasis 5
• Avoid hydroxychloroquine in patients with psoriasis unless the benefit outweighs the possible risk. 5

Hematologic Toxicity

• Hydroxychloroquine may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia 5
• Monitor blood cell counts periodically in patients on prolonged therapy 5
• Hemolysis can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, particularly in association with other drugs that cause hemolysis. 5, 2

Neuropsychiatric and Neuromuscular Toxicity

• Confusion, disorientation, and hallucination may occur within 24-48 hours of drug initiation 2
• CNS effects may progress through confusion, convulsions, and coma (more common in overdose) 1
• Toxic myopathy, peripheral neuropathy, and extremity weakness can occur with prolonged therapy but improve if the drug is promptly withdrawn 1, 7, 2
• Peripheral neuropathy risk increases when combined with platinum salts, anthracyclines, taxanes, or immunomodulators, especially with diabetes or alcohol abuse 7
• Pseudoparkinsonism has been rarely reported 2

Ototoxicity

• Irreversible ototoxicity can develop if oral doses exceed 250 mg/day. 1
• Hydroxychloroquine binds to melanin in inner-ear structures, leading to damage of cochlear and vestibular tissues and producing audiovestibular symptoms such as tinnitus and hearing loss 1
• The antimalarial regimen (800 mg loading dose followed by 400 mg at 6h, 24h, and 48h) represents standard short-term dosing; higher or prolonged regimens carry substantially greater ototoxicity risk 1

Hepatotoxicity

Cases of hepatotoxicity have been reported when hydroxychloroquine was used in patients with porphyria cutanea tarda, with marked elevations in transaminases (>20 times upper limit) within days to a month of initiation. 5

• Measure liver tests promptly in patients reporting symptoms of liver injury (fatigue, rash, nausea, dark urine, jaundice) 5
• If ALT exceeds three times the upper limit or total bilirubin exceeds two times the upper limit, interrupt treatment and investigate further 5

Metabolic Effects

• Alterations in blood glucose concentrations may occur but are rare with standard therapeutic use 2
• Hypoglycemia can develop, particularly in patients with diabetes 2

Renal Considerations

• Patients with renal insufficiency require lower doses and closer monitoring due to increased systemic levels 1
• Nephrotoxicity requires dose adjustment with reduced glomerular filtration rate 1

Drug Interactions

• CYP2D6 and P-glycoprotein inhibition requires intensified monitoring with gefitinib and tamoxifen 7
• D-penicillamine and cimetidine lead to higher hydroxychloroquine levels 7
• Chloroquine may interfere with intradermal rabies vaccine antibody response 1

Overdose

Deaths from overdoses most often result from cardiovascular collapse, with symptoms manifesting rapidly (minutes to hours). 2

• Cardiovascular shock and collapse are most prominent in overdose 2
• Neurotoxic effects such as psychosis and seizure may also occur 2
• The lethal dose is approximately 1 g for children and 4 g for adults 9

Special Populations

• Hydroxychloroquine is pregnancy category C, but all women with systemic lupus erythematosus should take it during pregnancy if possible, and if already taking it, should strongly continue during pregnancy 1, 7
• Hydroxychloroquine is present in human milk at low levels, but no adverse reactions have been reported in breastfed infants 1
• Limited safety information is available in pediatrics, though antimalarial agents have been used for rheumatologic diseases in children for many years 7

Key Clinical Pitfalls

• Do not stop hydroxychloroquine casually for borderline findings; the goal is to safely maintain use of this valuable medication for as long as possible. 1
• Do not attribute syncope to vasovagal mechanisms in hydroxychloroquine users without excluding cardiac causes through ECG and echocardiography 8
• Do not continue hydroxychloroquine if QTc exceeds 500 ms or any conduction abnormalities develop, as this represents unacceptable arrhythmia risk 8
• Store hydroxychloroquine where it is absolutely inaccessible to children due to rapid lethality in acute overdose 9