What are the potential side effects of Hydroxychloroquine (HCQ) therapy?

Hydroxychloroquine Side Effects

Hydroxychloroquine is generally well-tolerated at appropriate doses, but carries specific dose-dependent and time-dependent toxicities that require systematic monitoring, with retinopathy being the most serious long-term concern and cardiac toxicity (QT prolongation, cardiomyopathy, conduction abnormalities) representing the most critical acute and chronic risk. 1

Most Common Side Effects

Gastrointestinal Effects

• Nausea, vomiting, diarrhea, and stomach discomfort are the most frequently reported side effects, occurring in the short term (days to weeks) and accounting for most reported intolerances 2, 3
• These gastrointestinal disturbances typically occur early in treatment 4

Neurological Effects

• Headache occurs commonly with oral hydroxychloroquine therapy 4, 2
• Dizziness may develop during treatment 4, 2
• Blurred vision and diplopia (double vision) can occur but typically reverse with discontinuation 2

Dermatologic Effects

• Pruritus (itching) and urticaria (hives) are reported side effects 2
• Drug eruptions or rashes may occur within days to weeks of exposure but usually resolve with discontinuation 3
• Cutaneous hyperpigmentation can develop 3
• Hydroxychloroquine may exacerbate psoriasis 2

Critical Dose-Limiting Toxicities

Retinal Toxicity (Most Serious Long-Term Risk)

Irreversible retinal damage is the major dose-limiting toxicity with long-term use, related to cumulative dosage and treatment duration 1

Risk Factors for Retinopathy:

• Daily doses ≥5 mg/kg of actual body weight 5, 1
• Duration of use greater than 5 years 1
• Renal impairment (drug is excreted in urine) 5
• Concomitant use of tamoxifen 5
• Concurrent macular disease 1

Prevalence and Risk Timeline:

• At doses ≤5.0 mg/kg actual body weight, retinopathy develops in fewer than 2% of patients with usage up to 10 years 5
• Higher daily doses increase risk to approximately 10% after 10 years, with continued rise in risk with longer duration 5
• Risk increases sharply toward 1% after 5 to 7 years of use or cumulative dose of 1000g 6

Monitoring Requirements:

• Baseline ocular examination within the first year of starting hydroxychloroquine, including best corrected distance visual acuity (BCVA), automated threshold visual field (VF) of central 10 degrees, and spectral domain optical coherence tomography (SD-OCT) 1
• Annual screening should begin after 5 years of treatment (or sooner with unusual risk factors) 1, 6
• For patients at higher risk, annual examinations including BCVA, VF, and SD-OCT are required 1
• In patients of Asian descent, visual field testing should be performed in the central 24 degrees instead of central 10 degrees, as retinal toxicity may first be noticed outside the macula 1
• Mandatory ophthalmologic assessment every 6 to 12 months for all patients on long-term therapy 2

Cardiac Toxicity (Most Critical Acute and Chronic Risk)

Fatal and life-threatening cardiotoxicity, including cardiomyopathy, has been reported during both acute and chronic treatment 1

Acute Cardiac Effects:

• QT interval prolongation with risk of torsades de pointes (life-threatening ventricular arrhythmia) 5, 1
• ECG monitoring is mandatory when hydroxychloroquine is used, particularly with concomitant QT-prolonging drugs 5
• The magnitude of QT prolongation increases with increasing drug concentrations 1

Chronic Cardiac Effects:

• Cardiomyopathy with phospholipidosis (confirmed on endomyocardial biopsy) 1
• Ventricular hypertrophy and pulmonary hypertension 1
• Conduction disorders are the predominant cardiac complication, affecting 85% of patients with hydroxychloroquine cardiotoxicity, including bundle branch blocks, QRS widening, and atrioventricular blocks 7
• Sick sinus syndrome 1
• Conduction abnormalities, cardiomyopathy, and valvular disorders with long-term use 3

Contraindications and Precautions:

• 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 1
• Not recommended in patients taking other QT interval-prolonging agents 1
• Correct electrolyte imbalances prior to use 1
• Discontinue hydroxychloroquine immediately if cardiotoxicity is suspected or demonstrated 1
• Yearly ECGs are performed by some clinicians in asymptomatic patients on long-term therapy 2

High-Risk Drug Combinations:

• Contraindicated with ondansetron (>8mg), domperidone, and citalopram due to torsades de pointes risk 5
• Many tyrosine kinase inhibitors (cabozantinib, ceritinib, crizotinib, nilotinib, osimertinib, vandetanib, vemurafenib), oxaliplatin, and arsenic trioxide seriously increase QT interval 5
• Azithromycin combination increases QT prolongation risk 3

Other Serious Long-Term Toxicities

Neuromuscular Toxicity

• Toxic myopathy, peripheral neuropathy, and muscle weakness can occur with prolonged therapy but generally improve if the drug is promptly withdrawn 4, 2
• Risk of peripheral neuropathy increases when combined with platinum salts, anthracyclines, taxanes, and immunomodulators, especially with comorbidities like diabetes or chronic alcohol abuse 5
• Rarely: extremity weakness and pseudoparkinsonism 3

Neuropsychiatric Effects

• Confusion, disorientation, and hallucinations may occur within 24-48 hours of drug initiation 3
• CNS effects can progress through confusion, convulsions, and coma (more common in overdose) 2

Hematologic Effects

• Hemolysis and anemia may occur in patients with glucose-6-phosphate dehydrogenase deficiency 3

Metabolic Effects

• Alterations in blood glucose concentrations may occur but are rare with standard therapeutic use 3
• Hypokalemia can develop, particularly with corticosteroids, cisplatin, or digestive disorders 5

Renal and Hepatic Effects

• Reduced renal function is the greatest additional risk factor for toxicity, as the drug is excreted in urine and renal insufficiency increases systemic HCQ levels 5
• Patients with renal insufficiency need lower doses and closer monitoring 5
• Nephrotoxicity and hepatotoxicity require dose adjustment with reduced glomerular filtration rate or transaminase elevation 5

Other Rare Toxicities

• Irreversible ototoxicity can develop if oral doses exceed 250 mg/day 2
• Stevens-Johnson syndrome and toxic epidermal necrolysis may occur 3
• Vortex keratopathy (corneal deposits) can develop 2
• Ocular toxicity risk increases when combined with MEK inhibitors 5

Drug Interactions

Pharmacokinetic Interactions

• Hydroxychloroquine is a weak inhibitor of CYP2D6 and P-glycoprotein efflux protein, requiring intensified monitoring with narrow-window drugs like gefitinib and tamoxifen 5
• Concomitant use with tamoxifen increases retinopathy risk 5

Overdose Toxicity

Symptoms manifest rapidly (minutes to hours) with cardiovascular shock and collapse being most prominent 3

• Cardiovascular toxicity including QRS or QTc prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes, atrioventricular block, cardiac arrest, and death 1
• Life-threatening hypotension is common 1
• Severe hypokalemia secondary to intracellular shift 1
• CNS depression, seizures, visual disturbances, transient blindness, and coma 1
• Deaths from overdoses most often result from cardiovascular collapse 3

Special Populations

Pregnancy and Lactation

• Hydroxychloroquine readily crosses the placenta with cord blood levels corresponding to maternal plasma levels 1
• No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children exposed in utero 1
• All women with SLE should take hydroxychloroquine during pregnancy if possible, and if already taking it, strongly continue during pregnancy 5
• Present in human milk at low levels with no adverse reactions reported in breastfed infants 1

Pediatric Patients

• Safety and effectiveness established for malaria treatment and prophylaxis in pediatric patients ≥31 kg 1
• Cannot be administered to patients <31 kg because film-coated tablets cannot be crushed or divided 1
• Safety and effectiveness not established for rheumatoid arthritis or lupus in pediatric patients 1

Geriatric Patients

• Drug is substantially excreted by kidney; risk of toxic reactions greater in patients with impaired renal function 1
• Dose selection should start with lowest recommended dose, considering decreased hepatic, renal, or cardiac function 1

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 5
• Do not attribute syncope to vasovagal mechanisms in hydroxychloroquine users without excluding cardiac causes through ECG and echocardiography 7
• Do not continue hydroxychloroquine if QTc exceeds 500 ms or any conduction abnormalities develop 7
• Visible "bull's-eye" maculopathy represents advanced retinal damage that should no longer occur with proper screening 5
• Severe laboratory abnormalities while taking hydroxychloroquine are rare (3% persistent severe abnormalities), and most are likely due to disease progression or other medications rather than hydroxychloroquine itself 8