What are the adverse effects of hydroxychloroquine?

Adverse Effects of Hydroxychloroquine

Hydroxychloroquine causes a spectrum of adverse effects ranging from common, reversible gastrointestinal symptoms to rare but potentially irreversible retinal toxicity, cardiac complications, and serious skin reactions that require systematic monitoring and prompt recognition.

Most Critical Adverse Effects (Prioritized by Morbidity/Mortality)

Cardiac Toxicity

Cardiomyopathy and ventricular arrhythmias represent the most life-threatening complications 1. Hydroxychloroquine prolongs the QT interval and can cause:

• Conduction disorders (affecting 85% of cardiac toxicity cases) including heart block and sick sinus syndrome 2
• Ventricular arrhythmias including torsades de pointes 3, 1
• Cardiomyopathy with ventricular hypertrophy (22% of cardiac cases) and heart failure (26.8%) 2
• Cardiovascular collapse progressing through vasodilation, hypotension, suppressed myocardial function, cardiac arrhythmia, and cardiac arrest 4

Critical context: Among 127 patients with cardiac complications, 30.8% died and 12.9% had irreversible damage despite drug withdrawal 2. Median treatment duration before cardiac toxicity was 7 years with high cumulative doses 2.

Irreversible Retinal Toxicity

Retinopathy is the most significant ocular complication, potentially causing permanent vision loss 5, 1. The 2016 AAO guidelines demonstrate:

• Overall prevalence of 7.5% in patients using HCQ >5 years 5
• Risk dramatically increases with doses >5.0 mg/kg actual body weight 5, 6
• Risk escalates with duration: <2% at 10 years with proper dosing, but ~10% at 10 years with higher doses 6
• Retinopathy can progress even after drug discontinuation 5, 1

Racial variation matters: Asian patients typically show extramacular (peripheral) damage first, while European-descent patients show parafoveal patterns 5.

Serious Skin Reactions

Life-threatening dermatologic reactions include 1, 7:

• Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (26 reported cases) 8
• Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) 1, 7
• Acute generalized exanthematous pustulosis (AGEP) (27 cases) 8

These typically occur within 3 months of drug initiation 9.

Common Adverse Effects

Gastrointestinal Effects

The most frequent side effects are generally mild and reversible 4, 10:

• Nausea, vomiting, abdominal pain, diarrhea
• GI upset occurred in 9.5% receiving lopinavir/ritonavir combination therapy 11
• These rarely require drug discontinuation 10

Dermatologic Effects (Non-Life-Threatening)

Common skin manifestations include 4, 8:

• Drug eruption/rash (358 cases, most common) 8
• Cutaneous hyperpigmentation (116 cases) - affecting nail beds and mucous membranes 4, 8
• Pruritus (62 cases in HCQ; 464+ cases with chloroquine) 8, 9
• Hair bleaching and alopecia (12 cases) 4, 8
• Psoriasis exacerbation - HCQ can precipitate severe flare-ups 1

Neurological Effects

• Headache, dizziness, blurred vision (common, usually reversible) 4, 10
• Confusion, convulsions (with prolonged use) 4
• Ataxia, seizures, extrapyramidal disorders (dystonia, dyskinesia, tremor) 1

Neuropsychiatric Effects

Recent evidence highlights significant psychiatric complications 12:

• Psychosis, hallucinations, delusions, paranoia 1, 12
• Suicidal ideation and behavior 1, 12
• Depression, anxiety, mood changes 1, 12
• Mania/hypomania, agitation, confusion 1, 12
• Sleep disorders (insomnia, night terrors, nightmares) 1

These typically occur within the first month of treatment and may require several weeks off drug for symptom resolution due to long half-life 1.

Dose-Dependent and Chronic Use Toxicities

Irreversible Toxicities with Prolonged Use

When doses exceed 250 mg/day or with chronic use 4:

• Irreversible retinopathy and ototoxicity 4
• Toxic myopathy - progressive weakness, atrophy of proximal muscles, depressed reflexes 1
• Peripheral neuropathy - abnormal nerve conduction 4, 1
• These improve if drug is promptly withdrawn 4

Hematologic Toxicity

• Myelosuppression including aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia 1
• Hemolytic anemia in G6PD-deficient patients 1

Hepatotoxicity

• Elevated transaminases (23% in remdesivir study, but also reported with HCQ) 11
• Severe hepatotoxicity in porphyria cutanea tarda - marked transaminase elevations (>20× ULN) within days to one month 1

Metabolic Effects

• Severe, potentially life-threatening hypoglycemia - can occur with or without antidiabetic agents 1
• Enhanced effects of insulin and antidiabetic drugs 1

Renal Toxicity

• Proteinuria with or without reduced GFR 1
• Renal biopsy shows phospholipidosis without immune deposits 1
• Renal disease increases circulating drug levels and toxicity risk 5, 6

Critical Monitoring Requirements

Baseline and Ongoing Assessments

Ocular monitoring 4, 5, 6:

• Baseline exam within first year: BCVA, automated VF (central 10°), SD-OCT
• Annual exams after 5 years for low-risk patients
• Annual exams from start for high-risk patients (>5 mg/kg, renal disease, Asian descent)
• For Asian patients: VF testing of central 24° instead of 10° 5

Cardiac monitoring 4, 1:

• Baseline ECG
• Correct electrolyte imbalances (hypokalemia, hypomagnesemia) before starting
• Monitor cardiac function periodically, especially with yearly ECGs
• Avoid in patients with QT prolongation, heart failure, bradycardia <50 bpm 1

Other monitoring 4, 1:

• Periodic CBC for myelosuppression
• Muscle strength and deep tendon reflexes
• Liver function tests (especially in porphyria cutanea tarda)
• Blood glucose monitoring
• G6PD testing before use 10

Drug Interactions Increasing Risk

Contraindicated or high-risk combinations 1:

• QT-prolonging drugs (azithromycin, other antiarrhythmics) - increases torsades de pointes risk 3
• Antidiabetic agents - enhances hypoglycemic effects 1
• Mefloquine - lowers seizure threshold 1
• D-penicillamine and cimetidine - increase HCQ levels 4

Special Populations

Pregnancy: Pregnancy class C; appears safe when clinically indicated (117 live births from 133 pregnancies with no difference vs. controls) 4

Pediatrics: Generally believed safe but limited information available 4

Renal impairment: Dramatically increases toxicity risk; requires dose adjustment and closer monitoring 5, 6

Porphyria: Avoid use - can exacerbate porphyria and cause severe hepatotoxicity 1

Psoriasis: Avoid unless benefit outweighs risk - can precipitate severe flare-ups 1