What are the contraindications and side effects of hydroxychloroquine, including interactions with medications, herbal supplements, nutrients, and foods?

Hydroxychloroquine: Comprehensive Contraindications and Side Effects

Absolute Contraindications

Hydroxychloroquine is absolutely contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds. 1

Additional absolute contraindications include:

• Cardiac disease including heart failure and myocardial infarction 2
• Congenital or documented acquired QT prolongation 1
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency 3
• Pre-existing retinal or visual field deficits 3

Serious and Life-Threatening Side Effects

Cardiac Toxicity

• Fatal and life-threatening cardiomyopathy has been reported during both acute and chronic treatment 1
• Ventricular arrhythmias including torsades de pointes can occur, with risk increasing at higher drug concentrations 1
• QT interval prolongation is a significant concern requiring baseline ECG monitoring 2, 4, 1
• Patients may present with ventricular hypertrophy, pulmonary hypertension, conduction disorders including sick sinus syndrome, and bundle branch blocks 1
• Endomyocardial biopsy in multiple cases showed drug-induced phospholipidosis without inflammation or necrosis 1

Retinal Toxicity (Most Serious Long-Term Effect)

Irreversible retinal damage with potential vision loss is the most serious long-term adverse effect, occurring with prolonged use beyond 2 years. 4, 1

Risk factors for retinal toxicity include:

• Daily doses ≥5 mg/kg of actual body weight (not ideal body weight) 1, 5, 6
• Duration of use greater than 5 years 1, 5
• Cumulative dose >1,000 grams 7
• Renal impairment or chronic kidney disease stage 3 or greater 1, 8
• Concomitant tamoxifen citrate therapy (odds ratio 4.59) 5, 8
• Concurrent macular disease 1
• Older age at initiation (HR 5.68 for age ≥65 years vs <45 years) 8
• Female sex (HR 3.83 compared to males) 8

Quantified risk by dosage and duration:

• At doses >6 mg/kg/day: 21.6% cumulative incidence at 15 years 6
• At doses 5-6 mg/kg/day: 11.4% cumulative incidence at 15 years 6
• At doses ≤5 mg/kg/day: 2.7% cumulative incidence at 15 years, remaining <2% within first 10 years 5, 6
• Overall prevalence of 7.5% in long-term users, rising to almost 20% after 20 years at doses 4-5 mg/kg/day 5

Clinical presentation of retinopathy:

• Difficulty reading, decreased vision, missing central vision, glare, blurred vision, light flashes, metamorphopsia 9
• Can be asymptomatic initially 9
• Bull's-eye fundoscopic appearance (classic finding) 7, 9
• Field defects including paracentral, pericentral, central, and peripheral field loss 9
• In Asian patients, retinal toxicity may first appear outside the macula 1
• Pericentral pattern more common in Asian (HR 15.02) and Black patients (HR 5.51) 8
• Retinopathy can progress even after drug cessation in advanced cases 9

Rare accelerated onset: Cases of bull's-eye retinopathy have occurred with cumulative doses as low as 19.8 grams after only 2 months of therapy, despite absence of traditional risk factors 7

Common Side Effects (Generally Do Not Require Discontinuation)

• Gastrointestinal symptoms (generally infrequent at standard doses) 2, 4
• Headache 2, 4
• Dizziness 2, 4
• Blurred vision 2, 4
• Pruritus 2, 4
• Vortex keratopathy (corneal deposits) - benign but common 4, 9

Other Significant Side Effects

• Exacerbation of psoriasis - cases of psoriasis flare reported with antimalarial medications 3, 10, 4
• Photohypersensitivity to sunlight (both doxycycline and hydroxychloroquine can cause this) 3
• Rash (rare) 4
• Elevated liver enzymes (rare) 4
• Diarrhea (rare) 4
• Ciliary body involvement (benign) 9
• Lens opacities (benign) 9

Drug Interactions

Medications That Increase Risk

Avoid concomitant use with QT-prolonging agents as this significantly increases risk for ventricular arrhythmias 1

Specific drug interactions:

• Tamoxifen citrate - dramatically increases retinopathy risk (odds ratio 4.59) 5, 8
• D-penicillamine - leads to higher hydroxychloroquine levels 2
• Cimetidine - leads to higher hydroxychloroquine levels 2

Vaccine Interactions

• May interfere with antibody response to intradermal human diploid cell rabies vaccine 10, 2

Conditions Requiring Caution or Dose Adjustment

High-risk conditions requiring enhanced monitoring:

• Proarrhythmic conditions including bradycardia (<50 bpm) 1
• History of ventricular dysrhythmias 1
• Uncorrected hypokalemia and/or hypomagnesemia (must correct before use) 1
• Renal impairment - reduce dose by 25% if eGFR <30 ml/min per 1.73 m² 4
• Liver disease 9

Required Monitoring

Baseline Assessments

• Baseline ECG (mandatory due to QT prolongation risk) 2, 4
• G6PD testing in men of African, Asian, or Middle Eastern origin 4
• Baseline ophthalmologic examination within first year including best corrected distance visual acuity, automated threshold visual field of central 10 degrees, and spectral domain optical coherence tomography 1
• Correct electrolyte imbalances prior to use 1

Ongoing Monitoring

• Annual ophthalmologic screening beginning after 5 years for low-risk patients 4, 1
• Earlier and more frequent screening for high-risk patients (those with risk factors listed above) 4
• Periodic ophthalmologic examinations for extended use (>6 years cumulative weekly prophylaxis for malaria) 10
• Cardiac function monitoring as clinically indicated 1
• For chronic Q fever treatment: monthly serologic testing and clinical evaluations, with monthly hydroxychloroquine plasma level monitoring (target 0.8-1.2 μg/mL) if inadequate response 3

Special Populations

Pregnancy

• Hydroxychloroquine has been used during pregnancy for connective tissue diseases without increased complications compared to untreated pregnancies 2

Pediatric Patients

• Not recommended in children <31 kg because the lowest available strength (200 mg tablet) exceeds recommended dose and cannot be divided 1
• Limited information available on use in children, though antimalarial agents have been used for rheumatologic diseases in children for many years 2

Food and Nutrient Interactions

Administer with food or milk to minimize gastrointestinal side effects 1

No specific herb, nutrient, or food contraindications are documented in the guideline or FDA labeling evidence provided.

Critical Safety Actions

Discontinue hydroxychloroquine immediately if:

• Cardiotoxicity is suspected or demonstrated by tissue biopsy 1
• Retinopathy is detected on screening 9

Do not crush or divide tablets 1

The recommended dose should not be exceeded as QT prolongation magnitude increases with drug concentration 1