What are the guidelines for using hydroxychloroquine (HCQ) preparations?

Hydroxychloroquine Preparations: Dosing and Monitoring Guidelines

Dosing Recommendations

The maximum daily dose of hydroxychloroquine should not exceed 5.0 mg/kg based on actual body weight to minimize the risk of irreversible retinal toxicity. 1, 2

Standard Dosing for Rheumatic Diseases

• For systemic lupus erythematosus and chronic discoid lupus erythematosus: 200 mg once daily OR 400 mg once daily (or divided into two 200 mg doses) 2
• The 400 mg daily dose is acceptable for most patients, but individuals of short stature require dose calculation based on actual body weight to avoid overdosage 1
• Tablets should be taken with food or milk and must not be crushed or divided 2

Chloroquine Dosing (When HCQ Unavailable)

• Maximum dose: ≤2.3 mg/kg/day of actual body weight 1
• Chloroquine appears more toxic than hydroxychloroquine, though pharmacologic equivalence data are limited 1
• Intermediate doses can be achieved by splitting tablets or eliminating doses on certain days of the week, as blood levels stabilize over many weeks 1

Baseline and Monitoring Requirements

Baseline Examination (Within First Year)

A comprehensive baseline ophthalmologic examination must be performed within the first year of starting hydroxychloroquine to rule out preexisting maculopathy and establish a reference point. 2

The baseline examination should include:

• Best corrected distance visual acuity (BCVA) 2
• Automated threshold visual field testing of the central 10 degrees (with retesting if abnormalities noted) 2
• Spectral domain optical coherence tomography (SD-OCT) 2

Annual Screening Schedule

• For patients without significant risk factors: Annual retinal examinations should begin after 5 years of treatment 1, 2
• For patients with major risk factors: Annual screening should begin earlier than 5 years 2

Annual screening should include:

• Best corrected distance visual acuity 2
• Automated visual field testing (10-2 fields, or 24 degrees for patients of Asian descent) 2
• Spectral domain optical coherence tomography 2

Special Population Considerations

• Asian descent patients: Visual field testing should be performed in the central 24 degrees instead of central 10 degrees, as retinal toxicity may first appear outside the macula 2
• Renal impairment: Reduce dose by 25% if eGFR <30 mL/min/1.73 m² 3, 4
• G6PD deficiency risk: Check G6PD levels in men of African, Asian, or Middle Eastern origin before starting treatment to avoid hemolysis 5, 4

Risk Factors for Retinal Toxicity

Major risk factors that increase the likelihood of retinopathy include:

• Daily dosage ≥5 mg/kg of actual body weight 2
• Duration of use greater than 5 years 2
• Renal impairment 2
• Concomitant use of tamoxifen citrate 2
• Concurrent macular disease 2

Toxicity Risk Over Time

• At ≤5.0 mg/kg/day: Risk of retinopathy is <2% for usage up to 10 years 1
• After 10 years at recommended dosing, risk increases to approximately 4% 1
• After 20 years at recommended dosing, risk increases to approximately 20% 1
• Higher daily doses substantially increase toxicity risk to ~10% after 10 years 1
• For patients with normal screening in a given year, the annual incremental risk of developing retinopathy remains low (<5%) even after 20 years of use 1

Cardiac Monitoring and Contraindications

Cardiac Risks

Fatal and life-threatening cardiotoxicity, including cardiomyopathy and ventricular arrhythmias (including torsades de pointes), have been reported with hydroxychloroquine. 2

• Hydroxychloroquine has potential to prolong the QT interval, with risk increasing at higher drug concentrations 2
• Patients may present with ventricular hypertrophy, pulmonary hypertension, conduction disorders including sick sinus syndrome, and bundle branch blocks 2

Contraindications and Avoidance

Avoid hydroxychloroquine in patients with:

• Congenital or documented acquired QT prolongation 2
• Cardiac disease (heart failure, myocardial infarction) 2
• Proarrhythmic conditions (bradycardia <50 bpm) 2
• History of ventricular dysrhythmias 2
• Uncorrected hypokalemia and/or hypomagnesemia 2
• Concomitant use of other QT-prolonging agents 2
• Known hypersensitivity to 4-aminoquinoline compounds 2
• Psoriasis (unless benefit outweighs risk, as severe flare-ups may occur) 2
• Porphyria (may exacerbate condition) 2

Cardiac Monitoring Recommendations

• Correct electrolyte imbalances prior to initiating therapy 2
• Monitor cardiac function as clinically indicated during treatment 2
• Discontinue hydroxychloroquine if cardiotoxicity is suspected or demonstrated by tissue biopsy 2

Management of Suspected Retinal Toxicity

If ocular toxicity is suspected, discontinue hydroxychloroquine immediately, as retinal damage is irreversible and changes may progress even after cessation of therapy. 2

• The decision to discontinue should be made in conjunction with the prescribing physician, as hydroxychloroquine should not be stopped casually for borderline findings 1
• Visible bull's-eye maculopathy represents late-stage toxicity; the goal of screening is to detect earlier changes 6
• Even subtle abnormalities on 10-2 visual field testing should be taken seriously and warrant evaluation with objective testing 6
• Monitor patients closely after discontinuation, as visual disturbances may continue to progress 2

Additional Safety Monitoring

Serious Skin Reactions

• Monitor for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), DRESS syndrome, and acute generalized exanthematous pustulosis (AGEP) 2
• Advise patients to seek immediate medical attention for blisters on skin, eyes, lips, or mouth, or unexplained itching/burning with or without fever 2
• Discontinue hydroxychloroquine if severe skin reactions occur 2

Hypoglycemia

• Hydroxychloroquine has been associated with severe hypoglycemia 2
• Advise patients to monitor blood glucose if possible and seek medical attention for symptoms including sweating, shakiness, weakness, dizziness, tachycardia, nausea, blurred vision, confusion, fainting, or loss of consciousness 2

Neuromuscular Toxicity

• Monitor for skeletal muscle myopathy, muscle weakness, and atrophy 2
• Alert patients to seek immediate medical attention for new or worsening depression, suicidal thoughts, or other mood changes 2

COVID-19 Context

Current evidence does not support the use of hydroxychloroquine for COVID-19 treatment or prophylaxis. 5, 4, 7

• The World Health Organization and Centers for Disease Control and Prevention do not recommend hydroxychloroquine for COVID-19 5, 4
• Despite initial in vitro activity against SARS-CoV-2, this did not translate to clinical benefit 5, 8
• The FDA rescinded its emergency use authorization for hydroxychloroquine from the Strategic National Stockpile on June 15,2020 9
• Patients with rheumatic diseases on chronic hydroxychloroquine should continue their medication during acute infections, including COVID-19, due to immunomodulatory effects and risk of disease flares 5

Common Pitfalls and Caveats

• Do not use ideal body weight for dosing calculations—this results in overdosage in thin individuals; always use actual body weight 1
• Do not avoid hydroxychloroquine for fear of retinopathy when appropriately indicated—at recommended doses with proper screening, it is considered safe and valuable for rheumatic diseases 1
• Do not delay baseline ophthalmologic examination—it must be completed within the first year to establish a reference and rule out contraindications 2
• Do not use Amsler grid testing for screening—it is no longer recommended; use automated visual fields and SD-OCT instead 6
• Do not prescribe hydroxychloroquine in patients with porphyria cutanea tarda—marked hepatotoxicity with transaminase elevations >20 times upper limit can occur within days to a month 2
• Do not combine with other QT-prolonging medications—this significantly increases risk of ventricular arrhythmias 2