What are the indications, dosing, contraindications, monitoring requirements, adverse effects, and alternative therapies for Plaquenil (hydroxychloroquine)?

Plaquenil (Hydroxychloroquine): Clinical Overview

Indications

Hydroxychloroquine is indicated for malaria prophylaxis and treatment, rheumatoid arthritis, systemic lupus erythematosus, and chronic discoid lupus erythematosus. 1

FDA-Approved Indications:

• Malaria: Prophylaxis and treatment of uncomplicated malaria caused by susceptible strains 1
• Rheumatoid arthritis in adults 1
• Systemic lupus erythematosus in adults 1
• Chronic discoid lupus erythematosus in adults 1

Special Consideration for SLE:

• Hydroxychloroquine is recommended for ALL patients with SLE unless contraindicated, as it prevents disease flares, reduces organ damage accrual, improves long-term survival, and allows for glucocorticoid dose reduction 2, 3
• The drug should be continued even in patients with lupus nephritis and during pregnancy 4

Dosing

Malaria Prophylaxis:

• Adults: 400 mg once weekly, starting 2 weeks before travel, continuing during exposure, and for 4 weeks after leaving endemic area 1
• Pediatric patients ≥31 kg: 6.5 mg/kg actual body weight (up to 400 mg) once weekly, same schedule 1
• Not recommended for children <31 kg as the 200 mg tablet cannot be divided 1

Malaria Treatment (Uncomplicated):

• Adults: 800 mg initially, then 400 mg at 6,24, and 48 hours (total 2,000 mg) 1
• Pediatric patients ≥31 kg: 13 mg/kg initially, then 6.5 mg/kg at 6,24, and 48 hours (total 31 mg/kg, up to 2,000 mg) 1
• For P. vivax and P. ovale, add primaquine for radical cure after G6PD testing 1

Rheumatoid Arthritis:

• Initial: 400-600 mg daily (single or divided doses) 1
• Maintenance: 200-400 mg daily 1
• Maximum safe dose: ≤5 mg/kg actual body weight daily to minimize retinopathy risk 1, 3

Systemic Lupus Erythematosus & Chronic Discoid Lupus:

• Standard dose: 200-400 mg daily (single or divided doses) 1
• Critical dosing principle: Daily doses should not exceed 5 mg/kg actual body weight 2, 3, 4

Administration:

• Take with food or milk 1
• Do not crush or divide tablets 1

Contraindications

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

Additional Contraindications Based on Clinical Context:

• Cardiac disease including heart failure and myocardial infarction 5
• Congenital or acquired QT prolongation 1
• Proarrhythmic conditions (bradycardia <50 bpm) 1
• History of ventricular dysrhythmias 1
• Uncorrected hypokalemia or hypomagnesemia 1

Relative Contraindications:

• Pre-existing retinal or macular disease (major risk factor for retinopathy) 2
• Chronic kidney disease (increases retinopathy risk) 2
• Psoriasis (may be exacerbated) 6

Monitoring Requirements

Ophthalmologic Monitoring:

Baseline eye examination within the first year is mandatory, including best corrected visual acuity, automated threshold visual field of central 10 degrees, and spectral domain optical coherence tomography. 1

• Ongoing monitoring: Every 6-12 months during treatment 7, 5
• High-risk patients require annual examinations 5
• Extended use (>6 years cumulative prophylaxis): Periodic examinations recommended 6
• Asian patients: Retinal toxicity may first appear outside the macula 1

Cardiac Monitoring:

• ECG monitoring required, particularly when used with other QT-prolonging medications 7, 5
• Monitor cardiac function clinically as indicated during therapy 1
• Correct electrolyte imbalances before initiating therapy 1

Laboratory Monitoring:

• G6PD testing before adding primaquine for P. vivax or P. ovale treatment 2, 6
• Drug blood levels can assess compliance but routine monitoring not currently recommended 2

Adverse Effects

Common Side Effects:

• Gastrointestinal symptoms (nausea, vomiting) - generally infrequent at standard doses 5
• Headache, dizziness, blurred vision, pruritus (usually don't require discontinuation) 5

Serious Adverse Effects:

Retinal toxicity (irreversible retinopathy):

• Risk <1% in first 5 years, <2% up to 10 years when dosed ≤5.0 mg/kg actual body weight 7
• Dose-dependent and largely preventable with proper dosing 7
• Exceeds 10% after 20 years of continuous use 2
• Risk factors: Duration >5 years, dose >5 mg/kg, chronic kidney disease, concomitant tamoxifen, pre-existing macular disease 2, 1

Cardiotoxicity:

• Fatal cardiomyopathy reported (associated with phospholipidosis) 1
• QT interval prolongation with risk of ventricular arrhythmias including torsades de pointes 1
• Ventricular hypertrophy, pulmonary hypertension, conduction disorders 1
• ECG findings: AV block, bundle branch blocks 1

Drug Interactions:

• QT-prolonging agents: Avoid concomitant use due to increased arrhythmia risk 5, 1
• D-penicillamine and cimetidine: May lead to higher hydroxychloroquine levels 5
• Intradermal rabies vaccine: Hydroxychloroquine may interfere with antibody response 5, 6

Safety Profile & Special Populations

Pregnancy:

Hydroxychloroquine is safe during pregnancy when clinically indicated. 2, 7

• 133 pregnancies resulted in 117 live births with no difference in complications versus untreated patients 7
• Chloroquine/hydroxychloroquine safe for malaria prophylaxis during pregnancy 2
• Should be used aggressively for malaria treatment in pregnant women 2

Breastfeeding:

• Very small amounts secreted in breast milk, not thought harmful to nursing infant 2
• Insufficient to provide malaria protection; infants requiring prophylaxis need full dosing 2

Pediatric Use:

• Safe for children with rheumatologic diseases when used for many years 7
• Not recommended for children <31 kg due to inability to divide 200 mg tablet 1
• Contraindicated for children <8 years if using doxycycline as alternative 2

Renal Impairment:

• Increases risk of retinopathy 2, 1
• Use real body weight for dosing calculations, keep daily dose <5.0 mg/kg 7

Alternative Therapies

For Malaria Prophylaxis in Chloroquine-Resistant Areas:

• Mefloquine: 250 mg weekly for adults (first-line alternative) 6
• Doxycycline: Alternative for short-term travelers or mefloquine-resistant areas 6
• Atovaquone-proguanil: For chloroquine-resistant areas 6

For Malaria Treatment in Resistant Areas:

• Sulfa drugs combined with pyrimethamine (Fansidar, Maloprim) 2
• Tetracycline 2
• Quinine 2
• Mefloquine 2

For Lupus (Cutaneous):

• Quinacrine: Can be considered in patients with HCQ-induced retinal toxicity 2

Critical Clinical Pitfalls

Dosing Errors:

• Always use actual body weight, not ideal body weight, for dose calculations 7, 4
• Daily doses exceeding 5 mg/kg increase retinopathy incidence significantly 1
• Historical dosing of 6.5 mg/kg ideal body weight is outdated 4

Compliance Issues:

• Poor adherence common in SLE patients despite proven benefits 2
• Most malaria deaths occur in travelers who don't fully comply with prophylaxis 6
• Must start 2 weeks before travel and continue 4 weeks after leaving endemic area 6

Monitoring Failures:

• No prophylactic regimen guarantees complete malaria protection; patients must use insect repellents and protective clothing 6
• Seek immediate medical evaluation if fever develops during or after travel 6
• Discontinue immediately if cardiotoxicity suspected 1

Medication Storage:

• Overdose can be fatal - store in childproof containers out of reach of children 2