What is the recommended treatment protocol for Hydroxychloroquine (Plaquenil)?

Hydroxychloroquine Treatment Protocol

Hydroxychloroquine is FDA-approved for malaria prophylaxis/treatment and autoimmune conditions (rheumatoid arthritis, systemic lupus erythematosus, chronic discoid lupus), with specific dosing protocols that vary by indication, and it is NOT recommended for COVID-19 treatment based on current evidence. 1

FDA-Approved Indications and Dosing

Malaria Treatment and Prophylaxis

For malaria prophylaxis in chloroquine-sensitive areas:

• Adults: 400 mg once weekly, starting 2 weeks before travel, continuing during exposure, and for 4 weeks after leaving the endemic area 1
• Pediatric patients ≥31 kg: 6.5 mg/kg (up to 400 mg maximum) once weekly 1

For uncomplicated malaria treatment in chloroquine-sensitive areas:

• Adults: Total dose of 1,500 mg chloroquine (approximately 25 mg/kg) over 3 days: 600 mg at 0 hours, 600 mg at 24 hours, and 300 mg at 48 hours 2
• Children: 25 mg/kg total over 3 days: 10 mg/kg at 0 hours, 10 mg/kg at 24 hours, and 5 mg/kg at 48 hours 2
• Pregnant women: Use the adult regimen; chloroquine is safe during pregnancy 2

Critical limitations for malaria:

• Hydroxychloroquine is NOT recommended for complicated malaria, chloroquine-resistant strains, or for preventing P. vivax/P. ovale relapses (requires concomitant 8-aminoquinoline therapy) 1
• For severe malaria, intravenous artesunate is the first-line treatment, not hydroxychloroquine 3

Rheumatoid Arthritis

Dosing protocol:

• Initial dose: 400-600 mg daily 1
• Chronic maintenance: 200 mg once daily or 400 mg once daily (can be divided into two doses) 1
• Optimal dose: 200 mg daily is as effective as 400 mg daily with significantly fewer side effects (3 times less) and no reported retinopathy at this dose 4

Systemic Lupus Erythematosus (Including Lupus Nephritis)

Dosing protocol:

• Standard dose: 200 mg once daily or 400 mg once daily (can be divided) 1
• Recommended starting dose: Approximately 5 mg/kg/day (NOT 2-3 mg/kg/day, which may not achieve adequate blood levels and is associated with higher flare rates) 2
• Target blood level: Above 0.6 mg/L is associated with lower risk of lupus nephritis flare 2
• Renal adjustment: Reduce dose by 25% if eGFR <30 mL/min per 1.73 m² 2

Evidence for SLE/lupus nephritis:

• Hydroxychloroquine reduces mortality, prevents organ damage, reduces flare incidence, and has relatively low adverse event rates in lupus nephritis patients 2
• Nearly all well-informed patients would choose hydroxychloroquine treatment over no treatment given the benefit-risk profile 2

Chronic Discoid Lupus Erythematosus

Dosing protocol:

• 200 mg once daily or 400 mg once daily (can be divided) 1

Steroid-Refractory Chronic Graft-Versus-Host Disease

Alternative indication (off-label):

• Dose: 800 mg (12 mg/kg) per day 2
• Response rate: 53% overall response rate, with highest efficacy in skin, oral, and liver involvement; limited efficacy for GI manifestations 2
• Duration limitation: Not appropriate for long-term use (>2 years) due to retinal toxicity risk 2

Sarcoidosis (Off-Label)

Limited role:

• May be useful for managing hypercalcemia and skin disease in sarcoidosis, but did not reach consensus as a primary treatment 2

COVID-19: NOT RECOMMENDED

Hydroxychloroquine should NOT be used for COVID-19 treatment or prophylaxis:

• Early 2020 guidelines suggested possible use as a secondary drug only if patients worsened despite steroids and antibiotics, based solely on in vitro studies 2
• These recommendations were made under extreme uncertainty with very low-quality evidence 2
• Subsequent evidence showed no clinical benefit and increased concerns about cardiotoxicity, particularly QT prolongation when combined with azithromycin 5
• Current standard of care does not include hydroxychloroquine for COVID-19 5

Mandatory Safety Monitoring

Pre-Treatment Screening

Glucose-6-phosphate dehydrogenase (G6PD) testing:

• Preferred in men, especially those of African, Asian, or Middle Eastern origin, before starting hydroxychloroquine due to hemolysis risk 2
• However, the actual risk appears low based on recent data 2

Ophthalmologic Monitoring

Retinopathy screening protocol (updated 2020 UK guidelines):

• Baseline exam: NOT required before initiating treatment 2
• Yearly monitoring begins:
  • After 1 year if additional risk factors present (concomitant tamoxifen, eGFR <60 mL/min per 1.73 m², dose >5 mg/kg/day, or chloroquine use) 2
  • After 5 years otherwise 2

Retinopathy risk increases with duration:

• 0.5% after 6 years of treatment 2
• 7.5% in long-term users generally 2

• 20% when treatment duration exceeds 20 years 2

• Risk is dose-dependent and cumulative 1, 5

Cardiac Monitoring

Cardiotoxicity concerns:

• Short-term use can produce conduction abnormalities and QT/QTc prolongation 5
• Long-term use (years) associated with cardiomyopathy and conduction abnormalities 2, 5
• Antimalarials may rarely cause cardiomyopathy or conduction abnormalities with high cumulative exposure 2
• Fatal or life-threatening cardiomyopathy and ventricular arrhythmias have been reported 1

Contraindications and Precautions

Absolute contraindication:

• Hypersensitivity to 4-aminoquinoline compounds 1

Avoid or use with extreme caution:

• Psoriasis: May worsen disease 1
• Porphyria: Avoid use; hepatotoxicity reported in porphyria cutanea tarda 1
• Severe renal impairment: Dose reduction required; consider phospholipidosis as possible cause of renal injury 1

Common Adverse Effects

Most frequent (short-term):

• Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain (most common) 1, 5
• Dermatologic: drug eruptions, rashes, hyperpigmentation, pruritis (occur within days to weeks) 5

Serious but rare:

• Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis 1
• Hematologic toxicity: myelosuppression (discontinue if occurs) 1
• Neuropsychiatric: confusion, disorientation, hallucinations within 24-48 hours of initiation 5

Overdose Management

Clinical presentation:

• Symptoms manifest rapidly (minutes to hours) 5
• Cardiovascular shock and collapse are most prominent 5
• Neurotoxic effects including psychosis and seizures may occur 5
• Deaths most often result from cardiovascular collapse 5

Key Clinical Pitfalls to Avoid

1. Do not use doses of 2-3 mg/kg/day for SLE/lupus nephritis - inadequate blood levels and higher flare rates 2
2. Do not use hydroxychloroquine for severe malaria - artesunate is first-line 3
3. Do not use for chloroquine-resistant malaria - alternative agents required 1
4. Do not skip dose adjustment in renal impairment - 25% reduction needed if eGFR <30 2
5. Do not use for COVID-19 - no proven benefit and potential cardiac harm 5
6. Do not delay ophthalmologic monitoring in high-risk patients - start at 1 year, not 5 years 2