Hydroxychloroquine - Drug Monograph

Introduction

Hydroxychloroquine sulfate is a 4-aminoquinoline compound that has been used clinically for over 60 years. Originally developed as an antimalarial agent, it has since gained significant importance in the treatment of autoimmune conditions, particularly rheumatoid arthritis and systemic lupus erythematosus. The drug gained widespread public attention during the COVID-19 pandemic, though its efficacy for this indication remains controversial and not FDA-approved.

Mechanism of Action

Hydroxychloroquine's exact mechanism of action is multifactorial and varies by indication. As an antimalarial, it concentrates in parasitic food vacuoles, raising pH and interfering with hemoglobin degradation. In autoimmune conditions, it is believed to:

• Inhibit antigen processing and presentation
• Reduce cytokine production (particularly IL-1, IL-6, and TNF-α)
• Interfere with Toll-like receptor signaling
• Inhibit lysosomal enzyme activity and autophagy
• Stabilize lysosomal membranes

The drug also exhibits mild immunosuppressive properties through inhibition of phospholipase A2 and altered ribosomal DNA transcription.

Indications

• Treatment of uncomplicated malaria caused by Plasmodium falciparum, P. malariae, P. ovale, and P. vivax
• Treatment of chronic discoid lupus erythematosus and systemic lupus erythematosus in adults
• Treatment of acute and chronic rheumatoid arthritis in adults

• Sjögren's syndrome
• Porphyria cutanea tarda
• Q fever
• Solar urticaria
• Certain dermatological conditions

Dosage and Administration

• Renal impairment: Dose reduction may be necessary for severe impairment (CrCl <30 mL/min)
• Hepatic impairment: Use with caution; consider dose reduction
• Pediatrics: 5 mg/kg base (6.5 mg/kg salt) once weekly for malaria prophylaxis
• Geriatrics: Start at lower end of dosing range due to potential decreased renal function

Pharmacokinetics

Contraindications

• Hypersensitivity to 4-aminoquinoline compounds
• Known retinal field changes attributable to 4-aminoquinolines
• Concomitant use with other drugs known to cause retinal damage
• Psoriasis (may exacerbate condition)
• Porphyria (may exacerbate condition)

Warnings and Precautions

• Cardiomyopathy and heart failure (may be fatal)
• Severe hypoglycemia (may occur in diabetics on antidiabetic drugs)
• Neuropsychiatric reactions including suicidal behavior
• Severe dermatological reactions
• Skeletal muscle myopathy or neuropathy
• Hemolysis in patients with G6PD deficiency
• Use in pregnancy requires risk-benefit assessment (Pregnancy Category C)

Drug Interactions

• Digoxin: Hydroxychloroquine may increase digoxin levels
• Diabetes medications: May enhance hypoglycemic effects
• QT-prolonging agents: Increased risk of torsades de pointes (especially with azithromycin, antipsychotics, antiarrhythmics)
• Mefloquine: Increased seizure risk
• CYP2D6 substrates: May alter metabolism of drugs like metoprolol, dextromethorphan
• Antacids: May decrease absorption (separate administration by 4 hours)

Adverse Effects

• Nausea, vomiting, diarrhea
• Abdominal cramps
• Headache
• Dizziness
• Rash
• Pruritus

• Irreversible retinal toxicity
• Cardiomyopathy
• Severe hypoglycemia
• Blood dyscrasias (agranulocytosis, aplastic anemia, thrombocytopenia)
• Hepatotoxicity
• Neuropsychiatric events (psychosis, depression, suicidal ideation)
• Severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Monitoring Parameters

• Complete ophthalmologic examination including visual fields
• CBC with differential
• Liver function tests
• Renal function
• ECG (if cardiac risk factors present)
• G6PD screening in at-risk populations

• Annual ophthalmologic exams after 5 years of use (more frequent if high risk)
• Periodic CBC and LFTs
• Blood glucose monitoring in diabetics
• Cardiac monitoring if symptoms develop
• Neurological assessment if symptoms occur

Patient Education

• Take with food or milk to minimize GI upset
• Importance of regular eye exams even after stopping medication
• Report any visual changes, muscle weakness, or unusual bleeding/bruising immediately
• Use sun protection (photosensitivity risk)
• Inform all healthcare providers about hydroxychloroquine use
• Do not crush or break tablets
• Keep out of reach of children (potentially fatal in overdose)
• Adherence to prescribed dosing schedule is crucial
• Notify physician if pregnancy is planned or suspected

References

1. FDA Prescribing Information: Plaquenil (hydroxychloroquine sulfate) tablets 2. Marmor MF, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386-1394. 3. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-166. 4. Jorge AM, et al. Hydroxychloroquine retinopathy - implications of research advances for rheumatology care. Nat Rev Rheumatol. 2018;14(12):693-703. 5. Liu J, et al. Hydroxychloroquine: a comprehensive review and its controversial role in COVID-19. Ann Clin Microbiol Antimicrob. 2020;19(1):56. 6. American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy. 2016. 7. Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2023. 8. Micromedex Solutions, Greenwood Village, Colorado: IBM Watson Health; 2023.