Is hydroxychloroquine (Plaquenil) safe?

From the Guidelines

Hydroxychloroquine (Plaquenil) can be a potentially dangerous drug, especially when used at high doses or for prolonged periods.

Key Considerations

• It is generally recommended to use the lowest effective dose and for the shortest duration necessary to minimize risks, with typical doses ranging from 200 to 400 mg per day, and treatment not exceeding 5 years 1.
• Long-term use or high doses may increase the risk of retinal toxicity, cardiac effects, and other adverse reactions, with the risk of retinal toxicity being <2% for usage up to 10 years at a daily dosage of ≤5 mg/kg/day actual body weight 1.
• Patients should undergo regular eye exams and monitoring of their blood counts, liver function, and kidney function while taking Plaquenil, with annual screening beginning no more than 5 years after treatment initiation 1.
• The benefits and risks of Plaquenil should be carefully weighed under the guidance of a healthcare professional, taking into account the patient's individual risk factors, such as duration of treatment, dose, chronic kidney disease, and pre-existing retinal or macular disease 1.

Important Precautions

• Baseline testing is advised to rule out confounding disease when a patient is started on HCQ, and annual screening with sensitive tests should begin no more than 5 years after treatment initiation 1.
• Effective communication among prescribing physicians, patients, and eye care providers is essential to optimize the utility and safety of HCQ 1.
• HCQ is recommended for all patients with SLE, with evidence for multiple beneficial effects, yet poor adherence to treatment is not uncommon, and drug blood levels can be used to assess compliance 1.

From the FDA Drug Label

Data from published epidemiologic and clinical studies have not established an association with hydroxychloroquine sulfate use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes Hydroxychloroquine readily crosses the placenta with cord blood levels corresponding to maternal plasma levels. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine in utero Published lactation data report that hydroxychloroquine is present in human milk at low levels. No adverse reactions have been reported in breastfed infants. The safety and effectiveness of hydroxychloroquine sulfate have been established in pediatric patients for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. vivax, and P. ovale, as well as for the prophylaxis of malaria in geographic areas where chloroquine resistance is not reported Hydroxychloroquine sulfate overdosage symptoms have an onset within 1 hour to 3 hours of ingestion The following have been reported with hydroxychloroquine sulfate overdosage: Cardiovascular toxicity, including QRS or QTc prolongation, ventricular tachycardia, ventricular fibrillation, torsade de pointes, atrioventricular block, cardiac arrest and death.

Hydroxychloroquine safety is not fully established, as the available data have methodological limitations. However, the available data suggest that:

• No association has been found between hydroxychloroquine use and major birth defects, miscarriage, or adverse maternal or fetal outcomes.
• No adverse reactions have been reported in breastfed infants.
• The drug is effective and safe in pediatric patients for the treatment of uncomplicated malaria.
• Overdosage can cause severe cardiovascular toxicity, CNS depression, and other adverse effects. Overall, while the available data suggest that hydroxychloroquine is generally safe, its use should be approached with caution, especially in patients with underlying medical conditions or those who are pregnant or breastfeeding 2.

From the Research

Safety of Hydroxychloroquine

The safety of hydroxychloroquine (Plaquenil) has been evaluated in several studies, with findings indicating both short-term and long-term effects.

• Short-term use of hydroxychloroquine can produce gastrointestinal toxicities, such as nausea, vomiting, and diarrhea, as well as rare glucose abnormalities, dermatologic reactions, and neuropsychiatric events 3.
• Cardiotoxicity, including conduction abnormalities and QT/QTc prolongation, has been associated with short-term use, particularly when combined with other medications like azithromycin 3.
• Long-term use of hydroxychloroquine has been linked to retinopathy, neuromyotoxicity, and cardiotoxicity, including conduction abnormalities, cardiomyopathy, and valvular disorders 3.

Specific Populations

Certain populations may be at higher risk for adverse effects from hydroxychloroquine.

• Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be concerned about the safety of hydroxychloroquine, but a study using a "humanized" mouse model found no evidence of clinically significant intravascular hemolysis or organ damage with high-dose hydroxychloroquine administration 4.
• Patients with a history of ocular disease should be cautious when using hydroxychloroquine, as the proposed doses for COVID-19 treatment may exceed the maximum recommended daily safe doses for retinal toxicity 5.

Monitoring and Recommendations

Given the potential risks associated with hydroxychloroquine, monitoring and recommendations are essential.

• Routine baseline ocular examination is not absolutely necessary, but patients should be informed about the potential risk of retinal toxicity 5.
• Optometric review schedules are recommended for patients taking hydroxychloroquine to monitor for ocular side-effects, including irreversible macular damage 6.
• The Royal College of Ophthalmologists, UK (RCO) has recommended against the monitoring of patients receiving quinoline therapy due to the low incidence of retinal complications, but a proactive approach toward medical practitioners prescribing these drugs for optometric-based monitoring is suggested 6.