What are the risks and side effects of hydroxychloroquine in adults with rheumatoid arthritis or lupus?

Hydroxychloroquine Risks and Side Effects

Hydroxychloroquine is generally well-tolerated with a relatively low rate of drug-related adverse effects, but requires vigilant monitoring for retinopathy (the most serious long-term risk), cardiotoxicity with prolonged use, and common gastrointestinal symptoms. 1

Common and Mild Side Effects

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) are the most frequent adverse effects, accounting for most treatment intolerances, though these are usually mild and reversible. 1, 2

Serious Long-Term Toxicities

Retinopathy (Most Important Dose-Limiting Toxicity)

• Retinopathy risk increases dramatically with duration of use: 0.5% after 6 years, 7.5% in long-term users generally, and exceeds 20% after 20 years of treatment. 3, 1
• The risk remains less than 1% during the first 5 years when dosed at ≤5 mg/kg actual body weight daily, and less than 2% at 5-10 years with appropriate dosing. 1
• Retinopathy may progress even after drug cessation if detected late, making early detection crucial. 1

Ophthalmologic Monitoring Requirements

• No baseline ophthalmologic examination is required before initiating treatment. 3, 1
• Begin annual screening after 1 year in high-risk patients (concomitant tamoxifen use, eGFR <60 ml/min/1.73 m², dose >5 mg/kg/day, or use of chloroquine). 3, 1
• Begin annual screening after 5 years in standard-risk patients. 3, 1
• Screening must include 10-2 visual field testing, spectral-domain OCT, and fundus autofluorescence. 1

Cardiotoxicity

• Conduction abnormalities including heart block and QTc prolongation can occur, particularly with short-term use and when combined with other QTc-prolonging medications. 1, 2, 4
• Cardiomyopathy manifesting as heart failure can develop with high cumulative exposure, typically after many years of use (20-30 years). 3, 1, 5
• Some clinicians perform yearly ECGs in asymptomatic patients, especially with chloroquine use. 1
• Cardiotoxicity may be reversible with early detection and prompt discontinuation of hydroxychloroquine. 5

Less Common but Important Side Effects

Hematologic

• Risk of hemolysis in patients with G6PD deficiency exists, and G6PD levels should be measured before starting hydroxychloroquine in men, especially those of African, Asian, or Middle Eastern origin. 3, 1
• However, this risk appears low according to recent reports. 3

Neuropsychiatric

• Confusion, disorientation, and hallucinations may occur within 24-48 hours of drug initiation. 2
• If hallucinations develop, hydroxychloroquine should be immediately discontinued. 6

Dermatologic

• Drug eruptions, cutaneous hyperpigmentation, pruritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur within days to weeks but usually resolve with discontinuation. 2

Other Toxicities

• Ototoxicity can occur when doses exceed 250 mg/day. 1
• Rarely, neuromyotoxicity including myositis, muscle weakness, and pseudoparkinsonism have been reported with long-term use. 2

Critical Dosing Guidelines to Minimize Toxicity

• The daily dose should not exceed 5 mg/kg actual body weight to minimize retinopathy risk. 3, 1
• Doses of 2-3 mg/kg/day may not achieve adequate blood levels and are associated with higher flare rates. 3, 1
• In patients with eGFR <30 ml/min/1.73 m², reduce the dose by 25%. 3, 1
• Target blood hydroxychloroquine level should be >0.6 mg/L for optimal disease control. 3, 1

Overdose Toxicity

• Symptoms manifest rapidly (within 1-3 hours) and cardiovascular collapse is most prominent, including QRS/QTc prolongation, ventricular arrhythmias, torsade de pointes, cardiac arrest, and death. 7, 2
• Life-threatening hypotension is common in severe toxicity. 7
• CNS depression, seizures, visual disturbances, and coma may occur. 7
• Severe hypokalemia secondary to intracellular shift is common. 7

Important Drug Interactions

• Hydroxychloroquine may enhance hypoglycemic effects of insulin and antidiabetic drugs, requiring dose reduction of these medications. 7
• Concomitant use with digoxin may increase serum digoxin levels, requiring close monitoring. 7
• Concomitant use with methotrexate may increase incidence of adverse reactions. 7
• The activity of antiepileptic drugs might be impaired, and hydroxychloroquine can lower the seizure threshold. 7

Special Populations

• Hydroxychloroquine is safe during pregnancy and is associated with decreased lupus activity without harm to the fetus. 1
• The drug is present in human milk at low levels with no adverse reactions reported in breastfed infants. 7
• In geriatric patients, start with the lowest recommended dose due to substantial renal excretion and greater risk of toxic reactions with impaired renal function. 7