What are the potential side effects of hydroxychloroquine (Disease-Modifying Antirheumatic Drug - DMARD)?

Hydroxychloroquine Side Effects

Hydroxychloroquine carries multiple significant side effects ranging from common gastrointestinal symptoms to serious cardiac toxicity and irreversible retinal damage, requiring systematic monitoring with baseline and periodic ECGs, ophthalmologic examinations, and blood counts. 1, 2

Cardiac Toxicity (Most Critical)

Avoid hydroxychloroquine in patients with cardiac disease, heart failure, myocardial infarction, bradycardia <50 bpm, or congenital/acquired QT prolongation. 1, 2

• QT interval prolongation and ventricular arrhythmias (including torsades de pointes) are dose-dependent risks that increase with drug concentration 2
• ECG monitoring is mandatory, particularly when combined with other QT-prolonging medications like azithromycin 1, 3
• Long-term use can cause cardiomyopathy, conduction disorders (bundle branch blocks, sick sinus syndrome), ventricular hypertrophy, and pulmonary hypertension 2, 3
• Correct electrolyte imbalances (hypokalemia, hypomagnesemia) before initiating therapy 2
• Discontinue immediately if cardiotoxicity is suspected or demonstrated on biopsy 2

Retinal Toxicity (Irreversible)

Irreversible retinal damage is directly related to cumulative dosage and treatment duration, with highest risk at daily doses ≥5 mg/kg actual body weight and use beyond five years. 2

• Baseline ocular examination within the first year must include best corrected distance visual acuity (BCVA), automated threshold visual field testing of central 10 degrees, and spectral domain optical coherence tomography (SD-OCT) 1, 2
• High-risk patients (renal impairment, concurrent tamoxifen use, macular disease, Asian descent) require annual examinations 2
• Patients without significant risk factors can defer annual exams until five years of treatment 2
• Asian patients require visual field testing of central 24 degrees instead of 10 degrees, as toxicity may first appear outside the macula 2
• Retinal changes may progress even after drug cessation 2

Dermatologic Reactions

Serious skin reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) can occur. 2, 4

• Most common cutaneous effect is maculopapular/erythematous rash occurring within 4 weeks of initiation, typically resolving within weeks of discontinuation 3, 4
• Other reactions include cutaneous hyperpigmentation, pruritus, psoriasiform dermatitis, photodermatitis, stomatitis, melanonychia, and hair loss 4, 5
• Discontinue immediately if severe skin reactions develop 2
• Avoid in patients with psoriasis unless benefit clearly outweighs risk, as it may precipitate severe flare-ups 2

Gastrointestinal Effects

• Nausea, vomiting, and diarrhea are the most common side effects but are generally infrequent at standard doses 1, 3
• These symptoms account for most reported intolerances and usually don't require discontinuation 1

Hematologic Toxicity

Monitor blood cell counts periodically during prolonged therapy for myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. 2

• Hemolysis can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, particularly with other hemolysis-inducing drugs 2, 3
• Discontinue if myelosuppression develops that cannot be attributed to the underlying disease 2

Hepatotoxicity (Specific to Porphyria)

Avoid hydroxychloroquine in patients with porphyria, as it may exacerbate the condition. 2

• Cases of severe hepatotoxicity with transaminases >20 times upper limit of normal have occurred in porphyria cutanea tarda patients within days to one month of initiation 2
• Measure liver tests promptly if symptoms suggest liver injury (fatigue, rash, nausea, dark urine, jaundice) 2
• Interrupt treatment if ALT >3 times upper limit or total bilirubin >2 times upper limit 2

Neuropsychiatric and Neuromuscular Effects

• Headache, dizziness, and blurred vision may occur but usually don't require discontinuation 1
• Confusion, disorientation, and hallucinations can develop within 24-48 hours of initiation 3
• Rare neuromyotoxicity presents as insidious onset proximal myopathy, potentially with peripheral neuropathy, showing curvilinear bodies on muscle biopsy 6
• Resolution after discontinuation is slow and may be incomplete; Caucasian race and renal failure are possible predisposing factors 6

Drug Interactions

Exercise caution with D-penicillamine and cimetidine, which increase hydroxychloroquine levels. 1

• May interfere with antibody response to intradermal human diploid cell rabies vaccine 1
• Avoid concomitant QT-prolonging agents due to increased ventricular arrhythmia risk 2

Special Populations

• Has been used during pregnancy for connective tissue diseases without increased complications compared to untreated pregnancies 1
• Limited information available for pediatric use, though antimalarials have been used for years in children with rheumatologic diseases 1

Overdose

Overdose manifests rapidly (minutes to hours) with cardiovascular shock and collapse as the most prominent features, along with psychosis and seizures. 3