What are the side effects of Plaquenil (hydroxychloroquine)?

Plaquenil (Hydroxychloroquine) Side Effects

Hydroxychloroquine carries significant risks of irreversible retinal toxicity, cardiac complications including QT prolongation and cardiomyopathy, and serious skin reactions, requiring systematic monitoring with baseline and periodic ophthalmologic examinations, ECG surveillance, and laboratory testing. 1

Major Organ-Specific Toxicities

Ocular Toxicity (Most Critical)

• Irreversible retinal damage is the most significant concern, related to cumulative dosage and treatment duration 1
• Risk factors include daily doses ≥5 mg/kg actual body weight, duration >5 years, cumulative dose >1,000g, renal impairment, concurrent tamoxifen use, and pre-existing macular disease 1
• Retinopathy can progress even after drug discontinuation, making early detection critical 2
• Asian patients typically show extramacular damage near the arcades, while European-descent patients show parafoveal involvement 2
• Corneal deposits (verticillata) can occur but are reversible and not associated with vision loss 2
• Maximum safe daily doses: chloroquine 250 mg/day; hydroxychloroquine doses exceeding these thresholds increase irreversible retinopathy risk 2

Cardiac Toxicity

• QT interval prolongation with risk of torsades de pointes and ventricular arrhythmias 1
• Cardiomyopathy, heart failure, and conduction disorders including sick sinus syndrome 1
• Cardiac disease (heart failure, myocardial infarction) is a contraindication to use 1
• ECG abnormalities include widening of QRS interval, T-wave changes, and bundle branch blocks 2
• Avoid in patients with bradycardia <50 bpm, uncorrected electrolyte abnormalities, or congenital QT prolongation 1

Serious Skin Reactions

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), DRESS syndrome, and acute generalized exanthematous pustulosis (AGEP) 1
• Can precipitate severe flare-ups in patients with psoriasis 1
• Exacerbates porphyria and should be avoided in these patients 1

Hematologic Toxicity

• Myelosuppression including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia 1
• Hemolytic anemia in patients with G6PD deficiency 1
• Toxic myopathy, peripheral neuropathy (improves with prompt withdrawal) 2

Hepatotoxicity

• Particularly dangerous in porphyria cutanea tarda, with marked transaminase elevations (>20× upper limit) occurring within days to one month 1
• Measure liver tests promptly if symptoms suggest liver injury (fatigue, rash, nausea, dark urine, jaundice) 1

Common but Less Severe Side Effects

• Gastrointestinal upset, headache, visual disturbances, urticaria, and pruritus with oral therapy 2
• Skin hyperpigmentation, discoloration of nail beds and mucous membranes 2
• Hair bleaching in blonde and red-haired individuals 2

Drug Interactions Requiring Vigilance

• CYP2D6 and P-glycoprotein inhibition: intensified monitoring needed with gefitinib and tamoxifen 2
• Additive QT prolongation risk with multiple cancer drugs (cabozantinib, ceritinib, crizotinib, nilotinib, osimertinib, vandetanib, vemurafenib, oxaliplatin, arsenic trioxide) 2
• Contraindicated with ondansetron >8mg, domperidone, and citalopram due to torsades de pointes risk 2
• Peripheral neuropathy risk increases when combined with platinum salts, anthracyclines, taxanes, immunomodulators, especially with diabetes or alcohol abuse 2
• D-penicillamine and cimetidine lead to higher hydroxychloroquine levels 2

Mandatory Monitoring Protocol

Baseline Assessment (Within First Year)

• Ophthalmologic examination including best-corrected visual acuity, automated threshold visual field testing (central 10 degrees for non-Asian patients, central 24 degrees for Asian patients), and spectral domain optical coherence tomography 1
• ECG to assess QT interval and cardiac conduction 1
• Complete blood count 1
• Liver function tests 1
• Electrolytes (potassium, magnesium) 1
• G6PD testing if deficiency suspected 1

Ongoing Monitoring

• Annual ophthalmologic examinations for high-risk patients (those with risk factors listed above); can be deferred until 5 years for low-risk patients 1
• Routine ocular screening every 6-12 months per older guidelines 2
• Periodic complete blood counts on prolonged therapy 1
• ECG monitoring, particularly when combined with other QT-prolonging medications 2
• Correct electrolyte imbalances before and during use 1

Special Populations

Pregnancy

• Pregnancy category C 2
• Has been used safely in 133 pregnancies with connective tissue disease, showing no difference in live birth rates or complications compared to untreated patients 2
• Associated with decreased lupus activity without fetal harm 2

Pediatrics

• Limited safety information available, though antimalarial agents have been used for rheumatologic diseases in children for many years 2

Renal Impairment

• Increases risk of retinal toxicity; dose adjustment may be necessary 1

Critical Action Points

• Discontinue immediately if retinal toxicity, cardiotoxicity, serious skin reactions, or severe myelosuppression occurs 1
• Monitor cardiac function clinically during therapy 1
• Advise patients to seek immediate medical attention for blisters, severe itching/burning, chest pain, palpitations, or vision changes 1
• Store medication inaccessibly to children (lethal dose: 1g in children, 4g in adults) 3