Which is safer, Plaquenil (hydroxychloroquine) or Arava (leflunomide)?

Which is Safer: Plaquenil or Arava?

Plaquenil (hydroxychloroquine) is safer than Arava (leflunomide) for most patients with rheumatoid arthritis, based on its more favorable toxicity profile, reversibility of adverse effects, and established safety record including use in pregnancy.

Key Safety Advantages of Plaquenil

Toxicity Profile and Reversibility

• Hydroxychloroquine is generally believed to be safe with limited serious adverse effects when used at appropriate doses 1.
• Most side effects (GI upset, headache, visual disturbances, urticaria, pruritus) reverse with discontinuation of therapy 1.
• The drug has been used safely in children for rheumatologic diseases for many years 1.

Pregnancy Safety

• Hydroxychloroquine is safe during pregnancy if clinically indicated, with 133 pregnancies resulting in 117 live births showing no difference in complications compared to untreated patients 1.
• This is a critical safety advantage over leflunomide.

Retinal Toxicity Risk (Main Concern)

• The primary serious toxicity is irreversible retinopathy, but risk is <1% in the first 5 years and <2% up to 10 years when dosed at ≤5.0 mg/kg real body weight 1.
• Risk increases to approximately 20% after 20 years of use 1.
• Toxicity is dose-dependent and largely preventable with proper dosing and monitoring 1.
• Requires ophthalmologic screening every 6-12 months 1.

Key Safety Concerns with Arava (Leflunomide)

Severe Adverse Events

• Leflunomide was more often associated with severe adverse events than methotrexate or sulfasalazine, including elevated transaminases, hematological disorders, and cutaneous reactions 2.
• Primary toxicities include anemia (especially in renal patients) and liver enzyme elevation 3.
• Dose-limiting side effects occur in >15% of patients when serum levels exceed 80 μg/mL 3.

Teratogenicity and Long Half-Life

• Leflunomide is teratogenic in animals and requires a two-year period between conception and the end of treatment 2.
• The two-week half-life of the active metabolite is a major disadvantage when adverse effects occur, as the drug cannot be rapidly cleared 2.
• This prolonged half-life makes toxicity management significantly more challenging compared to hydroxychloroquine.

Comparative Efficacy Context

• In comparative trials, leflunomide showed no difference in clinical efficacy compared to sulfasalazine, but had more adverse events 2.
• One trial showed methotrexate was significantly more effective than leflunomide 2.

Clinical Recommendation Algorithm

For mild-to-moderate rheumatoid arthritis:

• Choose hydroxychloroquine as the safer first-line alternative to methotrexate 4.
• Reserve leflunomide for severe disease when hydroxychloroquine is insufficient 4.

For women of childbearing potential:

• Strongly favor hydroxychloroquine due to pregnancy safety data 1.
• Avoid leflunomide unless pregnancy is definitively not planned for 2+ years 2.

For patients with renal impairment:

• Exercise caution with leflunomide, as anemia is more common and dose adjustments are frequently needed when creatinine >3 mg/dL 3.

For long-term therapy:

• Hydroxychloroquine is preferable with appropriate ophthalmologic monitoring 1.
• Keep hydroxychloroquine dose <5.0 mg/kg real body weight to minimize retinopathy risk 1.

Critical Monitoring Requirements

For Hydroxychloroquine:

• Ophthalmologic examination every 6-12 months 1.
• Monitor for drug interactions with D-penicillamine and cimetidine 1.
• ECG monitoring if using with other QT-prolonging drugs 1.

For Leflunomide:

• Frequent monitoring of liver enzymes and complete blood counts 2, 3.
• Serum drug level monitoring recommended due to wide inter-patient variability 3.
• More intensive monitoring required in renal impairment 3.

Common Pitfall to Avoid

Do not dose hydroxychloroquine based on ideal body weight in thin patients, as this results in overdosage and increased toxicity risk 1. Always use real body weight for dosing calculations, keeping daily dose <5.0 mg/kg 1.