Moderate
Amiodarone × Methotrexate
Class III antiarrhythmics (Vaughan Williams)×Antimetabolites, folic acid analogues
Mechanism
No direct pharmacokinetic interaction. Cases of enhanced hepatotoxicity have been reported with long-term co-use, since both drugs can cause steatohepatitis and liver fibrosis.
Symptoms
Fatigue, nausea, jaundice, elevated liver enzymes. Symptoms develop with long-term therapy (over 6 months).
Management
On the combination, check ALT, AST, and alkaline phosphatase every 3 months. If enzymes rise 2–3-fold above the upper limit, repeat at 2 weeks; if persistently elevated, consider temporary methotrexate withdrawal. In rheumatoid arthritis, alternative: leflunomide (if no liver fibrosis).