Medication Interactions with Warfarin

Introduction to Warfarin Interactions

• The American Heart Association recommends monitoring the International Normalized Ratio (INR) closely when initiating, suspending, or modifying other treatments in patients anticoagulated with warfarin, as numerous medications can interact with warfarin, increasing the risk of bleeding or diminishing its anticoagulant effect 1

Medications that Interact with Warfarin

• Sulfonamides, such as trimethoprim/sulfamethoxazole, double the risk of bleeding and require a preventive reduction of warfarina dose by 25% 1
• Metronidazole requires a preventive reduction of warfarina dose by 33% 1
• Fluoroquinolones, such as ciprofloxacin, inhibit CYP1A2 1
• Macrolides, such as clarithromycin and erythromycin, inhibit CYP3A4 1
• Azithromycin significantly increases the risk of bleeding 1
• Triazoles, such as fluconazole and voriconazole, inhibit CYP2C9 1
• Selective serotonin reuptake inhibitors (SSRIs) double the risk of bleeding, with fluvoxamine and fluoxetine being particularly problematic due to inhibition of CYP2C9 and CYP3A4, while sertraline, citalopram, and escitalopram are safer alternatives 1
• Other psychotropic medications that potentiate warfarin include quetiapine, valproic acid, entacapona, and tramadol 1
• Nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, double the risk of bleeding due to displacement of proteins and effects on platelets 1
• Acetaminophen/paracetamol increases the INR in a dose-dependent manner, with doses >2g/day increasing the INR by 0.7 points in 3 days 1
• Fluoropyrimidines, such as fluorouracil and capecitabine, require a preventive reduction of warfarina dose by 20-70% 1
• Gemcitabine, even when administered intravesically, can elevate the INR 1
• Paclitaxel displaces warfarin from plasma proteins 1
• Nafcillin induces CYP3A4 and CYP2C9, requiring higher doses of warfarin 1
• Penicillins, such as flucloxacillin and cloxacillin, may require doubling the dose of warfarin 1
• Rifampicin is a potent enzyme inducer 1
• Carbamazepine decreases the INR by 0.63 and requires a 50% increase in the dose of warfarin 1
• Phenytoin has a biphasic effect, initially increasing the INR by displacing proteins and then decreasing it by enzyme induction 1
• St. John's Wort reduces the INR by 20% by inducing CYP2C9, 2C19, and 3A4 1
• Cannabidiol (CBD) inhibits CYP2C9, increasing warfarin plasma concentrations and the risk of bleeding, and may require a reduction of warfarin dose by 20-30% 2

Management of Warfarin Interactions

• The American Heart Association recommends monitoring the INR more frequently when initiating or suspending any medication in patients with warfarin, and making preventive dose adjustments when starting medications with known interactions, such as sulfamethoxazole, metronidazole, fluoropyrimidines, and CBD 1
• It is recommended to avoid high-risk combinations, such as warfarin with NSAIDs, azole antibiotics, macrolides, quinolones, SSRIs, and amiodarone, when possible 1
• Considering alternative, safer medications, such as sertraline or citalopram/escitalopram, when an SSRI is needed, is advised 1