What medications can increase International Normalized Ratio (INR) in patients taking warfarin?

Medications That Increase INR in Warfarin Users

Multiple drug classes significantly increase INR through CYP450 enzyme inhibition, protein displacement, or gut flora alteration, with antibiotics, NSAIDs, SSRIs, and certain chemotherapeutic agents posing the highest bleeding risk.

Antibiotics (Highest Risk Category)

Antibiotics represent the most clinically significant drug interaction class, with some agents nearly doubling bleeding risk compared to warfarin alone. 1

High-Risk Antibiotics Requiring Dose Adjustment:

• Trimethoprim/sulfamethoxazole (TMP/SMX): Doubles bleeding risk (HR 2.09) and requires close monitoring 2
• Metronidazole: Requires prophylactic 33% warfarin dose reduction when co-administered 3
• Fluoroquinolones:
  • Ciprofloxacin increases bleeding risk (HR 1.87) 2
  • Levofloxacin increases bleeding risk (HR 1.77), though some studies show variable effects 2, 4
  • FDA specifically warns about levofloxacin-warfarin interaction requiring close INR monitoring 5
• Macrolides:
  • Clarithromycin inhibits CYP3A4 and may require 25% warfarin dose reduction 3
  • Azithromycin significantly increases bleeding risk (HR 1.93 as primary diagnosis, 1.64 overall) despite FDA initially not listing this interaction 2, 6
  • Erythromycin potentiates warfarin effects 1
• Sulfonamides: Nearly double bleeding risk compared to warfarin alone 3

Mechanism of Antibiotic Interactions:

• All antibiotics can alter gut microbiome, reducing vitamin K production and potentiating warfarin 3
• Many inhibit CYP2C9 (metabolizes S-enantiomer) or CYP3A4 (metabolizes R-enantiomer) 3
• Full enzyme induction/inhibition takes 2-4 weeks to develop and persists 2-4 weeks after discontinuation 1, 3

Antifungals

Triazole antifungals pose severe bleeding risk through potent CYP2C9 inhibition. 1

• Fluconazole: 9.7% of patients develop INR >6 when co-prescribed with warfarin 2
• Voriconazole: Inhibits CYP2C9 and moderately inhibits CYP2C19 1
• Miconazole (even topical/vaginal): Increases INR; nystatin is safer alternative 1
• Ketoconazole and itraconazole: Strong CYP3A4 inhibitors requiring close monitoring 1

NSAIDs and Analgesics

NSAIDs double bleeding risk through both pharmacokinetic and pharmacodynamic mechanisms. 1

• All NSAIDs (non-selective COX and COX-2 selective): Double bleeding risk versus warfarin alone through protein displacement and direct antiplatelet effects 1
• Acetaminophen: Dose-dependent INR increase; doses >9.1 g/week increase risk of INR >6 by 10-fold 1
  • Doses >2 g/day increase INR by average 0.7 by day 3 1
  • Requires close INR monitoring during initiation 1

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs more than double bleeding risk through CYP450 inhibition and antiplatelet effects. 1

• Fluvoxamine and fluoxetine: Highest risk; inhibit both CYP2C9 and CYP3A4 1
• Sertraline and citalopram/escitalopram: Safer SSRI alternatives if antidepressant required 1
• Mechanism: CYP450 enzyme inhibition plus intrinsic antiplatelet effects 1

Cardiovascular Medications

Statins:

• Fluvastatin: Highest risk; inhibits CYP2C9 directly affecting potent S-isomer of warfarin 1
• Atorvastatin, rosuvastatin, simvastatin: Increase mean INR by ~0.3 at 4 weeks through protein displacement and CYP3A4 inhibition 1
• Pitavastatin and atorvastatin: Lowest impact on INR per AHA Scientific Statement 1

Lipid-Lowering Agents:

• Gemfibrozil: Recommend preemptive 20% warfarin dose reduction 1
• Fish oil (1-2 g/day): Increases INR and has antiplatelet effects 1
• Cholestyramine: Interferes with warfarin absorption; unavoidable interaction due to enterohepatic circulation 1

Chemotherapeutic Agents

Fluoropyrimidines require the most aggressive warfarin dose reductions. 1

• Fluorouracil: Requires prophylactic 20-70% warfarin dose reduction through CYP2C9 inhibition, GI tract injury, and gut flora alteration 1
• Capecitabine: Increases INR; effects persist up to 2 weeks after discontinuation 1
• Gemcitabine: Elevates INR even with intravesical administration 1
• Paclitaxel: Displaces warfarin from protein binding sites 1
• Trastuzumab: Case reports of warfarin potentiation 1

Other Psychotropic Medications

• Quetiapine, valproic acid, entacapone, tramadol: Potentiate warfarin via CYP450 inhibition 1
• Phenytoin: Biphasic interaction—initially displaces warfarin (increases bleeding), then induces CYP450 (requires higher warfarin doses) 1

Critical Monitoring Recommendations

Early INR evaluation significantly reduces bleeding risk. 2

• Patients with INR checked 3-14 days after high-risk antibiotic co-prescription have 39% reduced bleeding risk (HR 0.61) 2
• Monitor INR more frequently during initiation and discontinuation of any interacting medication 1, 3
• Consider preemptive dose reductions for highest-risk agents (metronidazole, fluorouracil, gemfibrozil) 1, 3

Common Pitfalls to Avoid

• Assuming azithromycin is safe: Despite initial FDA guidance, azithromycin significantly increases bleeding risk 2, 6
• Overlooking topical antifungals: Even vaginal miconazole can elevate INR 1
• Forgetting delayed effects: Enzyme induction/inhibition persists 2-4 weeks after drug discontinuation 1, 3
• Ignoring acetaminophen: Even this "safe" analgesic causes dose-dependent INR elevation 1
• Missing alcohol consumption: Inhibits hepatic enzymes and impairs warfarin clearance 1