Which medications should be avoided or used with caution in a patient on warfarin due to drug‑drug interactions?

Medications That Should Not Be Taken with Warfarin

Avoid NSAIDs (except low-dose aspirin in specific cardiovascular indications), and exercise extreme caution with antibiotics—particularly sulfonamides, metronidazole, fluoroquinolones, and macrolides—as these medications substantially increase bleeding risk and require dose adjustments or alternative therapy. 1, 2

Highest-Risk Medications Requiring Avoidance or Dose Reduction

NSAIDs and COX-2 Inhibitors

• All NSAIDs should be discouraged when combined with warfarin, as they double the bleeding risk through both pharmacodynamic (impaired hemostasis) and pharmacokinetic (protein displacement) mechanisms 1
• COX-2 selective inhibitors (celecoxib, rofecoxib, valdecoxib) carry similar bleeding risk as non-selective NSAIDs 1, 3
• The combination of warfarin with NSAIDs increases gastrointestinal bleeding risk with an odds ratio of 1.98 (95% CI: 1.55-2.53) 4
• If an NSAID must be used, add a proton pump inhibitor to reduce GI bleeding risk 1
• Low-dose aspirin may be acceptable for specific cardiovascular indications, though it increases gastrointestinal bleeding risk 5

Antibiotics Requiring Mandatory Dose Adjustment

• Metronidazole requires a 33% warfarin dose reduction when initiated, as it potentiates anticoagulation through inhibition of S-warfarin metabolism 2
• Sulfonamides (including trimethoprim/sulfamethoxazole) nearly double bleeding risk compared to warfarin alone 2, 3
• Fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, norfloxacin) significantly increase INR and bleeding risk 1, 2, 3
• Macrolides (clarithromycin, erythromycin, azithromycin) potentiate warfarin through CYP3A4 inhibition; consider 25% warfarin dose reduction with clarithromycin 2, 3
• Azithromycin (particularly intravenous) significantly increases bleeding risk per FDA citation 2

Antibiotics Requiring Close INR Monitoring

• Cephalosporins (second and third generation, including ceftriaxone): Check INR within 3-4 days of initiation and consider 25-33% preemptive dose reduction 2
• Doxycycline: Check INR within 3-4 days and continue frequent monitoring throughout therapy and for 7-14 days after discontinuation 2
• Penicillins have lower interaction potential than other classes but can still inhibit platelet function at high doses 2

Antifungals

• Fluconazole and other triazole antifungals inhibit CYP2C9, substantially increasing bleeding risk 2, 3
• Topical miconazole oral gel can interact with warfarin; nystatin oral solution is a safer alternative 2

Moderate-Risk Medications Requiring Monitoring

Cardiovascular Medications

• Amiodarone interacts through multiple mechanisms and is associated with 21% of bleeding events attributable to drug interactions 1, 6
• Lipid-lowering agents (fibrates, statins) require monitoring, accounting for 8% of attributable bleeding events 6

Gastrointestinal Medications

• Omeprazole inhibits CYP2C19, though this is clinically significant primarily in extensive CYP2C19 metabolizers 1, 3

Psychiatric Medications

• SSRIs increase bleeding risk through pharmacodynamic effects and account for 6% of attributable bleeding events 6

Acetaminophen

• Doses exceeding 9.1 grams per week increase risk of INR >6 by 10-fold 1
• Doses >2 grams/day significantly increase INR by an average of 0.7 by day 3 1
• Close INR monitoring is recommended during acetaminophen initiation 1

Chemotherapy Agents

• Gemcitabine (even intravesical instillation) can elevate INR 1
• Paclitaxel potentiates warfarin through protein displacement 1
• Fluorouracil consistently interacts with warfarin 7
• Enzalutamide (strong CYP2C9 inducer) enhances warfarin clearance; monitor INR closely during initiation and discontinuation 1

Medications That Decrease Warfarin Effect

Enzyme Inducers Requiring Dose Increases

• Rifampin is a potent CYP450 inducer that substantially decreases warfarin effect 2, 3
• Nafcillin induces CYP3A4 and CYP2C9, requiring higher warfarin doses during treatment; full effect takes 2-4 weeks to develop and persists 2-4 weeks after discontinuation 2
• St. John's Wort induces CYP2C9, 2C19, and 3A4, reducing INR by 20% 1, 3
• Phenobarbital, carbamazepine, phenytoin are enzyme inducers requiring warfarin dose increases 3

Other Medications Decreasing Effect

• Cholestyramine reduces warfarin absorption 3
• Vitamin K (dietary or supplemental) competitively antagonizes warfarin 3

Herbal Supplements and Foods

Supplements That Increase Bleeding Risk

• Cranberry products have multiple reports of fatal potentiation, though modest consumption may be safe 1, 3
• Garlic and Ginkgo biloba have antiplatelet and bleeding properties when taken alone 3
• Danshen, dong quai, bromelains are associated with increased warfarin effects 3

Supplements That Decrease Warfarin Effect

• Coenzyme Q10 decreases warfarin effects 3
• Green tea in excessive amounts (up to 1 gallon/day) can decrease INR due to vitamin K content 1

Foods Requiring Caution

• Mango: Limit intake to less than one whole fruit per day due to potential CYP2C9/3A4 inhibition 8
• Pomegranate, avocado, grapefruit, papaya have case reports of interactions 1, 8

Critical Monitoring Recommendations

INR Monitoring Algorithm

• Check INR within 3-4 days of starting any antibiotic 2
• Continue frequent monitoring throughout antibiotic therapy and for 7-14 days after discontinuation 2
• For elevated INR 3.0-5.0 without bleeding: withhold one warfarin dose or lower the dose 2
• For INR >5.0 without bleeding: consider low-dose vitamin K 2

Risk Factors for Severe Interactions

• Warfarin maintenance dose >40 mg/week significantly increases risk of INR elevation with NSAIDs 9
• Presence of multiple coadministered medications increases interaction risk 9
• Low baseline INR paradoxically increases risk of INR elevation when NSAIDs are added 9
• Elderly patients have increased pharmacodynamic response to warfarin 2

Common Pitfalls to Avoid

• Do not assume topical or intravesical medications are safe—even bladder instillation of gemcitabine can elevate INR 1
• Do not rely on "modest doses" of herbal supplements being safe—lack of standardization means active ingredient amounts vary 3
• Do not forget that all antibiotics can alter gut microbiome, which produces vitamin K, thereby potentiating warfarin 2
• Do not overlook the order of medication initiation—adding an antibiotic to stable warfarin causes more INR variability than starting both simultaneously 2
• Do not assume penicillins and cephalosporins are completely safe—they have lower but not absent interaction potential 2