In a patient on warfarin with an elevated INR, which drugs are contraindicated?

Drugs Contraindicated or Requiring Extreme Caution in Patients with Elevated INR on Warfarin

In patients on warfarin with an elevated INR, drugs that further increase bleeding risk through anticoagulant, antiplatelet, or fibrinolytic mechanisms should be avoided or used with extreme caution, including NSAIDs, SSRIs, antibiotics (especially trimethoprim-sulfamethoxazole, metronidazole, fluoroquinolones, and macrolides), acetaminophen at high doses, and antiplatelet agents. 1, 2, 3

High-Risk Drug Classes to Avoid

NSAIDs: Double the Bleeding Risk

• NSAIDs double the risk of bleeding compared to warfarin alone through both pharmacodynamic (impaired hemostasis, platelet dysfunction) and pharmacokinetic mechanisms (CYP2C9 inhibition) 1, 2, 3
• Meloxicam carries particularly high risk for INR elevation when combined with warfarin 3
• Risk is especially pronounced in patients taking warfarin maintenance doses >40 mg/week 3

Antibiotics: The Highest-Risk Medication Class

• Trimethoprim-sulfamethoxazole nearly doubles the risk of serious bleeding and requires prophylactic warfarin dose reduction of 25% in patients with bleeding history 1
• Metronidazole requires prophylactic warfarin dose reduction of 33% when co-administered, particularly in patients with renal impairment 1, 4
• Fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin) increase serum R-warfarin concentrations and elevate INR 1, 2
• Macrolides (clarithromycin, erythromycin, azithromycin) inhibit CYP3A4 and potentiate warfarin effects, with azithromycin specifically cited by the FDA as significantly increasing bleeding risk 1, 4, 2
• All antibiotics can alter vitamin K-producing gut flora, further potentiating anticoagulation 4

Psychotropic Medications

• SSRIs more than double the risk of bleeding compared to warfarin alone 1
• Fluvoxamine and fluoxetine are particularly dangerous as they inhibit both CYP2C9 and CYP3A4 1
• Sertraline and citalopram/escitalopram are safer alternatives if antidepressant therapy is necessary 1

Acetaminophen: Dose-Dependent Risk

• Acetaminophen increases INR in a dose-dependent manner, with risk of INR >6 increasing 10-fold once intake exceeds 9.1 grams per week (approximately 1,300 mg/day) 1
• This interaction is often overlooked but clinically significant in patients with chronic pain 1

Additional High-Risk Agents

Chemotherapy Agents

• Fluorouracil requires prophylactic warfarin dose reduction of 20-70% 1
• Capecitabine increases INR, with effects persisting up to two weeks after discontinuation 1

Cardiovascular Medications

• Fenofibrate requires close INR monitoring and potential warfarin dose adjustment during initiation 1
• Fish oil can increase INR and has additional antiplatelet effects 1

Herbal Supplements and Botanicals

• Bromelains, danshen, dong quai, garlic, Ginkgo biloba, ginseng, and cranberry products are associated with increased warfarin effects 2
• Cranberry consumption should be limited to ≤24 ounces/day 1
• Many botanicals have antiplatelet or fibrinolytic properties that are additive to warfarin's effects 2

Alcohol

• Alcohol ingestion inhibits hepatic enzymes and impairs warfarin clearance, significantly increasing INR levels 1, 2

Critical Management Principles

When INR is Already Elevated

• For INR 5-9 without bleeding: withhold warfarin and monitor; consider oral vitamin K 1-2.5 mg 5, 6
• For INR >9 without bleeding: withhold warfarin and give oral vitamin K 5 mg 5
• For major bleeding with elevated INR: hospital admission, vitamin K (slow IV infusion 5-10 mg over 30 minutes), fresh frozen plasma, and frequent monitoring 5, 6
• For emergent situations: hospitalization, clotting factor replacement (fresh frozen plasma or prothrombin concentrate), and IV vitamin K 5, 6

Monitoring Protocol for New Medications

• Check INR within 3-5 days of starting any CYP2C9 inhibitor or high-risk medication 1
• Continue weekly INR monitoring for 2-4 weeks until steady state is reached 1
• More frequent monitoring (2-4 times per week) immediately after medication changes 7

Common Pitfalls to Avoid

• Avoid high-dose vitamin K (10 mg) as it may lower INR more than necessary and lead to warfarin resistance for up to a week 5
• Do not use subcutaneous vitamin K as response is unpredictable and sometimes delayed 5
• Avoid IV vitamin K bolus due to risk of anaphylaxis; if IV route necessary, give as slow infusion over 30 minutes 5
• Do not assume bleeding caused the elevated INR—while bleeding can increase INR, drug interactions are more commonly the culprit 8
• Patients with high maintenance warfarin doses (>40 mg/week), multiple coadministered medications, renal failure, older age, and alcohol use are at highest risk for drug interactions and bleeding 3, 9