Lauryn E. Cyrus, PharmD, MBA

Warfarin (Jantoven, Coumadin) is the most commonly prescribed anticoagulant in the United States, having been indicated for the treatment and prevention of venous thromboembolism and the prevention of thromboembolic complications associated with atrial fibrillation, heart valve replacement, and myocardial infarction.

 The number of patients treated with warfarin has continued to increase as the population ages. Approximately 4 million outpatients in the United States are currently receiving long-term anticoagulation with warfarin, a number that is likely to increase as the population ages.

For decades, warfarin has been the cornerstone of anticoagulation therapy; however, it has the potential to interact with many medications and has a narrow therapeutic range. As a result, patients taking warfarin must undergo frequent monitoring using the international normalized ratio (INR) to avoid potentially life-threatening complications from undercoagulation and overcoagulation.

 Many antimicrobials are known to increase INR and are often unavoidable in patients receiving long-term warfarin therapy.

 This article aims to guide pharmacists in making evidence-based decisions in managing INR during high-risk antimicrobial therapy.

Warfarin Pharmacokinetics and Pharmacology

Warfarin, a racemic mixture of R and S isomers, exerts its anticoagulant effect by inhibiting the synthesis of vitamin K-dependent clotting factors produced by the liver (Online Figure 1).

 S-warfarin is the more potent isomer and is primarily metabolized by the cytochrome P450 (CYP) 2C9 isoenzyme, whereas R-warfarin is metabolized by CYP 1A2 and 3A4. Warfarin is highly protein bound: following a single dose, the terminal half-life is approximately 1 week, with a mean effective half-life of 40 hours.

 Most clinically significant warfarin interactions occur when 2C9 metabolism is altered, but other mechanisms are possible, including displacement of warfarin from albumin and inhibition of 1A2 and 3A4 (Figure 2).

Interactions with High-Risk Antimicrobials 

Warfarin can interact with a wide range of antimicrobials that are metabolized by CYP450 enzymes, resulting in an elevation of INR. High-risk antimicrobials that are commonly prescribed and most likely to interact with warfarin include trimethoprim/ sulfamethoxazole (TMP-SMX), ciprofloxacin, levofloxacin, metronidazole, erythromycin, clarithromycin, and fluconazole.

 A 2008 study of ciprofloxacin, levofloxacin, gatifloxacin, cotrimoxazole, fluconazole, cephalexin, and amoxicillin in patients stabilized on warfarin showed a significant increase in bleeding episodes across all antimicrobials.

Whether in a community or hospital setting, pharmacists can play a key role in preventing adverse effects due to warfarin— antimicrobial interactions. Once an interaction is identified in the community setting, pharmacists may need to both notify anticoagulation providers who are unaware that a high-risk antimicrobial has been prescribed, and counsel patients on the potential for increased bleeding. Pharmacists responsible for managing warfarin in hospital-based outpatient clinics should inquire about medication changes at each visit, estimate the significance and severity of interactions, and make appropriate adjustments. Ultimately, patients must understand that, if managed inappropriately, warfarin interactions with antimicrobials can be fatal.

Managing Interactions with High-Risk Antimicrobials 

Managing interactions between warfarin and antimicrobials can be preemptive or reactive, and is often necessary in preventing or correcting a nontherapeutic INR. A preemptive approach is to decrease the dose of warfarin on initiation of an antimicrobial and increase INR monitoring; a reactive approach is to make dose adjustments based on INR response. This latter approach may be used when the onset of the interaction is immediate; however, for interactions that are delayed, this may not be the preferred method. For a summary of suggested dose adjustments, see the Online Table.

Table: Summary of Suggested Dose Adjustments

				May consider empiric 25%-40% warfarin dose reduction.

 Patients should return for monitoring in 2-3 days.

				Most patients will have an increase in INR, but some will experience no effect. May consider empiric 10%-30% warfarin dose reduction.

				Short-term INR follow-up with no change in warfarin dosing is appropriate for patients treated with levofloxacin.

				Anticoagulation providers may consider an empiric 10%-15% warfarin dose reduction in patients taking concomitant erythromycin.

 INR should be monitored closely during therapy.

				Monitor INR more frequently when starting or stopping clarithromycin. May consider empiric 15%-25% warfarin dose reduction.

				Effects of fluconazole on INR are more pronounced in patients with reduced renal function due to reduced clearance of fluconazole. May consider empiric 25%-30% warfarin dose reduction with eventual reductions approaching 80%.

TMP-SMX, a sulfonamide-containing antibiotic, inhibits CYP2C9 and has the potential for protein-binding interactions. Because TMP-SMX is one of the most frequently prescribed antibiotics, the opportunities for coadministration with warfarin are quite prevalent. One study found that warfarin-stabilized patients older than 65 years taking a sulfonamide were nearly 3 to 5 times more likely to be hospitalized for bleeding than patients who were not exposed to the interaction.

 Another study reported an adjusted relative risk of 20.1 (95% CI, 10.7-37.9) for over-anticoagulation when TMP-SMX was started in a patient on stable doses of warfarin.

 Although the American College of Chest Physicians does not make specific dosing recommendations for anticoagulated patients, it does identify the interaction between TMP-SMX and warfarin as highly probable.

The exact mechanism of the quinolone— warfarin interaction is unknown, but it may be due to disruption of gut flora, displacement of warfarin from albumin, and inhibition of CYP1A2.

 Of the fluoroquinolones, ciprofloxacin and ofloxacin appear to be the most likely to interact with warfarin.

 In selecting quinolone antibiotics for patients stabilized on warfarin, providers should consider newer agents that do not significantly alter warfarin metabolism, such as levofloxacin. One study examined the impact of preemptive warfarin dose reduction on anticoagulation after initiation of TMP-SMX or levofloxacin and found that preemptive dose reduction with TMP-SMX was beneficial; preemptive dose reduction with levofloxacin was less beneficial, as the interaction had a milder effect on INR.

It has been suggested that metronidazole inhibits metabolism of the warfarin S-isomer, but not the R-isomer. For example, O’Reilly found that in 8 subjects given only the warfarin S-isomer, a daily dose of 750 mg of metronidazole for 1 week increased the half-life of warfarin by approximately one-third (this effect was not noted in patients receiving metronidazole and the warfarin R-isomer).

 Further, in separate cases, Kazmier and Dean reported significant bleeding in patients taking metronidazole and warfarin; the interaction had been suggested based on the disulfiram-like effect of metronidazole and the known interaction between warfarin and disulfiram.

 Concurrent use of warfarin and metronidazole is generally not preferred; however, for patients requiring metronidazole therapy, preemptive warfarin dose reduction may be beneficial.

Erythromycin is thought to interact with warfarin by stimulating liver enzymes to produce metabolites that bind to CYP450, form inactive complexes, and reduce warfarin metabolism. A study of 12 subjects who were given warfarin 1 mg/kg and erythromycin 250 mg orally for 8 days showed that the clearance of a single dose of warfarin was reduced by an average of 14%.

 As a precaution, anticoagulation providers may consider preemptive warfarin dose reduction with careful INR monitoring in patients taking erythromycin. Clarithromycin is thought to interact with warfarin in the same manner as erythromycin. According to one study, 2 men, aged 61 and 70 years, who received stable warfarin regimens, experienced supratherapeutic elevations in prothrombin time (98.4 and 26.8 sec, respectively) and had INRs of 90.3 and 5.6, respectively, 5 days after starting clarithromycin for atypical pneumonia.

 As with erythromycin, anticoagulation providers may consider preemptive warfarin dose reduction with careful INR monitoring in patients taking concomitant clarithromycin.

The interaction between azole antifungals and warfarin is likely due to doserelated inhibition of warfarin metabolism.

 Fluconazole significantly inhibits CYP2C9, potentiating the anticoagulant effect of warfarin. The effects of fluconazole on INR are more pronounced in patients with reduced renal function, which was observed in a 39-year-old man who received warfarin (for a lower extremity thrombus) and oral fluconazole (50 mg/day for a fungal urinary tract infection).

 After attaining consistent INR values between 2.0 and 2.7 with warfarin, the patient’s INR increased to 5.2 four days after fluconazole was started. The patient’s INR returned to 1.5 after discontinuing fluconazole. If warfarin is added after fluconazole has been initiated, the interaction is of less significance; however, pharmacists should urge anticoagulation providers to consider preemptive warfarin dose reduction prior to initiating fluconazole in patients with reduced renal function (creatinine clearance ≤59 mL/min).

For years, warfarin has been the gold standard for oral anticoagulation. However, a narrow therapeutic index requires frequent monitoring to avoid serious complications. Warfarin often interacts with antimicrobials, increasing INR and exposing patients to the risk of major bleeding. Whether in a community or hospital setting, many pharmacists are in a prime position to identify potential warfarin—antimicrobial interactions and mitigate bleeding risk. This can be accomplished by knowing which antimicrobials are most likely to interact with warfarin and reviewing current literature on managing INR during high-risk antimicrobial therapy.

Dr. Montney is the Director of Pharmacy at Star Medical Center in Plano, Texas, and part-time pharmacist at Walgreens Pharmacy. While writing this article, he was working as the Pharmacist-in-charge at Walgreens in Ennis, Texas. Dr. Cyrus is the Pharmacist-in-charge at Maplewood Pharmacy in Dallas, Texas.

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Articles

Warfarin is the most commonly prescribed anticoagulant in the United States, having been indicated for the treatment and prevention of venous thromboembolism and the prevention of thromboembolic complications.