Clinically Relevant Drug-Drug Interactions in Primary Care

Mary Carpenter, PharmD; Holly Berry, PharmD; Allen L. Pelletier, MD


Am Fam Physician. 2019;99(9):558-564. 

In This Article

Anticoagulation Interactions


Warfarin (Coumadin) inhibits vitamin K–dependent clotting factors and is metabolized by CYP450 isozymes. A wide range of drugs, including over-the-counter and herbal products, interact with warfarin.[7] Warfarin interactions can increase patients' risk for major bleeding or thrombotic complications. Vitamin K ingestion modulates warfarin's effects on coagulation, making a discussion of food-drug interactions with patients essential. Information for patients about warfarin interactions with foods and herbal products can be found at[8] Drugs that affect vitamin K (directly or indirectly) or alter warfarin metabolism may have a significant effect on the international normalized ratio (INR). Drugs that affect other parts of the coagulation system (e.g., platelets) when used in conjunction with warfarin may also affect risk of bleeding or thrombosis. Awareness of these interactions is critical to safely managing patients receiving warfarin. Collaborative care with pharmacists in anticoagulation clinics has been demonstrated to improve patient safety and outcomes.[3]

Warfarin and Antimicrobials

Antimicrobials can inhibit CYP450 isozymes, alter protein binding, and diminish absorption of vitamin K by altering the gut flora.[9] Protein-binding and metabolism alterations of warfarin are the mechanisms of interaction that pose clinical significance. The antimicrobials most likely to affect the INR significantly are trimethoprim/sulfamethoxazole, metronidazole (Flagyl), and fluconazole (Diflucan). Other antimicrobials such as ciprofloxacin, levofloxacin (Levaquin), azithromycin (Zithromax), and clarithromycin (Biaxin) may affect the INR; however, the effects are variable and tend to be patient specific.[9]

Antimicrobial agents with a lower likelihood of affecting the INR include penicillin G benzathine, clindamycin, and first- and fourth-generation cephalosporins.[9]

Empiric warfarin dosage adjustments should be considered with concomitant use of trimethoprim/sulfamethoxazole, rifampin, fluconazole, and/or metronidazole.[10,11] Considerable variability in patient-specific response occurs; knowledge of previous exposure and response should be considered. Regardless of the antimicrobial, the INR should be checked within three to five days of initiation and within three to five days after discontinuation of the antimicrobial.[12] Interactions and management strategies for the antimicrobials that consistently interact with warfarin are provided in Table 1.[9–12]

Warfarin and Amiodarone

The interaction between warfarin and amiodarone is mediated by inhibition of CYP2C9, 1A2, and 3A4 enzymes, leading to increased warfarin concentrations and increased bleeding risk.[13,14] The effects of this interaction are typically seen within the first few days; however, amiodarone has a long half-life so several warfarin adjustments may be needed before the INR has completely stabilized.[15] An empiric warfarin dosage reduction of 30% to 50% upon initiation of amiodarone therapy is recommended, followed by several weeks of weekly monitoring of the INR to ensure warfarin dosing remains optimal.

Warfarin and Statins

Fluvastatin (Lescol), lovastatin (Mevacor), rosuvastatin (Crestor), and simvastatin (Zocor) inhibit warfarin metabolism by the inhibition of CYP2C9, leading to increased warfarin concentrations and increased bleeding risk.[16] Atorvastatin (Lipitor) and pravastatin (Pravachol) appear to be safer alternatives. If these statins are not appropriate for treating a patient's lipids, the patient's INR should be monitored more frequently, and warfarin dosage adjustments should be performed accordingly.[17]

Warfarin and Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) increase gastric irritation and erosion of the protective lining of the stomach, potentially leading to the formation of gastrointestinal ulcers, which could result in gastrointestinal bleeding. These effects in combination with the anticoagulant effect of warfarin increase the risk of bleeding without affecting the INR.[18,19] The cyclooxygenase-2 inhibitor, celecoxib (Celebrex), does not affect platelet function and is associated with less gastrointestinal erosion. Literature correlating gastrointestinal bleeding risk with celecoxib use is limited. Patients should be educated to report abdominal pain or signs and symptoms of gastrointestinal bleeding to their physician when taking warfarin concomitantly with any NSAID.[20–22]

If concomitant therapy with warfarin and aspirin/dipyridamole (Aggrenox) is necessary, the dosage of aspirin/dipyridamole should be limited to 100 mg per day or less to minimize bleeding risk.[18] It is preferable to use alternatives to NSAIDs, such as acetaminophen, topical therapy, or judiciously prescribed opioid analgesics when indicated. Acetaminophen does not alter platelet function, but concomitant use may increase the pharmacodynamic effect of warfarin, increasing the INR. To be cautious, limit the acetaminophen dosage to 2 g per day for no more than seven days and complete more frequent INR testing.[18]

Direct Oral Anticoagulant Interactions

Direct oral anticoagulant interactions inhibit factor Xa (rivaroxaban [Xarelto], apixaban [Eliquis], edoxaban [Savaysa]) or directly inhibit thrombin (dabigatran [Pradaxa]).[23] Direct oral anticoagulant interactions are attractive alternatives to warfarin for some indications because of their ease of administration, no requirement for INR monitoring, no interaction between vitamin K or food, and comparable effectiveness and safety profiles.[24] However, clinically significant interactions occur with drugs that share common metabolic pathways with direct oral anticoagulant interactions.[23] Drugs that inhibit both CYP3A4 and P-gp can pose the greatest interaction and increase bleeding risk with direct oral anticoagulant interactions. Drugs that may increase bleeding risk include ketoconazole, ritonavir (Norvir), fluconazole, and amiodarone.[23,25] Specific dosing adjustments for the various direct oral anticoagulant interactions are found in Table 2.[26–29]