From the Guidelines
Warfarin's anticoagulant effect can be significantly increased by certain drug interactions, particularly with antibiotics, which can lead to dangerous bleeding risks. Medications that commonly increase warfarin's effect include antibiotics (especially fluoroquinolones, macrolides, and metronidazole) 1. These interactions occur through several mechanisms: inhibition of warfarin metabolism by affecting CYP2C9 enzymes, displacement of warfarin from protein binding sites, reduction of vitamin K production by altering gut flora, or direct effects on clotting factors.
Key Interactions
- Antibiotics such as sulfonamides, metronidazole, and fluoroquinolones can increase the anticoagulant effect of warfarin by inhibiting the CYP2C9 isoenzyme or altering the gut microbiome 1.
- Pre-emptive warfarin dose reductions of 25% and 33% for sulfamethoxazole and metronidazole respectively, are recommended when co-administered with warfarin 1.
- Patients taking warfarin should inform all healthcare providers about their medication before starting any new drugs, even over-the-counter medications or supplements.
Monitoring and Dosage Adjustments
- More frequent INR monitoring is necessary when starting or stopping interacting medications, and dosage adjustments may be required 1.
- Signs of excessive anticoagulation include unusual bruising, nosebleeds, bleeding gums, blood in urine or stool, and severe headaches, which require immediate medical attention.
Other Considerations
- Other medications such as amiodarone, statins, NSAIDs, SSRIs, and herbal supplements like garlic and ginkgo biloba can also increase warfarin's anticoagulant effect 1.
- The antibiotic dose will also contribute to the severity of this interaction, with higher doses leading to a greater increase in INR values 1.
From the FDA Drug Label
The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs. Classes of Drug also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
- Increased and decreased PT/INR responses have been reported (oral) (17-Alkyl Penicillins, intravenous, Gout Treatment Agents Testosterone Derivatives) (fluoroquinolones) (topical) ogen dextran (intravaginal, oral, systemic) activator (t-PA) dextrothyroxine moricizine hydrochloride* tolbutamide diazoxide nalidixic acid tramadol diclofenac naproxen trimethoprim/sulfamethoxazole dicumarol neomycin urokinase diflunisal norfloxacin valdecoxib disulfiram ofloxacin valproate doxycycline olsalazine vitamin E erythromycin omeprazole zafirlukast esomeprazole oxandrolone zileuton ethacrynic acid oxaprozin ezetimibe oxymetholone fenofibrate pantoprazole
The warfarin drug label lists several medications that may increase the anticoagulant effect of warfarin, including:
- 17-Alkyl Penicillins
- Gout Treatment Agents
- Testosterone Derivatives
- Fluoroquinolones
- Dextran
- Activator (t-PA)
- Dextrothyroxine
- Moricizine hydrochloride
- Tolbutamide
- Diazoxide
- Nalidixic acid
- Tramadol
- Diclofenac
- Naproxen
- Trimethoprim/sulfamethoxazole
- Dicumarol
- Neomycin
- Urokinase
- Diflunisal
- Norfloxacin
- Valdecoxib
- Disulfiram
- Ofloxacin
- Valproate
- Doxycycline
- Olsalazine
- Vitamin E
- Erythromycin
- Omeprazole
- Zafirlukast
- Esomeprazole
- Oxandrolone
- Zileuton
- Ethacrynic acid
- Oxaprozin
- Ezetimibe
- Oxymetholone
- Fenofibrate
- Pantoprazole 2
From the Research
Warfarin Drug Interactions
- Warfarin is an anticoagulant medication that can interact with other drugs, increasing the risk of bleeding 3, 4, 5.
- The interaction between warfarin and doxycycline can enhance the anticoagulant effect of warfarin, leading to severe bleeding 3.
- Other medications that can increase the risk of bleeding when used with warfarin include:
- Proton pump inhibitors (PPIs) may have a protective effect against warfarin-related gastrointestinal bleeding 4.
- The risk of bleeding associated with warfarin and antibiotic use is highest with azole antifungals 5.
- Warfarin may still be the preferred anticoagulant in certain clinical scenarios, such as patients with prosthetic valves, antiphospholipid syndrome, or a high risk of gastrointestinal bleeding 6.
Mechanism of Interaction
- The interaction between warfarin and other medications can be due to competitive binding to albumin and inhibition of the cytochrome P-450 system, leading to increased plasma levels of free warfarin 3.
- This increased level of free warfarin can result in enhanced anticoagulant effects and increased risk of bleeding 3, 4, 5.