Table 4:

Important warfarin-drug interactions and management recommendations

	Precipitant Drug	Nature of Interaction	Recommendations
Antibiotics	All antibiotics	Alteration in gut flora production of vitamin K21	Closer monitoring of INR levels
	Sulfonamides	CYP450 2C9 inhibition24	Reduce dose of warfarin by 25%24
	Metronidazole	CYP450 2C9 inhibition27	Reduce dose of warfarin by 33%27
	Ciprofloxacin	CYP450 1A2 inhibition28	Closer monitoring of INR levels
	Clarithromycin	CYP450 3A4 inhibition30	Closer monitoring of INR levels
	Erythromycin	CYP450 3A4 inhibition30	Closer monitoring of INR levels
	Azithromycin	CYP450 3A4 inhibition16	Closer monitoring of INR levels
	Nafcillin	CYP450 3A4 induction32, 33	Closer monitoring of INR levels; full induction of CYP450 enzymes occurs in 2–4 weeks after initiation and persists up to 2–4 weeks after discontinuation of nafcillin
	Flucloxacillin	CYP450 3A4 induction34	Closer monitoring of INR levels
	Cloxacillin	CYP450 3A4 induction35	Closer monitoring of INR levels
	Rifampin	CYP450 3A4 induction166	Closer monitoring of INR levels
Antifungals	Fluconazole	CYP450 2C9 inhibition 38	Use alternative if possible, otherwise closer monitoring is warranted
	Voriconazole	CYP450 2C9 inhibition 40	Use alternative if possible, otherwise closer monitoring is warranted
	Miconazole	CYP450 2C9 inhibition 38	Consider alternative such as nystatin, otherwise closer monitoring is warranted
Antiretrovirals	Ritonavir	CYP450 3A446	Closer monitoring of INR levels
Antiarrhythmic drugs	Amiodarone	CYP450 2C9 and 3A4 inhibition150	Decrease dose of warfarin by 25%152
	Dronedarone	CYP450 3A4 inhibition148	Closer monitoring of INR levels
Anti-lipidemic agents	Atorvastatin	CYP450 3A4 inhibition 51	Closer monitoring of INR levels
	Rosuvastatin	CYP450 3A4 inhibition51	Closer monitoring of INR levels
	Simvastatin	CYP450 3A4 inhibition 51	Closer monitoring of INR levels
	Fluvastatin	CYP450 2C9 inhibition 51	Decrease dose of warfarin by 25%
	Gemfibrozil	CYP450 2C9 inhibition56	Decrease dose of warfarin by 20% 58
Antiepileptic drugs	Carbamazepine	CYP450 enzyme induction 69	Increase dose of warfarin by 50% with close follow-up69
	Phenytoin	Biphasic interaction with initial displacement from protein binding and then enzyme induction72	Closer monitoring of INR levels
Antidepressants	Fluvoxamine	CYP450 2C9 and 3A4 inhibition (68, 71	Consider alternatives such as sertraline, citalopram, or escitalopram; otherwise closer monitoring of INR levels is warranted71
	Fluoxetine	CYP450 2C9 and 3A4 inhibition 71, 74	Consider alternatives such as sertraline, citalopram, or escitalopram; otherwise closer monitoring of INR levels is warranted71
Anti-platelet agents	Aspirin Clopidogrel Prasugrel Ticagrelor	Potentiation of bleeding	Minimize overlap to shortest duration indicated and consider starting a proton pump inhibitor 155
Chemotherapy	Fluorouracil	Multiple mechanisms 78	Decrease dose of warfarin by 20% 78
	Capecitabine	Possible enzyme induction	Closer monitoring of INR levels
	Paclitaxel	Displacement from protein binding or CYP450 3A4 inhibition 84	Closer monitoring of INR levels
	Enzalutamide	CYP450 enzyme induction79	Closer monitoring of INR levels
	Apreptiant	CYP450 enzyme induction 86	Closer monitoring of INR levels
Non-steroidal anti-inflammatory drugs	Both selective and non-selective cyclooxygenase inhibitors	Cyclooxygenase inhibition88	Avoid unless benefits clearly outweigh risk 14
Miscellaneous agents	Ethanol	CYP450 2C9 inhibition 56	Avoid excessive alcoholic consumption (< 60 gm/day) 93
	Acetaminophen	CYP450 enzyme inhibition92	When doses of acetaminophen exceed 2g/day, closer monitoring of INR levels is warranted
	Danazol	Inhibition of metabolism 96	Closer monitoring of INR levels
Herbal Agents	St. John’s Wort	CYP450 enzyme induction 66, 71, 102	Closer monitoring of INR levels
	Grapefruit Juice	CYP450 3A4 enzyme inhibition 100	Consume no more than 200 mL per day107
	Cranberry Juice	CYP450 enzyme inhibition 100	Consume no more than 24 ounces per day100