Important Drug-Drug Interactions Involving INR and Warfarin

Question 1

Amiodarone {when taken with Warfarin} causes INR to (increase/decrease).

Answer 1

Increase (based on CYP inhibition of 2C9 (metabolizes S-enantiomer of warfarin) in addition to potentially promoting a hyperthyroid state which leads to clotting factor breakdown)

Question 2

Androgens [Danazol, Methyltestosterone, Oxandrolone] {when taken with Warfarin} cause INR to (increase/decrease).

Answer 2

Increase (appears to cause increase in AUC of vitamin K antagonists)

Question 3

Antibiotics {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 3

Increase (based on CYP inhibition, alterations to vitamin K2 flora, as well as possible protein binding alterations) [POTENTIALLY STRONG INTERACTION]

Question 4

Azole antifungals (fluconazole, itraconazole) {when taken with Warfarin} cause INR to (increase/decrease).

Answer 4

Increase due to CYP2C9/3A4 inhibition [STRONG INTERACTION]

Question 5

Which antibiotics are commonly implicated in increasing INR {when taken with Warfarin}?

Answer 5

Sulfonamide antibiotics like Bactrim (due to CYP2C9 inhibition, protein displacement, GI flora alterations), metronidazole (CYP2C9 inhibition), doxycycline (potentially due to PT reductions or flora changes), macrolides (based on GI flora changes), cephalosporins (anticoagulant properties based on side chain properties, platelet inhibition and K2 GI flora killing)

Question 6

Cancer therapies (Capecitabine, Imatinib, Tamoxifen, 5-FU) {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 6

Increase, however limited data exists for the Imatinib-Warfarin interaction; Capecitabine, 5-FU and Tamoxifen (to a lesser extent) all inhibit CYP2C9 and can greatly raise the AUC of Warfarin

Question 7

Acetaminophen {when taken with Warfarin} causes INR to (increase/decrease).

Answer 7

Increase (at doses GREATER than 2,000 mg/day; may be due to ingestion of APAP leading to reduction in the concentration of vitamin K-dependent clotting factors)

Question 8

Fenofibrate and Gemfibrozil {when taken with Warfarin} cause INR to (increase/decrease).

Answer 8

Increase (via CYP2C9 inhibition, increased anticoagulant affinity for binding sites and potential protein displacement)

Question 9

Statins (Rosuvastatin, Fluvastatin) {when taken with Warfarin} cause INR to (increase/decrease).

Answer 9

Increase (from studies that demonstrate raised AUC/Cmax with concomitant administration; may be due to CYP2C9 inhibition)

Question 10

Steroids {when taken with Warfarin} cause INR to (increase/decrease).

Answer 10

Increase (via enhanced anticoagulation effect by an unclear mechanism).

Question 11

SSRIs [Fluoxetine, Duloxetine] and some SNRIs (Venlafaxine) {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 11

Increase (due to some antidepressants having antiplatelet properties that result in bleeding risk).

Question 12

Levothyroxine {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 12

Increase (enhanced via several pathways: hypothyroidism may be associated with slowed vitamin K dependent clotting factor metabolism, warfarin protein binding reduction, increased affinity for vitamin K-dependent epoxide reductase with warfarin)

Question 13

Phenytoin and Warfarin interaction

Answer 13

Phenytoin may raise warfarin response by displacing warfarin from binding sites (transiently), but this boost in response may be undone by induction of CYP3A4 and 1A2 (which partially metabolizes warfarin). This interaction may also cause increased phenytoin exposure.

Question 14

Tramadol {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 14

Increase (via enhanced anticoagulant effects through potential CYP3A4-mediated metabolism competition).

Question 15

Dicloxacillin {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 15

Decrease (via diminished anticoagulant effect by inducing CYP3A4 and 2C9).

Question 16

Nafcillin {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 16

Decrease (via profound CYP-induction) [POTENTIALLY STRONG INTERACTION]

Question 17

Griseofulvin {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 17

Decrease (may be due to CYP-induction but the mechanism is uncertain)

Question 18

Barbiturates {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 18

Decrease (due to CYP2C9 and CYP3A4 induction, though data is limited)

Question 19

Carbamazepine {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 19

Decrease (requires dose adjustments likely due to induction of CYP-enzymes)

Question 20

Ritonavir {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 20

Decrease (due to CYP2C9 induction, requires close monitoring)

Question 21

Sucralfate {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 21

Decrease (encourage patients to take warfarin 2 hours prior to sucralfate; interaction is potentially based around binding of sucralfate to warfarin, resulting in reduced effects)

Question 22

Cholestyramine {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 22

Decrease (separate warfarin and cholestyramine by 3-4 hours; based on gastrointestinal tract binding of cholestyramine to warfarin)

Question 23

St. John’s Wort {when taken with Warfarin} can cause INR to (increase/decrease).

Answer 23

Decrease (AVOID; interaction based on CYP-induction)

Question 24

Cimetidine and Warfarin interaction

Answer 24

This interaction may result in adverse bleeding events due to an enhanced anticoagulant effect

Question 25

NSAID and Warfarin interaction

Answer 25

NSAIDs and Warfarin may result in serious bleeding or bruising due to increased bleeding risk/protein displacement; NSAIDs may affect PT

Question 26

Penicillins (besides Nafcillin and Dicloxacillin) {when taken with Warfarin} cause INR to (increase/decrease).

Answer 26

Increase due to alterations in gut flora that produce Vitamin K

Question 27

Depakote/Valproate/
Valproic Acid {when taken with Warfarin} cause INR to (increase/decrease).

Answer 27

Increase (via displacement on proteins)