Common Medications That Reduce INR in Warfarin Patients
The most clinically significant medications that reduce INR in warfarin patients are rifampin (requiring up to 50% warfarin dose increases), carbamazepine (requiring 50% dose increases), phenytoin, phenobarbital, and other barbiturates, all acting as CYP450 enzyme inducers. 1, 2, 3
Primary CYP450 Enzyme Inducers
Rifampin - The Most Potent Interaction
- Rifampin causes the most dramatic reduction in warfarin efficacy, with 86.3% of patients experiencing clinically significant INR decreases (median INR dropping to 1.3) 3
- Warfarin dose increases of median 5.5 mg are required to restore therapeutic INR, with stabilization taking approximately 18 days 3
- Approximately 31% of patients fail to achieve target INR despite dose adjustments 3
- The interaction effect becomes maximal 5-7 days after rifampin initiation and persists for 5-7 days after discontinuation 4
- Mechanism: Strong induction of CYP2C9 enzyme, dramatically increasing warfarin metabolism 3
Anticonvulsants
- Carbamazepine decreases mean INR by 0.63 and requires 50% increases in warfarin maintenance doses 1
- Phenytoin exhibits biphasic interaction: initially increases INR through protein displacement, then ultimately decreases INR through CYP450 induction requiring higher warfarin doses 1
- Full CYP450 enzyme induction occurs 2-4 weeks after initiation and persists 2-4 weeks after discontinuation 1
Barbiturates
- Phenobarbital, pentobarbital, butabarbital, amobarbital, and secobarbital all reduce INR through CYP450 induction 2
- Primidone (metabolized to phenobarbital) similarly reduces warfarin efficacy 2
Additional Medications That Reduce INR
Bile Acid Sequestrants
- Cholestyramine interferes with intestinal absorption of warfarin 1, 2
- Spacing warfarin 2 hours before or 6 hours after cholestyramine administration only partially mitigates this interaction because warfarin undergoes enterohepatic circulation 1
Other CYP450 Inducers
- Nafcillin: Full enzyme induction occurs 2-4 weeks after initiation and persists 2-4 weeks after discontinuation 1
- Griseofulvin reduces warfarin efficacy through enzyme induction 2
- Glutethimide acts as CYP450 inducer 2
Herbal Products
- St. John's wort is most commonly associated with decreased warfarin effects through CYP450 enzyme induction 2
- Coenzyme Q10 (ubidecarenone) decreases warfarin effects 2
Miscellaneous Agents
- Azathioprine reduces INR 2
- Dicloxacillin decreases warfarin efficacy 2
- Vitamin K (dietary or supplemental) competitively antagonizes warfarin 1, 2
- High vitamin K diet reduces INR 2
Monitoring Protocol for INR-Reducing Medications
Immediate Actions When Starting Enzyme Inducers
- Increase INR monitoring frequency immediately upon initiation of any CYP450 inducer 1, 2
- Check INR within 3-5 days of starting rifampin, carbamazepine, or phenytoin 3, 4
- Continue weekly INR monitoring for 2-4 weeks until enzyme induction reaches steady state 1
Dose Adjustment Strategy
- For rifampin: Anticipate need for substantial warfarin dose increases (median 5.5 mg increase) 3
- For carbamazepine: Expect approximately 50% increase in warfarin requirements 1
- Monitor for 2-4 weeks after discontinuing enzyme inducers, as effects persist during this washout period 1
Critical Pitfalls to Avoid
- Failing to monitor after discontinuation: CYP450 enzyme activity returns gradually over 2-4 weeks, creating risk of supratherapeutic INR if warfarin dose is not reduced 1
- Underestimating rifampin's potency: This interaction is more severe than most other drug interactions, with nearly 90% of patients affected 3
- Missing dietary vitamin K: Patients starting high vitamin K diets (leafy greens, certain oils) will experience reduced INR 2
- Overlooking herbal supplements: St. John's wort is widely available over-the-counter and patients may not report its use 2