Warfarin Requires Dose Adjustment When Starting Anti-TB Drugs
Warfarin (Option A) is the medication that requires dose adjustment when initiating anti-tuberculosis therapy, while lisinopril does not require adjustment.
The Critical Warfarin-Rifampin Interaction
The primary concern is the interaction between warfarin and rifampin (a cornerstone of TB treatment), which creates a clinically significant drug-drug interaction through CYP450 enzyme induction:
- Rifampin is a potent inducer of the hepatic cytochrome P450 system, particularly CYP2C9, which dramatically increases warfarin metabolism and reduces its anticoagulant effect 1, 2
- A retrospective study of 102 patients found that 86.3% experienced a clinically significant interaction with median INR dropping to 1.3 (IQR 1.1-1.6) when rifampin was added to warfarin therapy 2
- Approximately 31% of patients failed to reach therapeutic INR despite dose adjustments, highlighting the severity of this interaction 2
Practical Warfarin Dose Adjustment Strategy
During TB Treatment Initiation (Onset Phase):
- Anticipate warfarin dose increases of 30-80% from week 1 to week 2, and a further 20-100% from week 2 to 4 3
- Overall warfarin dose typically needs to increase by approximately 165% (range 99-227%) to reach steady state at 30 days 3
- One case series documented warfarin doses doubling during rifampin therapy 1
- Monitor INR at least twice weekly for the first 2 weeks after starting rifampin 3
After TB Treatment Completion (Offset Phase):
- This is when bleeding risk is highest—anticipate proportionate warfarin dose decreases of 15-25% for weeks 1 and 2, and a further 20% for weeks 3 and 4 3
- Overall warfarin dose typically decreases by approximately 67% (range 58-70%) to reach steady state at 4 weeks 3
- One patient experienced an INR of 7.22 with macroscopic hematuria four weeks after rifampin discontinuation 1
- Continue weekly INR monitoring after stopping rifampin until warfarin dose stabilizes at pre-rifampin levels 1
Alternative Strategy: Consider Rifabutin
If achieving therapeutic anticoagulation proves difficult:
- Rifabutin interacts with warfarin to a lesser degree than rifampin and may be considered as an alternative 4
- One case achieved therapeutic INR with a lower warfarin dose (115 mg weekly vs 140 mg weekly) six days after switching from rifampin to rifabutin 4
Why Lisinopril Does NOT Require Adjustment
- ACE inhibitors like lisinopril are not metabolized by CYP450 enzymes and do not have clinically significant interactions with rifampin or other first-line TB drugs (general medical knowledge)
- The provided guidelines addressing renal dosing, hepatic disease, and drug interactions with TB medications make no mention of ACE inhibitor dose adjustments 5
- Lisinopril can be continued at the same dose throughout TB treatment
Common Pitfalls to Avoid
- Do not assume a "normal" warfarin dose increase will suffice—the interaction is profound and highly variable between patients 2, 3, 6
- Do not reduce INR monitoring frequency too quickly—maintain at least twice weekly checks during the first 2 weeks of both onset and offset phases 3
- Do not forget to adjust warfarin downward after completing TB therapy—this is when life-threatening bleeding occurs 1
- Genetic polymorphisms (CYP2C9, VKORC1) affect the magnitude of interaction, with slow metabolizers potentially responding at lower doses 6