1. Evidence Supporting Relabeling of Warfarin

2. Effect of CYP2C9 genotype on Warfarin Maintenance Dose
Daily maintenance Dose (mg)
[69% % % % % %]
N=185, median time= 543 days ( days)
< Adapted from Higashi MK et al, JAMA 2002; 287:1690>

3. Effect of CYP2C9 genotype on Warfarin Dose (Induction Period)
<Adopted from Peyvandi F et al Clin Pharmacol Ther 2004;75: >

4. Effect of CYP2C9 genotype on warfarin
- Proportion of subjects-
-Without Therapeutic INR-
- Without Stable Dosing-
With > 1 variant allele
HR=0.65
Wild
-Days-
Insignificant difference in initial INR
95 days difference
< Adapted from Higashi MK et al, JAMA 2002; 287:1690>

5. Effect of CYP2C9 genotype on warfarin
HR=3.9
(1st 3 mon)
- Proportion of subjects-
-Without above-range INR-
- Without bleeding Event
HR=2.4
HR=1.4
Wild
With > 1 variant allele
-Days-
Significant difference between patients
with wild and with variant alleles
< Adapted from Higashi MK et al, JAMA 2002; 287:1690>

6. Effect of CYP2C9 Genotype on Warfarin (Induction Period)
% of patients with INR >3
p = 0.012
p = 0.006
*1/*1 *2/- *3/-
<Adopted from Peyvandi F et al Clin Pharmacol Ther 2004;75: >.

7. Additional factors

8. Effect of CYP2C9 (*1, 2, 3) and VKORC1 (-1639G>A) on Warfarin Dose
Daily maintenance Dose (mg)
19%
56%
25%
N=297 [ /1]
Within a CYP2C9 genotypes, further differentiation among VKORC1 genotypes
< Adapted from Sconce et al, Blood, October 2005>

9. Modeling of Warfarin Dose Requirements
Variables
P value
R2 for model %
Age
.001
16.7
CYP2C9 genotype
17.5
VKORC1
genotype
15.0
Height
16.0
Above 4
54.2
Genetic polymorphism accounted for significant
interindividual variability }
< Adapted from Sconce et al, Blood, October 2005>

10. Warfarin Questions
Does the committee agree that sufficient mechanistic and clinical evidence exists to support the recommendation
a. to use lower starting doses of warfarin for patients with genetic variations in CYP2C9 that lead to reduced activities?
b. to use lower starting doses of warfarin for patients with genetic variations in VKORC1 that lead to reduced activities?

11. Questions for the Committee (warfarin-cont’d)
2. Does the committee believe that genotyping some or all patients prior to beginning warfarin therapy would reduce adverse events and improve achievement of stable INR?
a. in patients with genetic variations in CYP2C9
b. in patients with genetic variations in VKORC1

12. Questions for the Committee (warfarin-cont’d)
3a. Does the committee believe that existing evidence of the influence of CYP2C9 genotypes warrants relabeling of warfarin?
If no, what
additional
information is
needed to provide
the necessary
evidence for
labeling update?
If yes, what
information should
be provided in the
label?

13. Questions for the Committee (warfarin-cont’d)
3b. Does the committee believe that existing evidence of the influence of VKORC1 genotypes warrants relabeling of warfarin?
If no, what
additional
information is
needed to provide
the necessary
evidence for
labeling update?
If yes, what
information should
be provided in the
label?

14. Labeling Recommendations
Acknowledgement
Labeling Recommendations
Nina Chace Maria Chan Steve Gutman
Joe Hacket Courtney Harper Shiew-Mei Huang
Patricia Love Angel Torres-Cabassa
FDA Pharmacogenomics Working Group
(chair: Larry Lesko)
Warfarin
Felix Frueh Shiew-Mei Huang Myong-Jin Kim Lawrence J Lesko George Shashaty Robert Temple
Sue-Jane Wang
OCPB Pharmacogenomics Working Group
(chair: Atik Rahman)