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Effect of CYP2C9 genotype on Warfarin Maintenance Dose Daily maintenance Dose (mg) [69% 15% 2% 10% 1.6% 2.7%] N=185, median time= 543 days (14-4032 days) < Adapted from Higashi MK et al, JAMA 2002; 287:1690>
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1
Evidence Supporting Relabeling of Warfarin
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Effect of CYP2C9 genotype on Warfarin Maintenance Dose
< Adapted from Higashi MK et al, JAMA 2002; 287:1690>
Dai
ly m
aint
enan
ce D
ose
(mg)
0
1
2
3
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6
*1*1 *1*2 *2*2 *1*3 *2*3 *3*3
N=185, median time= 543 days (14-4032 days)[69% 15% 2% 10% 1.6% 2.7%]
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Effect of CYP2C9 genotype on Warfarin Dose (Induction Period)
0
1
2
3
4
5
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Days 1-3 Day 4 Days 4-10 Days 11-17 Days 18-24
*1/*1*2/-*3/-
<Adopted from Peyvandi F et al Clin Pharmacol Ther 2004;75:198-203>N=125, (*1*1=55, *2/- =33, *3/- =21)
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Effect of CYP2C9 genotypeon warfarin
< Adapted from Higashi MK et al, JAMA 2002; 287:1690>
0
0.2
0.4
0.6
0.8
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1.2
0 100 200 300 4000
0.2
0.4
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0.8
1
1.2
0 200 400 600 800 1000 1200
- Proportion of subjects-
-Without Therapeutic INR- - Without Stable Dosing-
Insignificant difference in initial INR
95 days difference
With > 1 variant allele
Wild
-Days-
HR=0.65
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Effect of CYP2C9 genotypeon warfarin
< Adapted from Higashi MK et al, JAMA 2002; 287:1690>
0
0.2
0.4
0.6
0.8
1
1.2
0 500 1000 1500 20000
0.2
0.4
0.6
0.8
1
1.2
0 1000 2000 3000 4000
- Proportion of subjects-
-Without above-range INR- - Without bleeding Event
Significant difference between patients with wild and with variant alleles
With > 1 variant allele
Wild
-Days-
HR=1.4
HR=3.9 (1st 3 mon)
HR=2.4
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Effect of CYP2C9 Genotype on Warfarin (Induction Period)
<Adopted from Peyvandi F et al Clin Pharmacol Ther 2004;75:198-203>.
0
10
20
30
40
50
60
70
80 % of patients with INR >3
p = 0.006 p = 0.012
*1/*1 *2/- *3/-
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Additional factors
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Effect of CYP2C9 (*1, 2, 3)and VKORC1 (-1639G>A)
on Warfarin Dose
0
1
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*1*1 *1*2 *2*2 *1*3 *2*3/*3*3
A/AG/AG/G
Dai
ly m
aint
enan
ce D
ose
(mg)
< Adapted from Sconce et al, Blood, October 2005>
Within a CYP2C9 genotypes, further differentiation among VKORC1 genotypes
N=297 [165 66 10 42 13/1]
19%56%25%
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Modeling of Warfarin Dose Requirements
< Adapted from Sconce et al, Blood, October 2005>
Variables P value R2 for model %
Age .001 16.7
CYP2C9 genotype
.001 17.5
VKORC1genotype
.001 15.0
Height .001 16.0
Above 4 .001 54.2
Genetic polymorphism accounted for significant interindividual variability
}
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Warfarin Questions1. Does the committee agree that sufficient
mechanistic and clinical evidence exists to support the recommendation
b. to use lower starting doses of warfarin for patients with genetic variations in VKORC1 that lead to reduced activities?
a. to use lower starting doses of warfarin for patients with genetic variations in CYP2C9 that lead to reduced activities?
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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
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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 yes, what information should be provided in the label?
-If no, what additional information is needed to provide the necessary evidence for labeling update?
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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 yes, what information should be provided in the label?
-If no, what additional information is needed to provide the necessary evidence for labeling update?
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Felix Frueh Shiew-Mei Huang Myong-Jin Kim Lawrence J Lesko George Shashaty Robert TempleSue-Jane WangOCPB Pharmacogenomics Working Group (chair: Atik Rahman)
Nina Chace Maria Chan Steve Gutman Joe Hacket Courtney Harper Shiew-Mei Huang Patricia Love Angel Torres-CabassaFDA Pharmacogenomics Working Group (chair: Larry Lesko)
Acknowledgement
Warfarin
Labeling Recommendations