# Presentation: 702282

## Evidence Supporting Relabeling of Warfarin

**Evidence Supporting Relabeling of Warfarin**

## Effect of CYP2C9 genotype 

**on Warfarin Maintenance Dose**

**< Adapted from Higashi MK et al, JAMA 2002; 287:1690> **

**Daily maintenance Dose (mg)**

**N=185, median time= 543 days (14-4032 days)**

**[69%     15%      2%      10%      1.6%    2.7%]**

## Effect of CYP2C9 genotype on Warfarin Dose (Induction Period) 

***<Adopted from Peyvandi F et al Clin Pharmacol Ther 2004;75:198-203>***

**N=125, (*1*1=55, *2/- =33, *3/- =21)**

## Effect of CYP2C9 genotype

**on warfarin**

**< Adapted from Higashi MK et al, JAMA 2002; 287:1690> **

**- 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**

## Effect of CYP2C9 genotype

**on warfarin**

**< Adapted from Higashi MK et al, JAMA 2002; 287:1690> **

**- 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**
** ****(1****st**** 3 mon)**

**HR=2.4**

## Effect of CYP2C9 Genotype on Warfarin (Induction Period) 

***<Adopted from Peyvandi F et al Clin Pharmacol Ther 2004;75:198-203>.***

** ****% of patients with INR >3**

** ****p = 0.006**

** ****p = 0.012**

***1/*1   *2/-    *3/-**

## Additional factors

## Effect of CYP2C9 (*1, 2, 3)and VKORC1 (-1639G>A)on Warfarin Dose

**Daily maintenance Dose (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%**

## 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 |
| VKORC1
genotype | .001
 | 15.0 |
| Height | .001 | 16.0 |
| Above 4 | .001 | 54.2 |

**Genetic polymorphism accounted for significant **
**interindividual variability **

**}**

## Warfarin Questions

**Warfarin Questions**

**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?**

## 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***_

## 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?**

## 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?**

## 	Acknowledgement

**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)**

**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)**

**	****Acknowledgement**

**	****Warfarin **

**	****Labeling Recommendations**