Warfarin Sodium: Package Insert and Label Information (Page 4 of 5)

12.5 Pharmacogenomics

CYP2C9 and VKORC1 Polymorphisms

The S -enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively.

Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians.

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., –1639G>A) have been associated with variable warfarin dose requirements. VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [ see Dosage and Administration (2.3)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.

14 CLINICAL STUDIES

14.1 Atrial Fibrillation

In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients*
N Thromboembolism % Major Bleeding
*All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks.
Study Warfarin-Treated Patients Control Patients PT Ratio INR % Risk Reduction p -value Warfarin-Treated Patients Control Patients
AFASAK 335 336 1.5 to 2.0 2.8 to 4.2 60 0.027 0.6 0.0
SPAF 210 211 1.3 to 1.8 2.0 to 4.5 67 0.01 1.9 1.9
BAATAF 212 208 1.2 to 1.5 1.5 to 2.7 86 <0.05 0.9 0.5
CAFA 187 191 1.3 to 1.6 2.0 to 3.0 45 0.25 2.7 0.5
SPINAF 260 265 1.2 to 1.5 1.4 to 2.8 79 0.001 2.3 1.5

Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [ see Dosage and Administration (2.2)].

14.2 Mechanical and Bioprosthetic Heart Valves

In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
Patients Treated With
py=patient years
Event Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin
Thromboembolism 2.2/100 py 8.6/100 py 7.9/100 py
Major Bleeding 2.5/100 py 0.0/100 py 0.9/100 py

In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
Event Moderate Warfarin Therapy INR 2.65 High Intensity Warfarin Therapy INR 9.0
py=patient years
Thromboembolism 4.0/100 py 3.7/100 py
Major Bleeding 0.95/100 py 2.1/100 py

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0 to 2.25 vs. INR 2.5 to 4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

14.3 Myocardial Infarction

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7.

Table 7: WARIS – Endpoint Analysis of Separate Events
% Risk
Warfarin Placebo Reduction
Event (N=607) (N=607) RR (95% CI) ( p -value)
RR=Relative risk; Risk reduction=(1 — RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years
Total Patient Years of
Follow-up 2018 1944
Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p=0.030)
Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p=0.068)
Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001)
Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002)

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR

2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the Table 8.

Table 8: WARIS II – Distribution of Events According to Treatment Group
Event Aspirin (N=1206) Warfarin (N=1216) Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p -value
a Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.
b The rate ratio is for aspirin plus warfarin as compared with aspirin.
c The rate ratio is for warfarin as compared with aspirin.
d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion.
e Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke.
CI=confidence interval
ND=not determined
No. of Events
Major Bleeding a 8 33 28 3.35 b (ND) 4.00 c (ND) ND ND
Minor Bleeding d 39 103 133 3.21 b (ND) 2.55 c (ND) ND ND
Composite Endpoints e 241 203 181 0.81 (0.69 to 0.95) b 0.71 (0.60 to 0.83) c 0.03 0.001
Reinfarction 117 90 69 0.56 (0.41 to 0.78) b 0.74 (0.55 to 0.98) c <0.001 0.03
Thromboembolic Stroke 32 17 17 0.52 (0.28 to 0.98) b 0.52 (0.28 to 0.97) c 0.03 0.03
Death 92 96 95 0.82

There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

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