Warfarin Sodium (Page 6 of 8)

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*

*
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.

N

Thromboembolism

% Major Bleeding

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

2.8 to 4.2

60

0.027

0.6

0

SPAF

210

211

1.3 to 1.8

2 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 to 3

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

Warfarin

Dipyridamole/Aspirin

Pentoxifylline/Aspirin

Event

Thromboembolism

2.2/100 py

8.6/100 py

7.9/100 py

Major Bleeding

2.5/100 py

0/100 py

0.9/100 py

py = patient years

In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4 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

Thromboembolism

4/100 py

3.7/100 py

Major Bleeding

0.95/100 py

2.1/100 py

py = patient years

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2 to 2.25 vs. INR 2.5 to 4) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2% 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)

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 (1/100 py)

44 (2.3/100 py)

0.46 (0.28, 0.75)

54 (p = 0.002)

RR = Relative risk; Risk reduction = (1 — RR); CI = Confidence interval; MI = Myocardial infarction; py = patient years

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 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 Table 8.

Table 8: WARIS II – Distribution of Events According to Treatment Group

*
Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.
†
The rate ratio is for aspirin plus warfarin as compared with aspirin.
‡
The rate ratio is for warfarin as compared with aspirin.
§
Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion.
¶
Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke.

Event

Aspirin

(N = 1206)

Warfarin

(N = 1216)

Aspirin plus Warfarin

(N = 1208)

Rate Ratio

(95% CI)

p-value

No. of Events

Major Bleeding*

8

33

28

3.35† (ND)

ND

4‡ (ND)

ND

Minor Bleeding§

39

103

133

3.21† (ND)

ND

2.55‡ (ND)

ND

Composite Endpoints¶

241

203

181

0.81 (0.69 to 0.95)†

0.03

0.71 (0.60 to 0.83)‡

0.001

Reinfarction

117

90

69

0.56 (0.41 to 0.78)†

< 0.001

0.74 (0.55 to 0.98)‡

0.03

Thromboembolic

Stroke

32

17

17

0.52 (0.28 to 0.98)†

0.03

0.52 (0.28 to 0.97)‡

0.03

Death

92

96

95

0.82

CI = confidence interval

ND = not determined

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.

15 REFERENCES

OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

Warfarin Sodium Tablets USP, 1 mg are available as pink, capsule-shaped, biconvex scored tablets, debossed with TV/1 on the scored side and 1712 on the other side containing 1 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1712-01) and 1000 (NDC 0093-1712-10) tablets.

Warfarin Sodium Tablets USP, 2 mg are available as lavender, capsule-shaped, biconvex scored tablets, debossed with TV/2 on the scored side and 1713 on the other side containing 2 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1713-01) and 1000 (NDC 0093-1713-10) tablets.

Warfarin Sodium Tablets USP, 2.5 mg are available as green, capsule-shaped, biconvex scored tablets, debossed with TV/21/2 on the scored side and 1714 on the other side containing 2.5 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1714-01) and 1000 (NDC 0093-1714-10) tablets.

Warfarin Sodium Tablets USP, 3 mg are available as tan, capsule-shaped, biconvex scored tablets, debossed with TV/3 on the scored side and 1715 on the other side containing 3 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1715-01) tablets.

Warfarin Sodium Tablets USP, 4 mg are available as blue, capsule-shaped, biconvex scored tablets, debossed with TV/4 on the scored side and 1716 on the other side containing 4 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1716-01) and 1000 (NDC 0093-1716-10) tablets.

Warfarin Sodium Tablets USP, 5 mg are available as peach, capsule-shaped, biconvex scored tablets, debossed with TV/5 on the scored side and 1721 on the other side containing 5 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1721-01) and 1000 (NDC 0093-1721-10) tablets.

Warfarin Sodium Tablets USP, 6 mg are available as teal, capsule-shaped, biconvex scored tablets, debossed with TV/6 on the scored side and 1718 on the other side containing 6 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1718-01) tablets.

Warfarin Sodium Tablets USP, 7.5 mg are available as yellow, capsule-shaped, biconvex scored tablets, debossed with TV/71/2 on the scored side and 1719 on the other side containing 7.5 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1719-01) tablets.

Warfarin Sodium Tablets USP, 10 mg are available as white, capsule-shaped, biconvex scored tablets, debossed with TV/10 on the scored side and 1720 on the other side containing 10 mg warfarin sodium, USP, packaged in bottles of 100 (NDC 0093-1720-01) tablets.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Protect from light. Keep tightly closed.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Special Handling

Procedures for proper handling and disposal of potentially hazardous drugs should be considered. Guidelines on this subject have been published [see References (15)].

Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Specific Populations (8.1)].

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.