Prescription Drug Information: Warfarin Sodium (Page 6 of 7)

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.

15 REFERENCES

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

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Warfarin Sodium Tablets USP, 7½ mg are supplied as yellow to light yellow, oval shaped uncoated scored tablets with debossing ‘768’ and ‘7½’ on either side of the breakline on one side and ‘AN’ on the other side. They are available as follows:

NDC: 70518-2717-00 100 in 1 BOX

NDC: 70518-2717-01 1 in 1 POUCH

Protect from light and moisture. Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.

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)].

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625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Instructions for Patients

Advise patients to:

  • Strictly adhere to the prescribed dosage schedule [ see Dosage and Administration ( 2.1) ].
  • If the prescribed dose of warfarin sodium is missed, take the dose as soon as possible on the same day but do not take a double dose of warfarin sodium the next day to make up for missed doses [ see Dosage and Administration (2.6) ].
  • Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy [ see Dosage and Administration ( 2.1) ].
  • Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days [ see Clinical Pharmacology ( 12.2) ].
  • Avoid any activity or sport that may result in traumatic injury [ see Use in Specific Populations ( 8.4) ] . And to tell their physician if they fall often as this may increase their risk for complications.
  • Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables [ see Drug Interactions ( 7.5) ].
  • Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see Warnings and Precautions (5) and Adverse Reactions (6)].
  • Immediately contact their physician when experiencing pain and discoloration of the skin (a purple bruise like rash) mostly on areas of the body with a high fat content, such as breasts, thighs, buttocks, hips and abdomen [ see Warnings and Precautions ( 5.2) ].
  • Immediately contact their physician when experiencing any unusual symptom or pain since warfarin sodium may cause small cholesterol or athero emboli. On feet it may appear as a sudden cool, painful, purple discoloration of toe(s) or forefoot [ see Warnings and Precautions ( 5.5) ].
  • Immediately contact their physician when taking warfarin sodium after any heparin formulation therapy and experiencing bloody or black stools or appearence of bruises, or bleeding [ see Warnings and Precautions ( 5.6) ].
  • To tell all of their healthcare professionals and dentists that they are taking warfarin sodium. This should be done before they have any surgery or dental procedure [ see Dosage and Administration ( 2.7) ].
  • Carry identification stating that they are taking warfarin sodium.

Bleeding Risks

Advise patients to:

  • Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness [ see Box Warning and Warnings and Precautions ( 5.1) ].

Concomitant Medications and Botanicals (Herbals)

Advise patients to:

  • Not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician [ see Drug Interactions ( 7) ].

Pregnancy and Nursing

Advise patients to:

  • Notify their physician if they are pregnant or planning to become pregnant or considering breast feeding [ see Use in Specific Populations (8.1, 8.2, 8.3) ].
  • Avoid warfarin sodium during pregnancy except in pregnant women with mechanical heart valves, who are at risk of thromboembolism [ see Contraindications (4) ]. Use effective measures to avoid pregnancy while taking warfarin sodium. This is very important because their unborn baby could be seriously harmed if they take warfarin sodium while they are pregnant [ see Use in Specific Populations (8.1, 8.3) ].

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.
Ahmedabad 382220, INDIA

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 08-2017-03

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