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WARFARIN DOSING

 

Therapeutic Recommendations

Initiation and Duration

Dosage Frequency

Monitoring

Drug Interactions

Increased INR

Reduced INR

Dietary Interactions

Initiation Warfarin Therapy

In-patients

Out-patients

After Day 3

Dose Changes in Stable Patients

Management of Serious Bleeding

References

About this Document

 

 

Warfarin is taken by mouth to inhibit vitamin K. This vitamin is essential for effective production of clotting factors V, VII, IX, X, and anticoagulant proteins C&S. Warfarin is given once daily. It is monitored by the prothrombin time and the international normalized ratio (INR).

 

Warfarin is a narrow therapeutic index drug. When the INR falls below 2.0 thrombosis risk increases and when the INR rises above 4.0 serious bleeding risk increases.

 

Therapeutic INR ranges

 

DVT/PE 2.0 3.0

Atrial Fibrillation 2.0 3.0

Myocardial Infarction 2.0 3.0

Mechanical Heart Valves 2.5 3.5

 

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Dosage Initiation and Duration

Warfarin takes 4 - 7 days to have its optimum effect. Large loading doses do not markedly shorten the time to achieve a full therapeutic effect but cause rapid falls in the level of protein C, which may precipitate paradoxical thrombosis in the first few days of warfarin therapy. The following general recommendations for warfarin use are made.

Initiate therapy with the estimated daily maintenance dose (2 - 5 mg.).

Elderly or debilitated patients often require low daily doses of warfarin (2 - 4 mg.).

Patients are confused by alternating daily doses (e.g. 7.5 and 5.0 mg).

In stable patients, significant changes in INR can usually be achieved by small changes in dose (15% or less) based on the weekly dose.

4 - 5 days are required after any dose change or any new diet or drug interaction to reach the new antithrombotic steady state.

 

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Frequency of Dosing

Daily

 

Monitoring

Warfarin is monitored by the one stage prothrombin time. Prothrombin times are reported in seconds, as a ratio of the prothrombin time in seconds to the mean normal prothrombin time of the laboratory, and as the international normalized ratio (INR). The INR is the most reliable way to monitor the prothrombin time.

 

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Some Drug Interactions With Warfarin

Drugs That May Lengthen PT (higher INR; increased warfarin effect)

Antibiotics

Carbenicillin

Erythromycin

Fluconazole

Isoniazid

Ketoconazole

Metronidazole

Moxalactam and other cephalosporins

Trimethoprim sulfa

Anti-inflammatories

Allopurinol

Fenoprofen

lbuprofen

Indomethacin

Naproxen

Phenylbutazone

Piroxicam

Sulfinpyrazone

Zileuton

Antiarrhythmics

Amiodarone

Quinidine

Others

Alcohol

Anabolic steroids

Cimetidine

Clofibrate

Disulfiram

Lovastatin

Omeprazole

Phenytoin

Tamoxifen

Thyroxine

Vitamin E (large doses)

 

Drugs That May Shorten PT (lower INR; decreased warfarin effect)

Antacids

Antihistamines

Barbiturates

Carbamazepine

Cholestyramine

Griseofulvin

Haloperidol

Oral contraceptives

Penicillin

Rifampin

Spironolactone

Sucralfate

Trazodone

Vitamin C (large doses)

 

Remember: Drug interactions with warfarin are not always known or predictable. Repeat an INR 5 to 7 days after adding, subtracting or changing the dose of any drug in a patient receiving warfarin.

 

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Dietary and Other Interactions with Warfarin

1.        Patients taking warfarin should eat a diet that is constant in vitamin K. Minimize changes in intake of green leafy vegetables (spinach, greens, and broccoli), green peas, and oriental green tea.

2.        Conditions that interfere with vitamin K uptake or interfere with liver function will increase the warfarin effect.

3.        Expect a longer prothrombin time in patients with CHF, jaundice, hepatitis, liver failure, diarrhea, or extensive cancer or connective tissue disease. Expect a longer prothrombin time when patients receiving warfarin are hospitalized for any reason.

4.        Metabolic alterations can affect prothrombin time. Expect a longer prothrombin time in patients with hyperthyroidism or fever.

 

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Initiating Warfarin Therapy

Are there any contraindications?

1.        Pregnancy

2.        History of warfarin - induced purpura

3.        Active Bleeding

Has the patient been instructed on drug interactions and a diet of constant vitamin K intake?

Has a baseline PT, APTT, and platelet count been obtained?

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Inpatient Anticoagulation Warfarin Dose *

 

Day 1 5 mg.

Day 2 5 mg.

Day 3 2 to 5 mg. Do INR

Day 4 2 to 5 mg. Do INR

* Should be overlapped for 3 to 5 days with heparin in cases with active thrombosis. The INR should be in therapeutic range for 2 consecutive days to allow for depletion of factors in the intrinsic clotting pathway.

 

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Outpatient Anticoagulation Warfarin Dose

 

Day 1 2 to 5 mg.

Day 2 2 to 5 mg.

Day 3 2 to 5 mg. Do INR

Day 4 2 to 5 mg. Do INR

** Starting on day 3, adjust subsequent doses as outlined below based on INR. The INR should be in therapeutic range for 2 consecutive days to allow for depletion of factors in the intrinsic clotting pathway. Obtain INR 3 - 4 times in week 1; twice in 2nd week; then weekly until stable; then monthly. Elderly or debilitated patients often require low daily doses of warfarin (2 to 3 mg).

 

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Initiating Therapy: Dose Adjustment

 

Day INR Dose mg.

3 <1.5 5.0 10.0

1.5 1.9 2.5 5.0

2.0 - 3.0 0.0 5.0

>3.0 0.0

4 <1.5 10.0

1.5 - 1.9 5.0 7.5

2.0 - 3.0 0.0-5.0

>3.0 0.0

5 <1.5 10.0

1.5 - 1.9 7.5 10.0

2.0 - 3.0 0.0 5.0

>3.0 0.0

6 <1.5 7.5 12.5

1.5 - 1.9 5.0 10.0

2.0 - 3.0 0.0 7.5

>3.0 0.0

 

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Stable Patients: Dosing Algorithm To Achieve INR Of 2.0 to 3.0

Warfarin Sodium*: Monitoring and Dosage Adjustment in Stable Anticoagulated Patients With No or Minimal Bleeding.

 

INR>9.0

         Stop warfarin temporarily.

         Daily INR

         Oral vitamin K 2.5 mg. If not available, IV preparation can be used PO.

         INR should drop in 24-48 hr

         Repeat vitamin K if INR >9 in 24 hours

         Resume warfarin once INR in therapeutic range at 20% reduced dosage

 

INR ≥5.0 - ≤9.0

         Stop warfarin for 2 days

         Daily INR

         Resume warfarin at 10 - 20% reduced dosage once INR in therapeutic range.

         If high risk for serious bleeding consider oral vitamin K 2-3 mg. If not available, IV preparation can be used PO.

 

INR >3.5 - <5

         Omit 1 dose

         INR in 2-5 days

         Resume warfarin at 10 - 20% lower dose once INR in therapeutic range.

 

INR >3 - ≤3.5

         No change in dose. Recheck in 1 week.

         If no change in INR, reduce warfarin dosage by 5 - 10%

 

INR ≥2.0 - ≤3.0 No change.

 

INR ≥1.5 ≤2 Increase weekly dosage by 5 - 10% and repeat INR in 1 week.

 

INR <1.5 I extra dose equal to 20% of weekly dose AND increase weekly dose by 10 - 20% and repeat INR in 1 week.

 

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Management of Elevated INR with Serious Bleeding:

1.        Admit to acute care

2.        Stop warfarin

3.        Attempt local hemostasis if possible.

4.        Give Vitamin K 5-10 mg. by Slow IV infusion over 20-60 min.

5.        Give Fresh Frozen Plasma 2-3 units initially, and more if subsequently indicated.

6.        Obtain consultation.

 

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References:

1.        Warfarin therapy management. Province of British Columbia Guideline 2010. Available online at: http://www.bcguidelines.ca/pdf/warfarin_management.pdf.Initiation and maintenance of warfarin therapy. Province of British Columbia Guideline 2004. Available online at: http://www.bcguidelines.ca/gpac/pdf/warfarin_therapy.pdf.

2.        Valentine KA, et al. Correcting excess anticoagulation after warfarin. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2008.

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* Coumadin 1 mg tablet

** INR: international Normalized Ratio = (x/y)z, where: x = Prothrombin Time of sample (sec) y = Mean Normal Prothrombin Time (sec) z = [ ISI of Thromboplastin]

 

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