Warfarin Sodium (Page 2 of 10)

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance warfarin sodium tablets doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5)]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (> 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Tablets Daily Doses Based on CYP2C9 and VKORC1 Genotypes *
*
Ranges are derived from multiple published clinical studies. VKORC1 -1639G > A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.
VKORC1 CYP2C9
*1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3
GG 5 mg to 7 mg 5 mg to 7 mg 3 mg to 4 mg 3 mg to 4 mg 3 mg to 4 mg 0.5 mg to 2 mg
AG 5 mg to 7 mg 3 mg to 4 mg 3 mg to 4 mg 3 mg to 4 mg 0.5 mg to 2 mg 0.5 mg to 2 mg
AA 3 mg to 4 mg 3 mg to 4 mg 0.5 mg to 2 mg 0.5 mg to 2 mg 0.5 mg to 2 mg 0.5 mg to 2 mg

2.4 Monitoring to Achieve Optimal Anticoagulation

Warfarin sodium tablets are a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin sodium tablet therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with warfarin sodium tablets, as well as whenever other medications are initiated, discontinued or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7)].

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin sodium tablet therapy.

2.5 Missed Dose

The anticoagulant effect of warfarin sodium tablets persists beyond 24 hours. If a patient misses a dose of warfarin sodium tablets at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.

2.6 Intravenous Route of Administration

The intravenous dose of warfarin sodium is the same as the oral dose. After reconstitution, warfarin sodium for injection should be administered as a slow bolus injection into a peripheral vein over 1 to 2 minutes. Warfarin sodium for injection is not recommended for intramuscular administration.

Reconstitute the vial with 2.7 mL of Sterile Water for Injection. The resulting yield is 2.5 mL of a 2 mg per mL solution (5 mg total). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is noted.

After reconstitution, warfarin sodium for injection is stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is for single use only, and any unused solution should be discarded.

2.7 Treatment during Dentistry and Surgery

Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium tablet therapy. Consider the benefits and risks when discontinuing warfarin sodium tablets even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium tablets to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

2.8 Conversion from Other Anticoagulants

Heparin

Since the full anticoagulant effect of warfarin sodium tablets is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium tablets, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium tablets may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin sodium tablets therapy with heparin for 4 to 5 days and until warfarin sodium tablets have produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

As heparin may affect the INR, patients receiving both heparin and warfarin sodium tablets should have INR monitoring at least:

  • 5 hours after the last intravenous bolus dose of heparin, or
  • 4 hours after cessation of a continuous intravenous infusion of heparin, or
  • 24 hours after the last subcutaneous heparin injection.

Warfarin sodium tablets may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (> 50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

Other Anticoagulants

Consult the labeling of other anticoagulants for instructions on conversion to warfarin sodium tablets.

3 DOSAGE FORMS AND STRENGTHS

Warfarin Sodium Tablets, USP are available containing 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg or 10 mg of warfarin sodium, USP.

The 1 mg tablet is a dark pink round, scored tablet with “WF ” above the score and “1 ” below the score on one side and “G ” on the other side.

The 2 mg tablet is a lavender round, scored tablet with “WF ” above the score and “2 ” below the score on one side and “G ” on the other side.

The 2.5 mg tablet is a green round, scored tablet with “WF ” above the score and “2.5 ” below the score on one side and “G ” on the other side.

The 3 mg tablet is a beige round, scored tablet with “WF ” above the score and “3 ” below the score on one side and “G ” on the other side.

The 4 mg tablet is a blue round, scored tablet with “WF ” above the score and “4 ” below the score on one side and “G ” on the other side.

The 5 mg tablet is a peach round, scored tablet with “WF ” above the score and “5 ” below the score on one side and “G ” on the other side.

The 6 mg tablet is a greenish-blue round, scored tablet with “WF ” above the score and “6 ” below the score on one side and “G ” on the other side.

The 7.5 mg tablet is a yellow round, scored tablet with “WF ” above the score and “7.5 ” below the score on one side and “G ” on the other side.

The 10 mg tablet is a white to off-white round, scored tablet with “WF ” above the score and “10 ” below the score on one side and “G ” on the other side.

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