The dosage and administration of Apo-Warfarin must be individualized for each patient according to the particular patient's PT/INR response to the drug.
The dosage should be adjusted based upon the patient's PT/INR. (See Laboratory Control for full discussion on INR under Dosage & Administration.)
Venous Thromboembolism (including pulmonary embolism): Available clinical evidence indicates that an INR of 2-3 is sufficient for prophylaxis and treatment of venous thromboembolism and minimizes the risk of hemorrhage associated with higher INRs.
Atrial Fibrillation: Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2-4.5) or low INR (1.4-3). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians' (ACCP) recommendation that an INR of 2-3 be used for long-term warfarin therapy in appropriate AF patients.
Post-Myocardial Infarction: In post-myocardial infarction patients, Apo-Warfarin therapy should be initiated early (2-4 weeks post-infarction) and dosage should be adjusted to maintain an INR of 2.5-3.5 long-term. The recommendation is based on the results of the WARIS study in which treatment was initiated 2-4 weeks after the infarction. In patients thought to be at an increased risk of bleeding complications or on aspirin therapy, maintenance of Apo-Warfarin therapy at the lower end of this INR range is recommended.
Mechanical and Bioprosthetic Heart Valves: In patients with mechanical heart valve(s), long-term prophylaxis with warfarin to an INR of 2.5-3.5 is recommended. In patients with bioprosthetic heart valve(s), based on limited data, the American College of Chest Physicians recommends warfarin therapy to an INR of 2-3 for 12 weeks after valve insertion. In patients with additional risk factors eg, atrial fibrillation or prior thromboembolism, consideration should be given for longer-term therapy.
Recurrent Systemic Embolism: In cases where the risk of thromboembolism is great eg, in patients with recurrent systemic embolism, a higher INR may be required.
An INR of >4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.
Initial Dosage: The dosing of Apo-Warfarin must be individualized according to patient's sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. Low initiation doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR response to Apo-Warfarin (see Precautions). Based on limited data, Asian patients may also require lower initiation and maintenance doses. It is recommended that Apo-Warfarin therapy be initiated with a dose of 2-5 mg/day with dosage adjustments based on the results of PT/INR determinations.
Maintenance: Most patients are satisfactorily maintained at a dose of 2-10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient's prothrombin response.
Duration of Therapy: The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.
Missed Dose: The anticoagulant effect of Apo-Warfarin persists beyond 24 hrs. If the patient forgets to take the prescribed dose of Apo-Warfarin at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.
Laboratory Control: The PT reflects the depression of vitamin K-dependent Factors VII, X and II. There are several modifications of the one-stage PT and the physician should become familiar with the specific method used in his laboratory. The degree of anticoagulation indicated by any range of PTs may be altered by the type of thromboplastin used; the appropriate therapeutic range must be based on the experience of each laboratory. The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician's judgment of the patient's reliability and response to Apo-Warfarin in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of 1-4 weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests are done when other warfarin products are interchanged with Apo-Warfarin and also if other medications are co-administered with Apo-Warfarin (see Precautions).
Different thromboplastin reagents vary substantially in their sensitivity to sodium warfarin-induced effects on PT. To define the appropriate therapeutic regimen, it is important to be familiar with the sensitivity to the thromboplastin reagent used in the laboratory and its relationship to the International Reference Preparation (IRP), a sensitive thromboplastin reagent prepared from human brain.
A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges. The INR system of reporting is based on a logarithmic relationship between the PT ratios of the test and reference preparation. The INR is the PT ratio that would be obtained if the International Reference Preparation (IRP), which has an ISI of 1, were used to perform the test. Early clinical studies of oral anticoagulants, which formed the basis for recommended therapeutic ranges of 1.5-2.5 times control mean normal PT, used sensitive human brain thromboplastin. When using the less sensitive rabbit brain thromboplastins commonly employed in PT assays today, adjustments must be made to the targeted PT range that reflect this decrease in sensitivity.
The INR can be calculated as: INR=(observed PT ratio)ISI.
where the ISI (International Sensitivity Index) is the correction factor in the equation that relates the PT ratio of the local reagent to the reference preparation and is a measure of the sensitivity of a given thromboplastin to reduction of vitamin K-dependent coagulation factors; the lower the ISI, the more "sensitive" the reagent and the closer the derived INR will be to the observed PT ratio.
The proceedings and recommendations of the 1992 National Conference on Antithrombotic Therapy review and evaluate issues related to oral anticoagulant therapy and the sensitivity of thromboplastin reagents and provide additional guidelines for defining the appropriate therapeutic regimen.
The conversion of the INR to PT ratios for the less intense (INR 2-3) and more intense (INR 2.5- 3.5) therapeutic range recommended by the ACCP for thromboplastins over a range of ISI values is shown in Table 3. (See Table 3.)
Click on icon to see table/diagram/image
Treatment During Dentistry and Surgery: The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists. PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of Apo-Warfarin to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation.
The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of Apo-Warfarin therapy. When discontinuing Apo-Warfarin even for a short period of time, the benefits and risks should be strongly considered.
Conversion from Heparin Therapy: Since the anticoagulant effect of Apo-Warfarin is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to Apo-Warfarin may begin concomitantly with heparin therapy or may be delayed 3-6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that Apo-Warfarin therapy be overlapped with heparin for 4-5 days, until Apo-Warfarin has produced the desired therapeutic response as determined by PT/INR. When Apo-Warfarin has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Apo-Warfarin may increase the aPTT test, even in the absence of heparin. During initial therapy with Apo-Warfarin, the interference with heparin anticoagulation is of minimal clinical significance.
As heparin may affect the PT/INR, patients receiving both heparin and Apo-Warfarin should have blood for PT/INR determination drawn at least: 5 hrs after the last IV bolus dose of heparin, or; 4 hrs after cessation of continuous IV infusion of heparin, or; 24 hrs after the last SC heparin injection.
Administration: Should be taken on an empty stomach.