Drug Information for JANTOVEN TABLETS (Warfarin Sodium Tablets, USP) (Upsher-Smith Laboratories, Inc.): DOSAGE AND ADMINISTRATION

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  • The dosage and administration of Jantoven® Tablets (Warfarin Sodium Tablets, USP) 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.15,16,17,18,19 The best available information supports the following recommendations for dosing of Jantoven® Tablets.

  • Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE])

  • For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.12,20 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations. These recommendations are supported by the American College of Chest Physicians' (7th ACCP) guidelines.15,17,21,22

  • Atrial Fibrillation

  • Five 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 (2.0 - 4.5) or low INR (1.4 - 3.0). There was a significant reduction in minor bleeds at the low INR. There are no adequate and well-controlled studies in populations with atrial fibrillation and valvular heart disease. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the 7th ACCP recommendation that an INR of 2.0 - 3.0 be used for warfarin therapy in appropriate AF patients.17

    Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age >75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus). In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day, is recommended. For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP). For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.17

  • Post-Myocardial Infarction

  • The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and low-risk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin. In healthcare settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long-term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0 to 4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0 to 3.0) with aspirin is recommended. For high-risk patients with MI, including those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0 to 3.0) oral warfarin plus low-dose aspirin (=100 mg/day) for 3 months after the MI is suggested.23

  • Mechanical and Bioprosthetic Heart Valves

  • For all patients with mechanical prosthetic heart valves, warfarin is recommended. For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0 to 3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5 to 3.5). For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/day is recommended. For patients with bioprosthetic valves, warfarin therapy with a target INR of 2.5 (range, 2.0 to 3.0) is recommended for valves in the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion.15

  • Recurrent Systemic Embolism and Other Indications

  • Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. A moderate dose regimen (INR 2.0 to 3.0) is recommended for these patients.17

    An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

  • Initial Dosage

  • The dose of Jantoven® Tablets must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by:

    • Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and
    • Genetic factors (CYP2C9 and VKORC1 genotypes).

    Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of Jantoven® Tablets is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients. (See CLINICAL PHARMACOLOGY and PRECAUTIONS).

    The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.

    In all patients, subsequent dosage adjustments must be made based on the results of PT/INR determinations.17, 18

    Table 5: Range of Expected Therapeutic Warfarin Doses Based on CYP2C9 and VKORC1 Genotypes
    VKORC1CYP2C9
    *1/*1*1/*2*1/*3*2/*2*2/*3*3/*3
    Ranges are derived from multiple published clinical studies. Other clinical factors (e.g., age, race, body weight, sex, concomitant medications, and comorbidities) are generally accounted for along with genotype in the ranges expressed in the Table. VKORC1 – 1639 G?A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin 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.
    GG5-7 mg5-7mg3-4 mg3-4 mg3-4 mg0.5-2 mg
    AG5-7 mg3-4 mg3-4 mg3-4 mg0.5-2 mg0.5-2 mg
    AA3-4 mg3-4 mg0.5-2 mg0.5-2 mg0.5-2 mg0.5-2 mg
  • Maintenance

  • Most patients are satisfactorily maintained at a dose of 2 to 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. Acquired or inherited warfarin resistance is rare, but should be suspected if large daily doses of warfarin are required to maintain a patient's PT/INR within a normal therapeutic range. Lower maintenance doses are recommended for elderly and/or debilitated patients and patients with a potential to exhibit greater than expected PT/INR response to warfarin sodium (see PRECAUTIONS).

  • 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.14,15,17,18,21,22

  • Missed Dose

  • The anticoagulant effect of Jantoven® Tablets persists beyond 24 hours. If the patient forgets to take the prescribed dose of Jantoven® Tablets 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. 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.24 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 Jantoven® Tablets in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, patients are in therapeutic range only 33%-64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.25 Self-testing patients had fewer bleeding events than patients in usual care.25

  • Treatment During Dentistry And Surgery The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.15,19 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 Jantoven® Tablets 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 Jantoven® Tablets therapy. When discontinuing Jantoven® Tablets even for a short period of time, the benefits and risks should be strongly considered.

  • Conversion From Heparin Therapy Since the anticoagulant effect of Jantoven® Tablets is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to Jantoven® Tablets may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that Jantoven® Tablets therapy be overlapped with heparin for 4 to 5 days, until Jantoven® Tablets has produced the desired therapeutic response as determined by PT/INR. When Jantoven® Tablets has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.

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

    During initial therapy with Jantoven® Tablets, the interference with heparin anticoagulation is of minimal clinical significance.

    As heparin may affect the PT/INR, patients receiving both heparin and Jantoven® Tablets should have blood for PT/INR determination drawn at least:

    • 5 hours after the last IV bolus dose of heparin, or
    • 4 hours after cessation of a continuous IV infusion of heparin, or
    • 24 hours after the last subcutaneous heparin injection.
  • Drug Information Provided by National Library of Medicine (NLM).
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