Jantoven

Jantoven Manufacturers

• Remedyrepack Inc.
  

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  Jantoven | Remedyrepack Inc.

  

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  The dosage and administration of JantovenTablets (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 JantovenTablets.
  
  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
  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 JantovenTablets 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 JantovenTablets 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 PHARMACOLOGYand 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/*3Ranges 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. VKORC11639 G(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 mgAG5-7 mg3-4 mg3-4 mg3-4 mg0.5-2 mg0.5-2 mgAA3-4 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 JantovenTablets persists beyond 24 hours. If the patient forgets to take the prescribed dose of JantovenTablets 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 JantovenTablets 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 JantovenTablets 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 JantovenTablets therapy. When discontinuing JantovenTablets even for a short period of time, the benefits and risks should be strongly considered.
  
  Conversion From Heparin Therapy Since the anticoagulant effect of JantovenTablets is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to JantovenTablets 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 JantovenTablets therapy be overlapped with heparin for 4 to 5 days, until JantovenTablets has produced the desired therapeutic response as determined by PT/INR. When JantovenTablets has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
  JantovenTablets 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 JantovenTablets, the interference with heparin anticoagulation is of minimal clinical significance.
  As heparin may affect the PT/INR, patients receiving both heparin and JantovenTablets 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.
  

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  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

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• Remedyrepack Inc.
  

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  Jantoven | Remedyrepack Inc.

  

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  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

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  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

  Close
  No Recall

  More Info
• Remedyrepack Inc.
  

  ×

  Jantoven | Remedyrepack Inc.

  

  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

  Close
  No Recall

  More Info
• Remedyrepack Inc.
  

  ×

  Jantoven | Remedyrepack Inc.

  

  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

  Close
  No Recall

  More Info
• Remedyrepack Inc.
  

  ×

  Jantoven | Remedyrepack Inc.

  

  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

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• Remedyrepack Inc.
  

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  Jantoven | Remedyrepack Inc.

  

  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

  Close
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  More Info
• Remedyrepack Inc.
  

  ×

  Jantoven | Remedyrepack Inc.

  

  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

  Close
  No Recall

  More Info
• Remedyrepack Inc.
  

  ×

  Jantoven | Remedyrepack Inc.

  

  ---

  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

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  Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8)

   

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

   

  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.

   

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

   

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

   

  Mechanical and Bioprosthetic Heart Valves

  For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

   

  Post-Myocardial Infarction

  For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

   

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

   

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

   

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

   

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

  1

   

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

   

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

   

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

   

  Heparin

  Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

   

  1 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.

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  2.1 Recommended Dosing

  Levetiracetam extended-release tablet is administered once daily.

  Initiate treatment with a dose of 1000 mg once daily. The once daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg/day.

  2.2 Dosage Adjustments in Adult Patients with Renal Impairment

  Levetiracetam extended-release tablets dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

                      [140-age (years)] x weight (kg)

       CLcr =     ---------------------------------------- x (0.85 for female patients

                      72 x serum creatinine (mg/dL)

  Then CLcr is adjusted for body surface area (BSA) as follows:

                                              CLcr  (mL/min)

  CLcr  (mL/min/1.73 m2) =          ---------------------- x 1.73

                                              BSA subject (m2)

  Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment Group
  Creatinine
  Clearance
  (mL/min/1.73m2)
  
  Dosage
  (mg)
  
  
  Frequency
  

  Normal
  

  > 80
  

  1000 to 3000
  

  Every 24 hours
  

  Mild
  

  50 to 80
  

  1000 to 2000
  

  Every 24 hours
  

  Moderate
  

  30 to 50
  

  500 to 1500
  

  Every 24 hours
  

  Severe
  

  < 30
  

  500 to 1000
  

  Every 24 hours
  

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  2.1 Individualized Dosing

  The dosage and administration of JANTOVEN must be individualized for each patient according to the patient's INR response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15)].

  2.2 Recommended Target INR Ranges and Durations for Individual Indications

  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.

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

  Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

  • For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. • For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. • For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

  Atrial Fibrillation

  In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

  • In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. • In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. • For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. • For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

  Mechanical and Bioprosthetic Heart Valves

  • For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. • For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. • For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. • For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

  Post-Myocardial Infarction

  • For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

  Recurrent Systemic Embolism and Other Indications

  Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

  2.3 Initial and Maintenance Dosing

  The appropriate initial dosing of JANTOVEN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  • Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities • Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

  Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

  Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

  Dosing Recommendations without Consideration of Genotype

  If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of JANTOVEN is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

  Dosing Recommendations with Consideration of Genotype

  Table 1 displays three ranges of expected maintenance JANTOVEN 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 JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 Genotypes* VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 * 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.

  GG

  5-7 mg

  5-7 mg

  3-4 mg

  3-4 mg

  3-4 mg

  0.5-2 mg

  AG

  5-7 mg

  3-4 mg

  3-4 mg

  3-4 mg

  0.5-2 mg

  0.5-2 mg

  AA

  3-4 mg

  3-4 mg

  0.5-2 mg

  0.5-2 mg

  0.5-2 mg

  0.5-2 mg

  2.4 Monitoring to Achieve Optimal Anticoagulation

  JANTOVEN is 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 JANTOVEN 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 JANTOVEN, 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 JANTOVEN therapy.

  2.5 Missed Dose

  The anticoagulant effect of JANTOVEN persists beyond 24 hours. If a patient misses a dose of JANTOVEN 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.

  2.7 Treatment During Dentistry and Surgery

  Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy. Consider the benefits and risks when discontinuing JANTOVEN 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 JANTOVEN 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 JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to JANTOVEN 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 JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has 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 JANTOVEN 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.

  JANTOVEN 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 JANTOVEN.

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