JANTOVEN® TABLETS
(warfarin sodium) Tablets, USP
WARNING: BLEEDING RISK
Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR > 4.0), age ≥ 65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients).
Jantoven® Tablets (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4 , and its structural formula may be represented by the following:
 |
Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether.
Jantoven® Tablets (Warfarin Sodium Tablets, USP) for oral use contain: 1 mg, 2 mg, 2½ mg, 3 mg, 4 mg, 5 mg, 6 mg, 7½mg or 10 mg of crystalline warfarin sodium, USP. They also contain:
All Strengths: Lactose monohydrate, magnesium stearate, povidone, and pregelatinized starch (corn).
1 mg: FD&C Red #40 Aluminum Lake
2 mg: FD&C Blue #2 Aluminum Lake and FD&C Red #40 Aluminum Lake
2½ mg: D&C Yellow #10 Aluminum Lake and FD&C Blue #1 Aluminum
Lake
3 mg: Brown #75 Synthetic Brown Iron Oxide
4 mg: FD&C Blue #1 Aluminum Lake
5 mg: FD&C Yellow #6 Aluminum Lake
6 mg: Yellow #10 Synthetic Yellow Iron Oxide, Black #85 Synthetic Black
Iron Oxide and FD&C Blue #1 Aluminum Lake 7½ mg: D&C Yellow #10
Aluminum Lake and FD&C Yellow #6 Aluminum Lake
10 mg: Dye Free.
Last updated on RxList: 3/24/2008
Jantoven® Tablets (Warfarin Sodium Tablets, USP) are indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.
Jantoven® Tablets are indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
Jantoven® Tablets are indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
The dosage and administration of Jantoven® Tablets (Warfarin Sodium Tablets, USP) must be individualized for each patient according to the particular patient's PT/INR response to the drug. The dosage should be adjusted based upon the patient's PT/INR.8,9,10,11,12 The best available information supports the following recommendations for dosing of Jantoven® Tablets.
Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE])
For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels ( > 90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.5,13 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 7th ACCP guidelines.8,10,14,15
Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0 - 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 American College of Chest Physicians' (7th ACCP) recommendation that an INR of 2.0 - 3.0 be used for warfarin therapy in appropriate AF patients.10
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.10
The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and low- risk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin. In healthcare settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long-term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0 to 4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0 to 3.0) with aspirin is recommended. For high-risk patients with MI, including those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0 to 3.0) oral warfarin plus low-dose aspirin ( ≤ 100 mg/day) for 3 months after the MI is suggested.16
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.8
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.10
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.
The dosing of Jantoven® Tablets must be individualized according to patient's sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. Lower initiation and maintenance doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR response to Jantoven® Tablets (see PRECAUTIONS). Based on limited data, Asian patients may also require lower initiation and maintenance doses of Jantoven® Tablets (see CLINICAL PHARMACOLOGY). It is recommended that Jantoven® Tablets therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.10,11
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.
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.7,8,10,11,14,15
The anticoagulant effect of Jantoven® Tablets persists beyond 24 hours. If the patient forgets to take the prescribed dose of Jantoven® Tablets at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.
LABORATORY CONTROL: The PT reflects the depression of vitamin K dependent Factors VII, X and II. A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges.17 The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician's judgment of the patient's reliability and response to Jantoven® Tablets in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, patients are in therapeutic range only 33%-64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.18 Self-testing patients had fewer bleeding events than patients in usual care.18
TREATMENT DURING DENTISTRY AND SURGERY: The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.8,12 PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of Jantoven® Tablets to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of Jantoven® Tablets therapy. When discontinuing Jantoven® Tablets even for a short period of time, the benefits and risks should be strongly considered.
CONVERSION FROM HEPARIN THERAPY: Since the anticoagulant effect of Jantoven® Tablets is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to Jantoven® Tablets may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that Jantoven® Tablets therapy be overlapped with heparin for 4 to 5 days, until Jantoven® Tablets has produced the desired therapeutic response as determined by PT/INR. When Jantoven® Tablets has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Jantoven® Tablets may increase the aPTT test, even in the absence of heparin. During initial therapy with Jantoven® Tablets, the interference with heparin anticoagulation is of minimal clinical significance. As heparin may affect the PT/INR, patients receiving both heparin and Jantoven® Tablets should have blood for PT/INR determination drawn at least:
Jantoven® Tablets (Warfarin Sodium Tablets, USP) for oral use, are supplied in the following forms:
1 mg - Compressed tablet, pink, round; one side scored and debossed WRF & 1, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
2 mg - Compressed tablet, lavender, round; one side scored and debossed WRF & 2, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
2 ½ mg - Compressed tablet, green, round; one side scored and debossed WRF & 2½, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
3 mg - Compressed tablet, tan, round; one side scored and debossed WRF & 3, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
4 mg - Compressed tablet, blue, round; one side scored and debossed WRF & 4, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
5 mg - Compressed tablet, peach, round; one side scored and debossed WRF & 5, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
6 mg - Compressed tablet, teal, round; one side scored and debossed WRF & 6, one side debossed 832, in bottles of 100 and 1000 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
7 ½ mg - Compressed tablet, yellow, round; one side scored and debossed WRF & 7½, one side debossed 832, in bottles of 100 and 500 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each). 10 mg - Compressed tablet, white, round; one side scored and debossed WRF & 10, one side debossed 832, in bottles of 100 and 500 and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each).
Store at 20-25°C (68-77°F). Excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Protect from light and moisture. Dispense in a tight, light-resistant container with a child-resistant closure.
Keep out of reach of children.
REFERENCES
10. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:429S-456S.
11. Jaffer AK, Bragg L. Practical tips for warfarin dosing and monitoring. Cleveland Clinic J Med. 2003;70:361-371.
12. Jaffer AK, Brotman DJ, Chukwumerije N. When patients on warfarin need surgery. Cleveland Clinic J Med. 2003;70:973- 984.
13. Kearon C, Ginsberg JS, Kovacs MJ, et al, for the Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639.
14. Schulman S, Granqvist S, Holmstrom M, et al, and the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997;336:393-398.
15. Ridker PM, Goldhaber SZ, Danielson E, et al, for the PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434.
16. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:513S-548S.
17. Ansell J, Hirsh J, Pollen L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:204S-233S.
18. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006;367:404-411.
Manufactured by: UPSHER-SMITH LABORATORIES, INC. Minneapolis, MN 55447. Revised 0307. FDA Rev date: 10/2/2003
Last updated on RxList: 3/24/2008
Potential adverse reactions to Jantoven® Tablets (Warfarin Sodium Tablets, USP) may include:
Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown. Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.
Numerous factors, alone or in combination, including changes in diet and medications, including botanicals, may influence response of the patient to anticoagulants. It is generally good practice to monitor the patient's response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including botanicals, are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response.
Drugs may interact with Jantoven® Tablets (Warfarin Sodium Tablets, USP) through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with Jantoven® Tablets are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with Jantoven® Tablets are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.
The following factors, alone or in combination, may be responsible for INCREASED PT/INR response:
ENDOGENOUS FACTORS:
| blood dyscrasias - see CONTRAINDICATIONS cancercollagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
EXOGENOUS FACTORS:
Potential drug interactions with Jantoven® Tablets are listed below by drug class and by specific drugs.
| Classes of Drugs | ||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents, Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
| Specific Drugs Reported | |||
| acetaminophen alcohol† allopurinol aminosalicyclic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide diclofenac |
dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole Jantoven® Tablets overdose ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine |
liothyronine lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole, (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone propoxyphene |
propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E zafirlukast zileuton |
| also: other medications affecting
blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
The following factors, alone or in combination, may be responsible for DECREASED PT/INR response:
ENDOGENOUS FACTORS:
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
EXOGENOUS FACTORS:
Potential drug interactions with Jantoven® Tablets (Warfarin Sodium
Tablets, USP) are listed below by drug class and by specific drugs.
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antaids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsantst Antidepressants† Antihistamines Antineoplastics† Antipsychotic Medications |
Antithyroid Drugs† Barbiturates Diuretics† Enteral NutritionaSupplements Fungal Medications,Systemic† Gastric Acidity and PepticUlcer Ajents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrojen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
| Specific Drugs Reported | ||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbitalcar bamazepine chloral hydrate† chlordiazepoxide chlorthalidone cholestyramine† clozapine corticotropin cortisone |
cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol Jantoven® Tablets underdosage meprobamate 6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital |
phenytoin † pravastatin † prednisone primidone propylthiouracil† raloxifeneranitidine† rifampin secobarbita spironolactone sucralfate vitamin C (high dose) vitamin K |
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
||
Because a patient may be exposed to a combination of the above factors, the net effect of Jantoven® Tablets on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable. It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with Jantoven® Tablets. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and Jantoven® Tablets. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient's response with additional PT/INR determinations when initiating or discontinuing botanicals. Specific botanicals reported to affect Jantoven® Tablets therapy include the following:
Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of Jantoven® Tablets. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of Jantoven® Tablets. Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all- inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed.
| Botanicals that contain coumarins with potential anticoagulant effects: | |||
| Alfalfa Angelica (Dong Quai) Aniseed Arnica Asa Foetida Bogbean1 Boldo Buchu |
Capsicum2 Cassia3 Celery Chamomile (German and Roman) Dandelion3 Fenugreek Horse Chestnut |
Horseradish Licorice3 Meadowsweet1 Nettle Parsley Passion Flower Prickly Ash (Northern) Quassia |
Red Clover Sweet Clover Sweet Woodruff Tonka Beans Wild Carrot Wild Lettuce |
| Miscellaneous botanicals with anticoagulant properties: | |
| Bladder Wrack (Fucus) | Pau d'arco |
| Botanicals that contain salicylate and/or have antiplatelet properties: | ||
| Agrimony4 Aloe Gel Aspen Black Cohosh Black Haw Bogbean1 Cassia3 Clove |
Dandelion3 Feverfew Garlic5 German Sarsaparilla Ginger Ginkgo Biloba Ginseng (Panax)5 Licorice3 |
Meadowsweet1 Onion5 Policosanol Poplar Senega Tamarind Willow Wintergreen |
| Botanicals with fibrinolytic properties: | ||
| Bromelains Capsicum2 |
Garlic5 Ginseng (Panax)5 |
Inositol Nicotinate Onion5 |
| Botanicals with coagulant properties: | |
| Agrimony4 Goldenseal |
Mistletoe Yarrow |
| 1Contains coumarins and salicylate. 2Contains coumarins and has fibrinolytic properties. 3Contains coumarins and has antiplatelet properties. 4Contains salicylate and has coagulant properties. 5Has antiplatelet and fibrinolytic properties. |
|
Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.
Jantoven® Tablets is a narrow therapeutic range (index) drug, and caution should be observed when warfarin sodium is administered to certain patients such as the elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present.
Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages. Caution should be observed when Jantoven® Tablets (or warfarin) are administered concomitantly with nonsteroidal anti- inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation. Acquired or inherited warfarin resistance should be suspected if large daily doses of Jantoven® Tablets are required to maintain a patient's PT/INR within a normal therapeutic range.
Last updated on RxList: 3/24/2008
The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ5 (see BLACK BOX WARNING) and, less frequently ( < 0.1%), necrosis and/or gangrene of skin and other tissues. Hemorrhage and necrosis have in some cases been reported to result in death or permanent disability. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast or penis has been reported. Careful diagnosis is required to determine whether necrosis is caused by an underlying disease. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See below for information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases.
It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. Jantoven® Tablets (Warfarin Sodium Tablets, USP), a narrow therapeutic range (index) drug, may be affected by factors such as other drugs and dietary vitamin K. Dosage should be controlled by periodic determinations of prothrombin time (PT)/International Normalized Ratio (INR) or other suitable coagulation tests. Determinations of whole blood clotting and bleeding times are not effective measures for control of therapy. Heparin prolongs the one-stage PT. When heparin and Jantoven® Tablets are administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for recommendations.
Caution should be observed when Jantoven® Tablets are administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage, necrosis and/or gangrene is present.
Anticoagulation therapy with Jantoven® Tablets may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the "purple toes syndrome." Discontinuation of Jantoven® Tablets therapy is recommended when such phenomena are observed.
Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death.
Purple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3 - 10 weeks, or later, after the initiation of therapy with warfarin or related compounds. Major features of this syndrome include purple color of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time. While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation.
Heparin-induced thrombocytopenia: Jantoven® Tablets should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. Cases of venous limb ischemia, necrosis and gangrene have occurred in patients with heparin-induced thrombocytopenia and deep venous thrombosis when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients sequelae have included amputation of the involved area and/or death.6
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.
The decision to administer anticoagulants in the following conditions must be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the benefits:
Lactation: Based on very limited published data, warfarin has not been detected in the breast milk of mothers treated with warfarin. The same limited published data reports that some breast-fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times, although not as prolonged as those of the mothers. The decision to breast-feed should be undertaken only after careful consideration of the available alternatives. Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants at risk for bleeding tendencies before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated.
Severe to moderate hepatic or renal insufficiency.
Infectious diseases or disturbances of intestinal flora: sprue, antibiotic therapy.
Trauma which may result in internal bleeding.
Surgery or trauma resulting in large exposed raw surfaces.
Indwelling catheters.
Severe to moderate hypertension.
Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with Jantoven® Tablets may minimize the incidence of tissue necrosis. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation.
Miscellaneous: polycythemia vera, vasculitis, and severe diabetes.
Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported.
In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to Jantoven® Tablets have been reported. Exaggerated therapeutic responses have been reported in other patients.
Patients with congestive heart failure may exhibit greater than expected PT/INR response to Jantoven® Tablets, thereby requiring more frequent laboratory monitoring, and reduced doses of Jantoven® Tablets.
Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)
Periodic determination of PT/INR or other suitable coagulation test is essential. (See DOSAGE AND ADMINISTRATION: Laboratory Control.)
The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter medications, and botanical (herbal) products (e.g.,bromelains, coenzyme Q10 , danshen, dong quai, garlic, Ginkgo biloba, ginseng and St. John's wort) except on advice of the physician. Avoid alcohol consumption. Do not take Jantoven® Tablets during pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS). Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that Jantoven® Tablets are being taken. If the prescribed dose of Jantoven® Tablets is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of Jantoven® Tablets the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with Jantoven® Tablets. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. You should also avoid intake of cranberry juice or any other cranberrry products. Notify your healthcare provider if any of these products are part of your normal diet. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with Jantoven® Tablets is discontinued, patients should be cautioned that the anticoagulant effects of Jantoven® Tablets may persist for about 2 to 5 days. Patients should be informed that all warfarin sodium, USP products represent the same medication, and should not be taken concomitantly, as overdosage may result. A Medication Guide7 should be available to patients when their prescriptions for warfarin sodium are issued.
Carcinogenicity and mutagenicity studies have not been performed with Jantoven® Tablets. The reproductive effects of Jantoven® Tablets have not been evaluated.
Pregnancy Category X - See CONTRAINDICATIONS.
Safety and effectiveness in pediatric patients below the age of 18 have not been established, in randomized, controlled clinical trials. However, the use of Jantoven® Tablets in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements.
Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). Jantoven® Tablets are contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of Jantoven® Tablets are recommended for elderly patients (see DOSAGE AND ADMINISTRATION).
REFERENCES
5. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:401S-428S.
6. Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MG, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804-812.
7. Jantoven® Tablets Medication Guide. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2007.
Last updated on RxList: 3/24/2008
Suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level.
Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Jantoven® Tablets (Warfarin Sodium Tablets, USP) therapy and if necessary, by administration of oral or parenteral vitamin K1 . (Please see recommendations accompanying vitamin K1 preparations prior to use.)8,9
Such use of vitamin K1 reduces response to subsequent Jantoven® Tablets therapy. Patients may return to a pretreatment 1 thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of Jantoven® Tablets administration reverses the effect of vitamin K, and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy.
If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K1 . In emergencysituations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex.
A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to Jantoven® Tablets overdosage.
Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of Jantoven® Tablets treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease.
Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:
Jantoven® Tablets (Warfarin Sodium Tablets, USP) are contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.
Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness, and other central nervous system abnormalities have been reported in association with second and third trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly.
Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported.
Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks.
Recent or contemplated surgery of: (1) central nervous system; (2) eye; (3) traumatic surgery resulting in large open surfaces.
Bleeding tendencies associated with active ulceration or overt bleeding of: (1) gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial endocarditis.
Threatened abortion, eclampsia and preeclampsia.
Inadequate laboratory facilities.
Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation.
Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.
Miscellaneous: major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product.
REFERENCES
8. Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart disease-native and prosthetic. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:457S-482S.
9. American Geriatrics Society Clinical Practice Guidelines. The use of oral anticoagulants (warfarin) in older people. J Amer Geriatr Soc. 2000;48:224-227.
Last updated on RxList: 3/24/2008
Jantoven® Tablets (Warfarin Sodium Tablets, USP) and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4 - 6 hours, IX - 24 hours, and X - 48 - 72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.
An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of Jantoven® Tablets may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Jantoven® Tablets are a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2 - 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
Jantoven® Tablets are essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.
There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins.
The elimination of warfarin is almost entirely by metabolism. Jantoven® Tablets are stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolities (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 41-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18,1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.
The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.
Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.
Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.
Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.
Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic A F, warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (See Table 1). 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. Similar data from clinical studies in valvular atrial fibrillation patients are not available.
Table 1: Clinical Studies of Warfarin In Non-Rheumatic AF
Patients*
| N | Thromboembolism | % Major Bleeding | ||||||
| Study | Warfarin- Treated Patients |
Control Patients |
PT Ratio |
INR | % Risk Reduction |
p-value | Warfarin- Treated Patients |
Control Patients |
| AFASAK | 335 | 336 | 1.5 - 2.0 | 2.8 - 4.2 | 60 | 0.027 | 0.6 | 0.0 |
| SPAF | 210 | 211 | 1.3 - 1.8 | 2.0 - 4.5 | 67 | 0.01 | 1.9 | 1.9 |
| BAATAF | 212 | 208 | 1.2 - 1.5 | 1.5 - 2.7 | 86 | < 0.05 | 0.9 | 0.5 |
| CAFA | 187 | 191 | 1.3 - 1.6 | 2.0 - 3.0 | 45 | 0.25 | 2.7 | 0.5 |
| SPINAF | 260 | 265 | 1.2 - 1.5 | 1.4 - 2.8 | 79 | 0.001 | 2.3 | 1.5 |
| *All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage and transient ischemic attacks. | ||||||||
WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table:
Table 2 :
| Event | Warfarin (N=607) |
Placebo (N=607) |
RR (95%CI) |
% Risk Reduction (p-value) |
| Total Patient Years of Follow-up | 2018 | 1944 | ||
| Total Mortality | 94 (4.7/100 py) | 123 (6.3/100 py) | 0.76 (0.60, 0.97) | 24 (p=0.030) |
| Vascular Death | 82 (4.1/100 py) | 105 (5.4/100 py) | 0.78 (0.60, 1.02) | 22 (p=0.068) |
| Recurrent MI | 82 (4.1/100 py) | 124 (6.4/100 py) | 0.66 (0.51, 0.85) | 34 (p=0.001) |
| Cerebrovascular Event | 20 (1.0/100 py) | 44 (2.3/100 py) | 0.46 (0.28, 0.75) | 54 (p=0.002) |
| RR = Relative risk; Risk reduction = (I-RR); CI = Confidence interval; MI = Myocardial infarction; py = patient years | ||||
WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin target INR 2.8 to 4.2, aspirin 160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day prior to hospital discharge. There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the following table1:
Table 3: WARIS II - Distribution of Separate Events According
to Treatment Group*
| Event | Aspirin (N=1206) |
Warfarin (N=1216) |
Aspirin plus Warfarin (N=1208) |
Rate Ratio (95% CI) |
p-value |
| No. of Events | |||||
| Reinfarction | 117 | 90 | 69 | 0.56 (0.41-0.78)a 0.74 (0.55-0.98)b |
< 0.001 0.03 |
| Thromboembolic stroke | 32 | 17 | 17 | 0.52 (0.28-0.98)a 0.52 (0.28-0.97)b |
0.03 0.03 |
| Major Bleedingc | 8 | 33 | 28 | 3.35a (ND) 4.00b (ND) | ND ND |
| Minor Bleedingd | 39 | 103 | 133 | 3.21a (ND) 2.55b (ND) | ND ND |
| Death | 92 | 96 | 95 | 0.82 | |
| * CI denotes confidence interval. a The rate ratio is for aspirin plus warfarin as compared with aspirin. b The rate ratio is for warfarin as compared with aspirin. c Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention. d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention of blood transfusion. ND =not determined. |
|||||
In a prospective, randomized, open label, positive-controlled study2 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole- aspirin (p < 0.005) and pentoxifylline-aspirin (p < 0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.
In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group.3
In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0 - 2.25 vs. INR 2.5 - 4.0) for a three- month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs.10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity.4
REFERENCES
1. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974.
2. Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for prevention of prosthetic valve thromboembolism: a prospective randomized clinical trial. Circ. 1985;72:1059-1063.
3. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med. 1990;322:428-432.
4. Turpie AG, Hirsh J, Gunstensen J, Nelson H, Gent M. Randomized comparison to two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988;331:1242-1245.
Last updated on RxList: 3/24/2008
Medication Guide
Jantoven®
(JAN-to-ven) Tablets
(Warfarin Sodium Tablets, USP)
Read this Medication Guide before you start taking Jantoven® Tablets (Warfarin Sodium Tablets, USP) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Yo u and your healthcare provider should talk about Jantoven® Tablets when you start taking it and at regular checkups.
What is the most important information I should know about Jantoven® Tablets?
Tell your healthcare provider about all the medicines you take. Do not stop medicines or take anything new unless you have talked to your healthcare provider. Keep a list of your medicines with you at all times to show your healthcare provider and pharmacist.
What are Jantoven® Tablets?
Jantoven® Tablets are an anticoagulant medicine. They are used to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions such as blood clots in the legs or lungs.
Who should not take Jantoven® Tablets?
Do not take Jantoven® Tablets if:
What should I tell my healthcare provider before starting Jantoven® Tablets?
Tell your healthcare provider about all of your health conditions, including if you:
Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. See "What is the most important information I should know about Jantoven® Tablets?"
How should I take Jantoven® Tablets?
What should I avoid while taking Jantoven® Tablets?
What are the possible side effects of Jantoven® Tablets?
Other side effects with Jantoven® Tablets include allergic reactions, liver problems, low blood pressure, swelling, low red blood cells, paleness, fever, and rash. Call your healthcare provider if you have any side effect that bothers you.
These are not all of the side effects of Jantoven® Tablets. For more information, ask your healthcare provider or pharmacist.
How should I store Jantoven® Tablets?
General Information about Jantoven® Tablets
Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use Jantoven® Tablets for a condition for which it was not prescribed. Do not give Jantoven® Tablets to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about Jantoven® Tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Jantoven® Tablets that was written for healthcare professionals. This Medication Guide may have been revised after this copy was produced. For more information and the most current Medication Guide, please visit www.jantoven.com or www.upsher-smith.com or call our professional services department toll-free at 1-800-654-2299. This Medication Guide has been approved by the U.S. Food and Drug Administration.
Last updated on RxList: 3/24/2008
IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.
WARFARIN - ORAL
(WARF-uh-rin)
COMMON BRAND NAME(S): Coumadin
WARNING: Warfarin can cause very serious (possibly fatal) bleeding. This is more likely to occur when you first start taking this medication and/or when you are taking too much warfarin.
To decrease your risk for bleeding, your doctor or other health care provider will monitor you closely and check your lab results (INR test) to make sure you are not taking too much warfarin. Keep all medical and laboratory appointments. Tell your doctor immediately if you notice any signs of serious bleeding. See also Side Effects section.
USES: This medication is used to treat blood clots (such as in deep vein thrombosis-DVT or pulmonary embolus-PE) and/or to prevent new clots from forming in your body. Preventing harmful blood clots helps to reduce the risk of a stroke or heart attack. Conditions that increase your risk of developing blood clots include a certain type of irregular heart rhythm (atrial fibrillation), heart valve replacement, recent heart attack, and certain surgeries (such as hip/knee replacement).
Warfarin is commonly called a "blood thinner," but its more correct term is "anticoagulant." It helps to keep blood flowing smoothly in your body by decreasing the amount of certain substances (clotting proteins) in your blood.
HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking warfarin and each time you get a refill. If you have any questions, consult your doctor or pharmacist.
Take this medication by mouth with or without food, usually once a day or as directed by your doctor or other health care professional. It is very important to take it exactly as directed. Do not increase the dose, take it more frequently, or stop using it unless directed by your doctor.
Dosage is based on your medical condition, laboratory tests (such as INR), and response to treatment. Your doctor or other health care provider will monitor you closely while you are taking this medication to determine the right dose for you.
Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.
It is important to eat a balanced, consistent diet while taking warfarin. Some foods can affect how warfarin works in your body and may affect your treatment and dose. Avoid sudden large increases or decreases in your intake of foods high in vitamin K (such as broccoli, cauliflower, cabbage, Brussels sprouts, kale, spinach, and other green leafy vegetables, liver, green tea, certain vitamin supplements). If you are trying to lose weight, check with your doctor before you try to go on a diet.
Cranberry products may also affect how your warfarin works. Limit the amount of cranberry juice (2 cups/16 ounces a day) or other cranberry products you may drink or eat.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
This medication can cause serious bleeding if it affects your blood clotting proteins too much (shown by unusually high INR lab results). Even if your doctor stops your medication, this risk of bleeding can continue for up to a week. Tell your doctor immediately if you have any signs of serious bleeding, including: unusual pain/swelling/discomfort, unusual/easy bruising, prolonged bleeding from cuts or gums, persistent/frequent nosebleeds, unusually heavy/prolonged menstrual flow, pink/dark urine, coughing up blood, vomit that is bloody or looks like coffee grounds, severe headache, dizziness/fainting, unusual or persistent tiredness/weakness, bloody/black/tarry stools, chest pain, shortness of breath, difficulty swallowing.
Tell your doctor immediately if any of these unlikely but serious side effects occur: persistent nausea/vomiting, severe stomach/abdominal pain, yellowing eyes/skin.
This drug rarely has caused very serious (possibly fatal) problems if its effects lead to small blood clots (usually at the beginning of treatment). This can lead to severe skin/tissue damage that may require surgery or amputation if left untreated. Patients with certain blood conditions (protein C or S deficiency) may be at greater risk. Seek immediate medical attention if any of these rare but very serious side effects occur: painful/red/purplish patches on the skin (such as on the toe, breast, abdomen), change in the amount of urine, vision changes, confusion, slurred speech, weakness on one side of the body.
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.
PRECAUTIONS: Before taking warfarin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.
This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: bleeding disorders (such as hemophilia).
Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, alcohol use/abuse, mental/mood disorders (including memory problems), recent major injury/surgery, bleeding problems (such as bleeding of the stomach/intestines, bleeding in the brain), blood vessel disorders (such as aneurysms), blood disorders (such as anemia, polycythemia), heart failure, thyroid problems, family member who did not respond to warfarin treatment, frequent falls/injuries, vitamin deficiency or absorption problems.
It is important that all your doctors and dentists know that you take warfarin. Before having surgery or any medical/dental procedures, tell your doctor or dentist that you are using this medication.
Avoid getting injections into the muscles. If you must have an injection into a muscle (for example, a flu shot), it should be given in the arm. This way, it will be easier to check for bleeding and/or apply pressure bandages.
This medication may cause stomach bleeding. Daily use of alcohol while using this medicine will increase your risk for stomach bleeding and may also affect how this medication works. Limit or avoid alcoholic beverages.
If you have not been eating well, if you have an illness or infection that causes fever, vomiting, or diarrhea for more than 2 days, or if you start using any antibiotic medications, contact your doctor or pharmacist immediately because these conditions can affect how warfarin works.
This medication can cause heavy bleeding. To lower the chance of getting cut, bruised, or injured, use great caution with sharp objects like safety razors and nail cutters. Use an electric razor when shaving and a soft toothbrush when brushing your teeth. Avoid activities such as contact sports. If you fall or injure yourself, especially if you hit your head, call your doctor immediately. Your doctor may need to check you.
The Food & Drug Administration has stated that generic warfarin products are interchangeable. However, consult your doctor or pharmacist before switching warfarin products. Be careful not to take more than one medication that contains warfarin unless specifically directed by the doctor or health care provider who is monitoring your warfarin treatment.
Older adults may be at greater risk for bleeding while using this drug.
This medication is not recommended for use during pregnancy because of serious (possibly fatal) harm to an unborn baby. Discuss reliable forms of birth control with your doctor. If you become pregnant or think you may be pregnant, tell your doctor immediately. If you are planning pregnancy, discuss a plan for managing your condition with your doctor before you become pregnant. Your doctor may switch the type of medication you use during pregnancy.
This medication does not pass into breast milk. While there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.
Warfarin interacts with many prescription, nonprescription, vitamin, and herbal products. This includes medications that are applied to the skin or inside the vagina or rectum. The following interactions listed do not contain all possible drug interactions. The interactions with warfarin usually result in an increase or decrease in the "blood-thinning" (anticoagulant) effect. Your doctor or other health care professional should closely monitor you to prevent serious bleeding or clotting problems. While taking warfarin, it is very important to tell your doctor or pharmacist of any changes in medications, vitamins, or herbal products that you are taking.
This drug should not be used with the following medications because very serious interactions may occur: imatinib, mifepristone.
If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting warfarin.
Aspirin and aspirin-like drugs (salicylates) and nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen, celecoxib) may have effects similar to warfarin. These drugs may increase the risk of bleeding problems if taken during treatment with warfarin. Carefully check all prescription/nonprescription product labels (including drugs applied to the skin such as pain-relieving creams) since the products may contain NSAIDs or salicylates. Talk to your doctor about using a different medication (such as acetaminophen) to treat pain/fever. Low-dose aspirin and related drugs (such as clopidogrel, ticlopidine) should be continued if prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention. Consult your doctor or pharmacist for more details.
Many herbal medications have "blood-thinning" or "blood-clotting" effects, and some may directly affect warfarin. Tell your doctor before taking any herbal products, especially bromelains, coenzyme Q10, cranberry, danshen, dong quai, fenugreek, garlic, ginkgo biloba, ginseng, goldenseal, and St. John's wort, among others.
This medication may interfere with a certain laboratory test to measure theophylline levels, possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.
This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.
OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: bloody/black/tarry stools, pink/dark urine, unusual/prolonged bleeding.
NOTES: Do not share this medication with others.
Laboratory and/or medical tests (such as INR, complete blood count) must be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.
MISSED DOSE: For the best possible benefit, do not miss any doses. If you do miss a dose, take it as soon as you remember if it is on the same day. If it is the next day, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up because this could increase your risk for bleeding. Keep a record of missed doses to give to your doctor or pharmacist. Contact your doctor or pharmacist if you miss 2 or more doses in a row.
STORAGE: Store at room temperature away from light and moisture. Storage temperature ranges differ according to different manufacturers, so consult your pharmacist for more information. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.
MEDICAL ALERT: Your condition and medication can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).
Information last revised September 2008 Copyright(c) 2008 First DataBank, Inc.
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