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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.
WARNINGS
The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ-12 (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). 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.
Increased caution should be observed when Jantoven® Tablets are administered 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.
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.-13
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 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.
PRECAUTIONS
Periodic determination of PT/INR is essential. (See DOSAGE AND ADMINISTRATION: Laboratory Control.)
Numerous factors, alone or in combination, including changes in diet and medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICAL PHARMACOLOGY, Pharmacogenomics) may influence the response of the patient to warfarin.
Drug/Drug and Drug/Disease Interactions
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 | diarrhea | hyperthyroidism |
| cancer | elevated temperature | poor nutritional state |
| collagen vascular disease | hepatic disorders | steatorrhea |
| congestive heart failure | infectious hepatitis | vitamin K deficiency |
| jaundice | |
EXOGENOUS FACTORS:
Potential drug interactions with Jantoven® Tablets are listed below by drug class and by specific drugs.
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†Increased and decreased PT/INR responses have been reported.
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| Classes of Drugs |
| 5-lipoxygenase Inhibitor | Antithyroid Drugs† | Leukotriene Receptor |
| Adrenergic Stimulants, Central | Beta-Adrenergic Blockers | Antagonist |
| Alcohol Abuse Reduction | Cholelitholytic Agents | Monoamine Oxidase |
| Preparations | Diabetes Agents, Oral | Inhibitors |
| Analgesics | Diuretics† | Narcotics, prolonged |
| Anesthetics, Inhalation | Fungal Medications, | Nonsteroidal Anti- |
| Antiandrogen | Intravaginal, Systemic† | Inflammatory Agents |
| Antiarrhythmics† | Gastric Acidity and Peptic | Proton Pump Inhibitors |
| Antibiotics† | Ulcer Agents† | Psychostimulants |
| Aminoglycosides (oral) | Gastrointestinal | Pyrazolones |
| Cephalosporins, parenteral | Prokinetic Agents | Salicylates |
| Macrolides | Ulcerative Colitis Agents | Selective Serotonin |
| Miscellaneous | Gout Treatment Agents | Reuptake Inhibitors |
| Penicillins, intravenous, high dose | Hemorrheologic Agents | Steroids, |
| Quinolones (fluoroquinolones) | Hepatotoxic Drugs | Adrenocortical† |
| Sulfonamides, long acting | Hyperglycemic Agents | Steroids, Anabolic (17- |
| Tetracyclines | Hypertensive Emergency | Alkyl Testosterone |
| Anticoagulants | Agents | Derivatives) |
| Anticonvulsants† | Hypnotics† | Thrombolytics |
| Antidepressants† | Hypolipidemics† | Thyroid Drugs |
| Antimalarial Agents | Bile Acid-Binding Resins† | Tuberculosis Agents† |
| Antineoplastics† | Fibric Acid Derivatives | Uricosuric Agents |
| Antiparasitic/Antimicrobials | HMG-CoA Reductase | Vaccines |
| Antiplatelet Drugs/Effects | Inhibitors† | Vitamins† |
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also: other medications affecting blood elements which may modify hemostasis
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dietary deficiencies
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prolonged hot weather
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unreliable PT/INR determinations
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†Increased and decreased PT/INR responses have been reported.
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| Specific Drugs Reported |
| acetaminophen | fluconazole | oxymetholone |
| alcohol† | fluorouracil | pantoprazole |
| allopurinol | fluoxetine | paroxetine |
| aminosalicylic acid | flutamide | penicillin G, intravenous |
| amiodarone HCI | fluvastatin | pentoxifylline |
| argatroban | fluvoxamine | phenylbutazone |
| aspirin | gefitinib | phenytoin† |
| atenolol | gemfibrozil | piperacillin |
| atorvastatin† | glucagon | piroxicam |
| azithromycin | halothane | pravastatin† |
| bivalirudin | heparin | prednisone† |
| capecitabine | ibuprofen | propafenone |
| cefamandole | ifosfamide | propoxyphene |
| cefazolin | indomethacin | propranolol |
| cefoperazone | influenza virus vaccine | propylthiouracil† |
| cefotetan | itraconazole | quinidine |
| cefoxitin | Jantoven® Tablets overdose | quinine |
| ceftriaxone | ketoprofen | rabeprazole |
| celecoxib | ketorolac | ranitidine† |
| cerivastatin | lansoprazol | rofecoxib |
| chenodiol | lepirudin | sertraline |
| chloramphenicol | levamisole | simvastatin |
| chloral hydrate† | levofloxacin | stanozolol |
| chlorpropamide | levothyroxine | streptokinase |
| cholestyramine† | liothyronine | sulfamethizole |
| cimetidine | lovastatin | sulfamethoxazole |
| ciprofloxacin | mefenamic acid | sulfinpyrazone |
| cisapride | methimazole† | sulfisoxazole |
| clarithromycin | methyldopa | sulindac |
| clofibrate | methylphenidate | tamoxifen |
| cyclophosphamide† | methylsalicylate ointment | tetracycline |
| danazol | (topical) | thyroid |
| dextran | metronidazole | ticarcillin |
| dextrothyroxine | miconazole, (intravaginal, oral, | ticlopidine |
| diazoxide | systemic) | tissue plasminogen |
| diclofenac | moricizine hydrochloride† | activator (t-PA) |
| dicumarol | nalidixic acid | tolbutamide |
| diflunisal | naproxen | tramadol |
| disulfiram | neomycin | trimethoprim/sulfamethoxazole |
| doxycycline | norfloxacin | urokinase |
| erythromycin | ofloxacin | valdecoxib |
| esomeprazole | olsalazine | valproate |
| ethacrynic acid | omeprazole | vitamin E |
| ezetimibe | oxandrolone | zafirlukast |
| fenofibrate | oxaprozin | zileuton |
| fenoprofen | | |
The following factors, alone or in combination, may be responsible for DECREASED PT/INR response:
ENDOGENOUS FACTORS:
| edema | hypothyroidism |
| hereditary coumarin resistance | nephrotic syndrome |
| hyperlipemia | |
EXOGENOUS FACTORS:
Potential drug interactions with Jantoven® Tablets (Warfarin Sodium Tablets, USP) are listed below by drug class and by specific drugs.
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†Increased and decreased PT/INR responses have been reported.
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| Classes of Drugs |
| Adrenal Cortical Steroid | Barbiturates | Immunosuppressives |
| Inhibitors | Diuretics† | Oral Contraceptives, |
| Antacids | Enteral Nutritional | Estrogen Containing |
| Antianxiety Agents | Supplements | Selective Estrogen |
| Antiarrhythmics† | Fungal Medications, | Receptor Modulators |
| Antibiotics† | Systemic† | Steroids, |
| Anticonvulsants† | Gastric Acidity and Peptic | Adrenocortical† |
| Antidepressants† | Ulcer Agents† | Tuberculosis Agents† |
| Antihistamines | Hypnotics† | Vitamins† |
| Antineoplastics† | Hypolipidemics† | |
| Antipsychotic Medications | Bile Acid-Binding | |
| Antithyroid Drugs† | Resins† | |
| HMG-CoA Reductase | |
| Inhibitors† | |
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also: diet high in vitamin K
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unreliable PT/INR determinations
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†Increased and decreased PT/INR responses have been reported.
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| Specific Drugs Reported |
| alcohol† | cyclophosphamide† | phenytoin† |
| aminoglutethimide | dicloxacillin | pravastatin† |
| amobarbital | ethchlorvynol | prednisone† |
| atorvastatin† | glutethimide | primidone |
| azathioprine | griseofulvin | propylthiouracil† |
| butabarbital | haloperidol | raloxifene |
| butalbital | Jantoven® Tablets
underdosage | ranitidine† |
| carbamazepine | meprobamate | rifampin |
| chloral hydrate† | 6-mercaptopurine | secobarbital |
| chlordiazepoxide | methimazole† | spironolactone |
| chlorthalidone | moricizine hydrochloride† | sucralfate |
| cholestyramine† | nafcillin | trazodone |
| clozapine | paraldehyde | vitamin C (high dose) |
| corticotropin | pentobarbital | vitamin K |
| cortisone | phenobarbital | |
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.
Botanical (Herbal) Medicines
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:
- Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of Jantoven® Tablets.
- Coenzyme Q10 (ubidecarenone) and St. John's wort are associated most often with a DECREASE in the effects of Jantoven® Tablets.
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 coagulent 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 | Celery | Parsley |
| Angelica (Dong Quai) | Chamomile (German and | Passion Flower |
| Aniseed | Roman) | Prickly Ash (Northern) |
| Arnica | Dandelion3 | Quassia |
| Asa Foetida | Fenugreek | Red Clover |
| Bogbean-2 | Horse Chestnut | Sweet Clover |
| Boldo | Horseradish | Sweet Woodruff |
| Buchu | Licorice-4 | Tonka Beans |
| Capsicum-3 | Meadowsweet-2 | Wild Carrot |
| Cassia-4 | Nettle | Wild Lettuce |
| Miscellaneous botanicals with anticoagulant properties: |
| Bladder Wrack (Fucus) | Pau d'arco | |
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1Contains coumarins and salicylate.
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2Contains coumarins and has fibrinolytic properties.
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3Contains coumarins and has antiplatelet properties.
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4Contains salicylate and has coagulant properties.
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5Has antiplatelet and fibrinolytic properties.
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| Botanicals that contain salicylate and/or have antiplatelet properties: |
| Agrimony1 | Dandelion4 | Meadowsweet2 |
| Aloe Gel | Feverfew | Onion5 |
| Aspen | Garlic5 | Policosanol |
| Black Cohosh | German Sarsaparilla | Poplar |
| Black Haw | Ginger | Senega |
| Bogbean2 | Ginkgo Biloba | Tamarind |
| Cassia4 | Ginseng (Panax) 5 | Willow |
| Clove | Licorice4 | Wintergreen |
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1Contains coumarins and salicylate.
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2Contains coumarins and has fibrinolytic properties.
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3Contains coumarins and has antiplatelet properties.
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4Contains salicylate and has coagulant properties.
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5Has antiplatelet and fibrinolytic properties.
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| Botanicals with fibrinolytic properties: |
| Bromelains | Garlic5 | Inositol Nicotinate |
| Capsicum3 | Ginseng (Panax) 5 | Onion5 |
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1Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible Vitamin K content.
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2Contains coumarins and salicylates.
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3Contains coumarins and has fibrinolytic properties.
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4Contains coumarins and has antiplatelet properties.
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5Has antiplatelet and fibrinolytic properties.
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| Botanicals with coagulant properties: |
| Agrimony1 | Mistletoe | |
| Goldenseal | Yarrow | |
Effect on Other Drugs
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.
Considerations for Increased Bleeding Risk
Jantoven® Tablets is a narrow therapeutic range (index) drug, and additional caution should be observed when warfarin sodium is administered to certain patients. Reported 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. Identification of risk fators for bleeding and certain genetic variations in CYP2CP and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see CLINICAL PHARMACOLGY: Metabolism and DOSAGE AND ADMINISTRATION) Bleeding is more likely to occur during the starting period and with a higher dose of Jantoven® Tablets (resulting in a higher INR).
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) is 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.
Information for Patients
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 - 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. Prothombin 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 cranberry 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 Guide-14 should be available to patients when their prescriptions for warfarin sodium are issued.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and mutagenicity studies have not been performed with Jantoven® Tablets. The reproductive effects of Jantoven® Tablets have not been evaluated. The use of warfarin during pregnancy has been associated with the development of fetal malformations in humans (see CONTRAINDICATIONS).
Use in Pregnancy
Pregnancy Category X - See CONTRAINDICATIONS.
Pediatric Use
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.
Geriatric Use
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).
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