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

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  • Periodic determination of PT/INR is essential. (See DOSAGE AND ADMINISTRATION: Laboratory Control.)

    Numerous factors, alone or in combination, including changes in diet, 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 CONTRAINDICATIONSdiarrhea 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.

    †Increased and decreased PT/INR responses have been reported.

    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†

    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.

    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.

    †Increased and decreased PT/INR responses have been reported.

    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†

    also: diet high in vitamin K

    unreliable PT/INR determinations

    †Increased and decreased PT/INR responses have been reported.

    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:
    Agrimony1 Alfalfa Celery Parsley
    Angelica (Dong Quai) Chamomile (German and Passion Flower
    Aniseed Roman) Prickly Ash (Northern)
    Arnica Dandelion3Quassia
    Asa Foetida Fenugreek Red Clover
    Bogbean2Horse Chestnut Sweet Clover
    Boldo Horseradish Sweet Woodruff
    Buchu Licorice4Tonka Beans
    Capsicum3Meadowsweet2Wild Carrot
    Cassia4Nettle Wild Lettuce
    Miscellaneous botanicals with anticoagulant properties:
    Bladder Wrack (Fucus) Pau d'arco
    Botanicals that contain salicylate and/or have antiplatelet properties:
    Agrimony1Dandelion4Meadowsweet2
    Aloe Gel Feverfew Onion5
    Aspen Garlic5Policosanol
    Black Cohosh German Sarsaparilla Poplar
    Black Haw Ginger Senega
    Bogbean2Ginkgo Biloba Tamarind
    Cassia4Ginseng (Panax)5Willow
    Clove Licorice4Wintergreen
    Botanicals with fibrinolytic properties:
    Bromelains Garlic5Inositol Nicotinate
    Capsicum3Ginseng (Panax)5Onion5

    1Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible Vitamin K content.

    2Contains coumarins and salicylate.

    3Contains coumarins and has fibrinolytic properties.

    4Contains coumarins and has antiplatelet properties.

    5Has antiplatelet and fibrinolytic properties.

    Botanicals with coagulant properties:
    Agrimony1Mistletoe
    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 factors for bleeding and certain genetic variations in CYP2C9 and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see CLINICAL PHARMACOLOGY: Pharmacokinetics: 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 (IM) 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.

  • 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. 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 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 Guide14 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).

  • Drug Information Provided by National Library of Medicine (NLM).
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