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.
TreatmentExcessive 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 (warfarin sodium tablets) ® Tablets therapy. Patients may return to a pretreatment 1 thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of Jantoven® Tablets (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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:
PregnancyJantoven® 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.
Hemorrhagic tendencies or blood dyscrasias.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.
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.
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 (warfarin sodium tablets) are indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
Jantoven® Tablets (warfarin sodium tablets) are indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
Jantoven® Tablets (warfarin sodium 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.
AbsorptionJantoven® Tablets (warfarin sodium tablets) are essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.
DistributionThere 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.
MetabolismThe elimination of warfarin is almost entirely by metabolism. Jantoven (warfarin sodium tablets) ® 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.
ExcretionThe 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.
ElderlyPatients 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.
AsiansAsian 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 DysfunctionRenal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.
Hepatic DysfunctionHepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
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.
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). 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
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 (warfarin sodium tablets) are administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for recommendations.
Caution should be observed when Jantoven® Tablets (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium tablets) , thereby requiring more frequent laboratory monitoring, and reduced doses of Jantoven® Tablets (warfarin sodium tablets).
Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)
PRECAUTIONSPeriodic determination of PT/INR or other suitable coagulation test is essential. (See DOSAGE AND ADMINISTRATION: Laboratory Control.)
Information for PatientsThe 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 (warfarin sodium tablets) ® 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 (warfarin sodium tablets) are being taken. If the prescribed dose of Jantoven® Tablets (warfarin sodium 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 (warfarin sodium tablets) the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with Jantoven® Tablets (warfarin sodium 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 (warfarin sodium tablets) is discontinued, patients should be cautioned that the anticoagulant effects of Jantoven® Tablets (warfarin sodium 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.
Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity and mutagenicity studies have not been performed with Jantoven® Tablets (warfarin sodium tablets). The reproductive effects of Jantoven® Tablets (warfarin sodium tablets) have not been evaluated.
Use in PregnancyPregnancy Category X - See CONTRAINDICATIONS.
Pediatric UseSafety 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 (warfarin sodium 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 UsePatients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). Jantoven® Tablets (warfarin sodium 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 (warfarin sodium tablets) ® 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 (warfarin sodium tablets) Medication Guide. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2007.
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 (warfarin sodium 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
Atrial FibrillationFive 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
Post-Myocardial InfarctionThe 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
Mechanical and Bioprosthetic Heart ValvesFor 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
Recurrent Systemic Embolism and Other IndicationsOral 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.
Initial DosageThe dosing of Jantoven® Tablets (warfarin sodium 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 (warfarin sodium 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
MaintenanceMost 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.
Duration of TherapyThe 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
Missed DoseThe anticoagulant effect of Jantoven® Tablets (warfarin sodium tablets) persists beyond 24 hours. If the patient forgets to take the prescribed dose of Jantoven® Tablets (warfarin sodium 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 (warfarin sodium tablets) ® 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 (warfarin sodium 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 (warfarin sodium tablets) therapy. When discontinuing Jantoven (warfarin sodium tablets) ® 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 (warfarin sodium tablets) ® Tablets is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to Jantoven® Tablets (warfarin sodium 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 (warfarin sodium tablets) therapy be overlapped with heparin for 4 to 5 days, until Jantoven® Tablets (warfarin sodium tablets) has produced the desired therapeutic response as determined by PT/INR. When Jantoven (warfarin sodium tablets) ® Tablets has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Jantoven® Tablets (warfarin sodium tablets) may increase the aPTT test, even in the absence of heparin. During initial therapy with Jantoven® Tablets (warfarin sodium 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 (warfarin sodium tablets) should have blood for PT/INR determination drawn at least:
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.
DRUG INTERACTIONS Drug-Drug and Drug-Disease InteractionsNumerous 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 (warfarin sodium 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 (warfarin sodium tablets) ® 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 (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium 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) MedicinesCaution should be exercised when botanical medicines (botanicals) are taken concomitantly with Jantoven® Tablets (warfarin sodium tablets). Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and Jantoven® Tablets (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium tablets). Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of Jantoven® Tablets (warfarin sodium 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.
Special Risk PatientsJantoven® Tablets (warfarin sodium 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 (warfarin sodium 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 (warfarin sodium tablets) are required to maintain a patient's PT/INR within a normal therapeutic range.
