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All about: Jantoven

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Generic Name: warfarin sodium
Dosage Form: Tablets

Anticoagulant
Rx Only

Rev. 09-05
15084-05

Jantoven Description

Jantoven® (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following:

Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether.

Jantoven® (Warfarin Sodium Tablets, USP) for oral use contain: 1 mg, 2 mg, 2½ mg, 3 mg, 4 mg, 5 mg, 6 mg, 7½ mg or 10 mg of crystalline warfarin sodium, USP. They also contain:

All Strengths: Lactose monohydrate, magnesium stearate, povidone, and pregelatinized starch (corn)

1 mg: FD&C Red #40 Aluminum Lake

2 mg: FD&C Blue #2 Aluminum Lake and FD&C Red #40 Aluminum Lake

2½ mg: D&C Yellow #10 Aluminum Lake and FD&C Blue #1 Aluminum Lake

3 mg: Brown #75 Synthetic Brown Iron Oxide

4 mg: FD&C Blue #1 Aluminum Lake

5 mg: FD&C Yellow #6 Aluminum Lake

6 mg: Yellow #10 Synthetic Yellow Iron Oxide, Black #85 Synthetic Black Iron Oxide and FD&C Blue #1 Aluminum Lake

7½ mg: D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Aluminum Lake

10 mg: Dye Free.

Jantoven - Clinical Pharmacology

Jantoven® (Warfarin Sodium Tablets, USP) and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII – 4 - 6 hours, IX - 24 hours, and X – 48 - 72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.

An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of Jantoven® may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

Pharmacokinetics

Jantoven® is 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.

Absorption

Jantoven® is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

Distribution

There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Jantoven® is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (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, 4'-, 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.

Excretion

The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Elderly

Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.

Asians

Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.

Renal Dysfunction

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.

Hepatic Dysfunction

Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

Clinical Trials

Atrial Fibrillation (AF)

In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (See Table 1). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0 - 4.5) or low INR (1.4 - 3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.

Table 1: Clinical Studies Of Warfarin In Non-Rheumatic AF Patients*

*All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage and transient ischemic attacks.

Study N PT Ratio INR Thromboembolism % Major Bleeding
Warfarin-Treated Patients Control Patients % Risk Reduction p-value Warfarin-Treated Patients Control Patients
AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0
SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9
BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5
CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5
SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5

Myocardial Infarction

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table:

Table 2:

RR = Relative risk; Risk reduction = (I – RR); CI = Confidence interval; MI = Myocardial infarction; py = patient years

Event Warfarin (N=607) Placebo (N=607) RR (95%CI) % Risk Reduction
(p-value)
Total Patient Years of Follow-up 2018 1944
Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p=0.030)
   Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p=0.068)
Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51,0.85) 34 (p=0.001)
Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002)

Mechanical and Bioprosthetic Heart Valves

In a prospective, randomized, open label, positive-controlled study (Mok et al, 1985) in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.

In a prospective, open label, clinical trial (Saour et al, 1990) comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group.

In a randomized trial (Turpie et al, 1988) in 210 patients comparing two intensities of warfarin therapy (INR 2.0 - 2.25 vs. INR 2.5 - 4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2 %, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity.

Indications and Usage for Jantoven

Jantoven® (Warfarin Sodium Tablets, USP) is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.

Jantoven® is indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.

Jantoven® is indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Contraindications

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:

Pregnancy

Jantoven® (Warfarin Sodium Tablets, USP) is 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, and corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly.

Spontaneous abortion and still birth 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.

Warnings

The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ and, less frequently (<0.1%), necrosis and/or gangrene of skin and other tissues. The risk of hemorrhage is related to the level of intensity and the duration of anticoagulant therapy. 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® (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® are administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for recommendations.

Caution should be observed when Jantoven® is 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® 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® 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® 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 (Warkentin et al, 1997).

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® 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® 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®, thereby requiring more frequent laboratory monitoring, and reduced doses of Jantoven®.

Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)

Precautions

Periodic determination of PT/INR or other suitable coagulation test is essential.

Numerous factors, alone or in combination, including travel, changes in diet, environment, physical state and medication, 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® (Warfarin Sodium Tablets, USP) through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with Jantoven® 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® 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® are listed below by drug class and by specific drugs.

Classes of Drugs

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

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†
Specific Drugs Reported

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.

acetaminophen fluoxetine oxymetholone
alcohol† flutamide pantoprazole
allopurinol fluvastatin paroxetine
aminosalicylic acid fluvoxamine penicillin G, intravenous
amiodarone HCI gefitinib pentoxifylline
aspirin gemfibrozil phenylbutazone
atorvastatin† glucagon phenytoin†
azithromycin halothane piperacillin
capecitabine heparin piroxicam
cefamandole ibuprofen pravastatin†
cefazolin ifosfamide prednisone†
cefoperazone indomethacin propafenone
cefotetan influenza virus vaccine propoxyphene
cefoxitin itraconazole propranolol
ceftriaxone Jantoven® overdose propylthiouracil†
celecoxib ketoprofen quinidine
cerivastatin ketorolac quinine
chenodiol lansoprazol rabeprazole
chloramphenicol levamisole ranitidine†
chloral hydrate† levofloxacin rofecoxib
chlorpropamide levothyroxine sertraline
cholestyramine† liothyronine simvastatin
cimetidine lovastatin stanozolol
ciprofloxacin mefenamic acid streptokinase
cisapride methimazole† sulfamethizole
clarithromycin methyldopa sulfamethoxazole
clofibrate methylphenidate sulfinpyrazone
cyclophosphamide† methylsalicylate ointment sulfisoxazole
danazol     (topical) sulindac
dextran metronidazole tamoxifen
dextrothyroxine miconazole, (intravaginal, tetracycline
diazoxide    systemic) thyroid
diclofenac moricizine hydrochloride† ticarcillin
dicumarol nalidixic acid ticlopidine
diflunisal naproxen tissue plasminogen
disulfiram neomycin    activator (t-PA)
doxycycline norfloxacin tolbutamide
erythromycin ofloxacin tramadol
esomeprazole olsalazine trimethoprim/sulfamethoxazole
ethacrynic acid omeprazole urokinase
fenofibrate oxandrolone valproate
fenoprofen oxaprozin vitamin E
fluconazole   zafirlukast
fluorouracil   zileuton

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® (Warfarin Sodium Tablets, USP) are listed below by drug class and by specific drugs.

Classes of Drugs

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

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

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