Coumadin®

Warfarin Sodium

Anticoagulant

Bristol-Myers Squibb

http://www.bms.com/landing/data/index.html

Coumadin Monograph PDF download here.

 

CPS:PIS_m143200

 

 

 

Pharmacology

Warfarin 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 to 6 hours, IX - 24 hours, and X - 48 to 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. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of g-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 warfarin 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.

     The administration of warfarin via the i.v. route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72 to 96 hours after dosing, indicating that the administration of i.v. warfarin should not provide any increased biological effect or earlier onset of action.

 

Pharmacokinetics

Warfarin is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. It is important that all warfarin sodium products provide the same ratio of enantiomers as that which is present in warfarin.

Absorption: Warfarin is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours. Studies using warfarin sodium indicate the rate but not the extent of absorption of the drug is decreased by the presence of food in the GI tract. Warfarin is also absorbed percutaneously. Individuals differ in the rate at which they absorb warfarin.

Distribution: There are no differences in the apparent volumes of distribution after i.v. and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid i.v. 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. Warfarin is distributed to the liver, lungs, spleen, kidney, and crosses the placenta. 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: Individual patients vary greatly in the rate at which they metabolize warfarin. The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P450) 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, 2 diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxywarfarin. Numerous cytochrome P450 isozymes may be involved in the metabolism of warfarin, including CYP 2C9, 2C19, 2C8, 2C18, 1A2 and 3A4. CYP2C9 is likely to be the principal isozyme modulating anticoagulant activity in clinical use. This enzyme constitutes the primary pathway for the metabolism of S-warfarin, the more potent enantiomer found in racemic mixtures of warfarin. Its complete inhibition in vivo may be expected to result in lower maintenance dose requirement of warfarin. Individuals with allelic polymorphisms of CYP2C9 have been identified and have been shown to have lower maintenance dose requirements of warfarin and increased risk of overanticoagulation.

Elimination: The terminal half-life of warfarin after a single dose is approximately 1 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.

Geriatrics: Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulation effects of warfarin. The cause of this increased sensitivity in this age group is not known. This increased anticoagulant effect of 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 that there is no difference in the clearance of S-warfarin in the elderly, compared to that seen in young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly, compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.

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

 

Indications

For the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, atrial fibrillation with embolization, and as an adjunct in the prophylaxis of systemic embolism after myocardial infarction, including stroke, reinfarction and death.

     The following are some of the more common clinical disorders which may be associated with or predispose patients to the above indications:

1. Thrombophlebitis

2. Congestive heart failure

3. Surgical procedure or trauma associated with a high risk of thromboembolism

4. Myocardial infarction

5. Cerebral embolism.

 

     It may also be useful as an adjunct in the treatment of transient cerebral ischemic attacks due to intravascular clotting.

 

Contraindications

Anticoagulation is contraindicated in any localized or general physical condition or personal circumstances in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:

Pregnancy

Warfarin is contraindicated in pregnancy because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Women of childbearing potential must take precautions not to become pregnant while on warfarin therapy. 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. CNS 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 CNS 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 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 the 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 pre-eclampsia.

     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 Coumadin.

 

Warnings

Hemorrhage: The most serious risks associated with anticoagulant therapy with warfarin 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 débridement 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. Warfarin, 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 times (PT) ratio/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 warfarin are administered concomitantly, refer below to Dosage, Conversion from Heparin Therapy for recommendations.

     Caution should be observed when warfarin 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 warfarin may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toe syndrome”. Discontinuation of warfarin therapy is recommended when such phenomena are observed. While the “purple toe syndrome” is reported to be reversible, other complications of microembolization may not be reversible.

     Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toe 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 toe syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3 to 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 toe syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require débridement of the affected area, or may lead to amputation.

     A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT ratio/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. This has been noted in patients undergoing elective hip surgery receiving warfarin alone.

     Administration of anticoagulants in the following conditions will be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the risk of thrombosis or embolization in untreated cases. The following may be associated with these increased risks:

1. Severe to moderate hepatic or renal insufficiency.

2. Infectious diseases or disturbances of intestinal flora, such as sprue or as seen with antibiotic use.

3. Trauma which may result in internal bleeding.

4. Surgery or trauma resulting in large exposed raw surfaces.

5. Indwelling catheters.

6. Severe to moderate hypertension.

7. 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 Coumadin 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.

8. Diseases affecting the microvasculature or microcirculation, such as polycythemia vera, vasculitis, and severe diabetes.

 

Heparin-induced Thrombocytopenia: Warfarin should be used with caution in patients with heparin-induced thrombocytopenia and deep vein thrombosis. Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients when heparin treatment was discontinued and warfarin therapy was started or continued especially when large initiation doses were used. In some patients sequelae have included amputation of the involved area and/or death. The use of alternative anticoagulant therapy should be considered in patients with heparin-induced thrombocytopenia and deep vein thrombosis.

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 breast-fed infants, whose mothers were treated with warfarin, had neither detectable warfarin in their plasma, nor clinically significant changes in coagulation tests. Although warfarin was not detected in the plasma of the breast-fed infants, the possibility of an anticoagulant effect by warfarin cannot be excluded. It is prudent to perform coagulation tests on infants at risk for bleeding before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated.

Miscellaneous: Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported.

     In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to warfarin have been reported. Exaggerated therapeutic responses have been reported in other patients.

     Patients with congestive heart failure may become more responsive to warfarin, thereby requiring more frequent laboratory monitoring, and reduced doses of warfarin.

     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 ratio/INR or other suitable coagulation test is essential.

     Numerous factors, alone or in combination, including travel, changes in diet, environment, physical state or medication, or the use of natural medicines, may influence the patient's response to anticoagulants. It is generally good practice to monitor the patient's response with additional PT ratio/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including natural medicines, are initiated, discontinued or taken irregularly.  Table 1  and  Table 2 provide a listing of factors, alone or in combination, which may effect the PT. However, other factors may also affect the anticoagulant response and the tables are provided for your reference only.

     Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin 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 warfarin 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.

     Because a patient may be exposed to a combination of listed factors, the net effect of warfarin on PT ratio/INR responses may be unpredictable.

     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.

 

Drug Interactions

The complete in vivo inhibition of the CYP2C9 isozyme may be expected to result in lower maintenance dose requirement of warfarin. Individuals with allelic polymorphisms of CYP2C9 have been identified and have been shown to have lower maintenance dose requirements of warfarin and increased risk of overanticoagulation. Acquired or inherited warfarin resistance should be suspected if large daily doses of warfarin are required to maintain a patient's PT ratio/INR within a normal therapeutic range.

     Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT ratio/INR monitoring is advisable. 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.

     It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.

     Close monitoring of patients receiving NSAIDs is recommended to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect prothrombin time, NSAIDs can inhibit platelet aggregation, and can cause GI bleeding, peptic ulceration and/or perforation.

CPS:Coumadin_t1Click here for Table 1

Table 1: Coumadin

The Following Factors, Alone or in Combination, May Be Responsible for ↑  PT Ratio or INR, or ↑  Risk of Bleeding

 

Endogenous Factors:
blood dyscrasias cancer collagen 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 warfarin are listed below by drug class and by specific drugs.
Classes of Drugs
5-lipoxygenase Inhibitors Adrenergic Stimulants, central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, inhalation Antiandrogens Antiarrhythmicsa      Antibioticsa      Aminoglycosides (oral)     Cephalosporins, parenteral     Macrolides     Penicillins, i.v., high dose     Quinolones (fluoroquinolones)     Sulfonamides, long acting     Tetracyclines Anticoagulants Anticonvulsantsa Antidepressantsa Antifungal Medications,      Intravaginal, systemica Antimalarial Agents Antineoplasticsa Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects  Antithyroid Drugsa Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diureticsa Gastric Acidity and Peptic Ulcer Agentsa Gastrointestinal, ulcerative colitis agents Gastrointestinal, prokinetic agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnoticsa Leukotriene Receptor Antagonists Lipid Lowering Agentsa      Bile Acid-Binding Resinsa      Fibrates     HMG-CoA Reductase Inhibitorsa	MAO Inhibitors Narcotics, prolonged Natural Medicines Nonsteroidal Anti-Inflammatory Agents      COX-2 Inhibitors     Nonselective NSAIDs Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, adrenocorticala Steroids, anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agentsa Uricosuric Agents Vaccines Vitaminsa
Specific Drugs Reported
acetaminophen alcohola allopurinol aminosalicylic acid amiodarone HCl ASA azithromycin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib chenodiol chloramphenicol chloral hydratea chlorpropamide cholestyraminea cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamidea danazol  danshen (Chinese herb) dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin ethacrynic acid fenofibrate	fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac levamisole levofloxacin levothyroxine liothyronine lovastatin mefenamic acid methimazolea methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, systemica ) moricizine HCla nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxaprozin oxymetholone	paroxetine penicillin G, i.v. pentoxifylline phenylbutazone phenytoina piperacillin piroxicam prednisonea propafenone propoxyphene propranolol propylthiouracila quinidine quinine ranitidinea rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/sulfamethoxazole trovafloxacin urokinase valproate vitamin E warfarin overdose zafirlukast
Also: Other medications affecting blood elements which may modify hemostasis dietary deficiencies; prolonged hot weather; unreliable PT determinations.

 

 ^a Increased and decreased PT ratio/INR responses have been reported.

 

 

CPS:Coumadin_t2Click here for Table 2

Table 2: Coumadin

The Following Factors Alone or in Combination, May Be Responsible for Decreased PT Ratio or INR, or Increased Potential Risk of Thromboembolic Events

 

Endogenous Factors:
edema hereditary coumarin resistance	hyperlipemia hypothyroidism	nephrotic syndrome
Exogenous Factors: Potential drug interactions with warfarin are listed below by drug class and by specific drugs.
Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmicsa Antibioticsa Anticonvulsantsa Antidepressantsa Antifungal Medications, systemica Antihistamines Antineoplasticsa	Antipsychotic Medications Antithyroid Drugsa Barbiturates Diureticsa Enteral Nutritional Supplements Gastric Acidity and Peptic Ulcer Agentsa Hypnoticsa	Immunosuppressives Lipid Lowering Agents      Bile Acid-Binding Resinsa      HMG-CoA Reductase Inhibitorsa Natural Medicines Oral Contraceptives, estrogen containing Selective Estrogen Receptor Modulators Steroids, adrenocorticala Tuberculosis Agentsa Vitaminsa
Specific Drugs Reported
alcohola aminoglutethimide amobarbital atorvastatin azathioprine butabarbital butalbital carbamazepine chloral hydratea chlordiazepoxide chlorthalidone cholestyraminea corticotropin cortisone cyclophosphamidea	dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate 6-mercaptopurine methimazolea moricizine HCla nafcillin paraldehyde pentobarbital phenobarbital phenytoina prednisonea	primidone propylthiouracila raloxifene ranitidinea rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage
Also: diet high in vitamin K unreliable PT determinations

 

 ^a Increased and decreased PT ratio/INR responses have been reported.

 

 

Natural Medicines (Including Herbals and Botanicals): Caution should be exercised when natural medicines are taken concomitantly with warfarin. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between natural medicines and warfarin. Due to a lack of manufacturing standardization with natural medicines, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulants. It is good practice to monitor the patient's response with additional PT/INR determinations when initiating or discontinuing natural medicines.

     Specific natural medicines reported to affect warfarin therapy include the following:

•  Bromelains, danshen, dong quai (Angelica sinensis), garlic, and Ginkgo biloba are associated most often with an increase in the effects of warfarin.

•  Coenzyme Q₁₀ (ubidecarenome) and St. John's wort are associated most often with a decrease in the effects of warfarin.

 

     Some natural medicines 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 warfarin. Conversely, other natural medicines may have coagulant properties when taken alone or may decrease the effects of warfarin.

     Some natural medicines that may affect coagulation are listed in  Table 3 for reference; however, this list should not be considered all-inclusive. Many natural medicines have several common names and scientific names.

CPS:Coumadin_t3Click here for Table 3

Table 3: Coumadin

Natural Medicines That Contain Coumarins with Potential Anticoagulant Effects:

 

Alfalfa (Medicago sativa) Aniseed (Pimpinella anisum) Arnica Asa Foetida (Asafetida) Bogbeana  (Menyanthis folium) Peumus Boldo Buchu (Barosmae boldo) Paprika (Capsicum) Cassiac Celery (Apium graveolens) Chamomile, German and Roman (Anthemis nobilis) Dandelionc  (Taraxacum officinale) Dong Quai (Angelica sinensis) Fenugreek (Trigonella fœnumgraecum) Horse Chestnut (Æsculus hippocastanum)	Horseradish (Cochleria armoracia) Licoricec  (Glycyrrhiza globra) Meadowsweeta  (Spiraea ulmaria) Nettle (Urtica dioica) Parsley (Carum petroselinum) Passion Flower (Passiflora edulis) Prickley Ash, Northern (Zanthoxylum americanum) Quassia (Amara) Red Clover (Trifolium pratense) Sweet Clover (Melilotus officinalis) Sweet Woodruff (Galii odorati herba) Tonka Beans (Dipteryx odorata) Wild Carrot (Daucus carota) Wild Lettuce (Lactuca virosa)
Miscellaneous Natural Medicines with Anticoagulant Properties:
Bladder Wrack (Fucus vesiculosus)	Pau d'arco (Tabebuia avellanedae)
Natural Medicines that Contain Salicylate and/or Have Antiplatelet Properties:
Agrimonyd  (Argimonia eupatoria) Aloe Gel Aspen (Populus tremuloides) Black Cohosh (Cimicifuga racemosa) Black Haw (Viburnum prunifolium) Bogbeana Cassiac Clove (Eugenia caryophyllus) Dandelionc Feverfew (Chrysanthenum parthenum) Garlice  (Tremuloides) German Sarsaparilla (Corex arenaria)	Ginger Ginko Biloba Ginseng (Panax)e Licoricec Meadowsweeta Onione  (Allium cepa) Policosanol Poplar (Populi gemma) Senega (Polygala) Tamarind (Tamarindus Indica) Willow (Salix nigra) Wintergreen (Gaultheria procumbens)
Natural Medicines with Fibrinolytic Properties:
Bromelains (Bromelainum) Capsicumb Garlice	Ginseng (Panax)e Inositol Nicotinate Onione
Natural Medicines with Coagulant Properties:
Agrimonyd Goldenseal (Chrysanthenum)	Mistletoe (Viscum album) Yarrow (Achillea millefolium)

 

 ^a Contains coumarins and salicyclate.

 ^b Contains coumarins and has fibrinolytic properties.

 ^c Contains coumarins and has antiplatelet properties.

 ^d Contains salicylate and has coagulant properties.