The P-I-E-N-O Parkinsn's List Drug Database
warfarin / CoumadinTM
ANTICOAGULANT
Description: Warfarin is an oral coumarin anticoagulant. The original discovery in 1939 that spoiled sweet clover possessed anticoagulant properties is a classic story in pharmacology. Warfarin is a racemic mixture of roughly equal amounts of two active isomers; the S-form is roughly 5 times as potent as a vitamin K antagonist than the R-form. Clinically, warfarin is used to prevent and treat thromboembolic disease. Warfarin is currently being actively studied to determine its role in acute myocardial infarction. It is also the active ingredient in various rodenticides and insecticides. Warfarin was approved by the FDA in 1954.
Mechanism of Action: Warfarin interferes with the action of vitamin K, a cofactor essential for converting precursor proteins into the active coagulation factors II, VII, IX, and X. As a result, the vitamin K-dependent factors that have been affected by warfarin during synthesis are dysfunctional. Warfarin does not affect the activity of coagulation factors in which synthesis was complete before exposure to warfarin. Thus, depletion of these mature factors through normal catabolism must occur before therapeutic effects of warfarin are seen. Each factor differs in its degradation half-life, ranging from as short as 5 hours (factor VII) to as long as 60 hours (factor II). As a result, several days of therapy are required before a clinical response is seen. Exogenous vitamin K as well as transfusions of plasma proteins will overcome the effects of warfarin. In contrast to heparin, warfarin has no anticoagulant effect in vitro. Warfarin has little effect on preexisting thrombi and does not affect prostaglandin-mediated platelet aggregation. The drug prolongs both prothrombin time (PT) and thromboplastin time (APTT), but prothrombin time is used clinically to guide therapy.
Pharmacokinetics: Warfarin is well absorbed from the GI tract, but individual brands of warfarin can exhibit different rates or degrees of absorption. Administration with food can delay the rate but not the extent of absorption. Warfarin also can be readily absorbed through the skin, and systemic manifestations are possible with significant exposure to rodenticides. Although warfarin plasma concentrations are detectable within 1 hour of administration, antithrombogenic effects are dependent on the gradual catabolism of circulating activated factors. A similar delay in return to normal blood coagulation time occurs following discontinuation of the drug.
Warfarin is highly bound (about 97%) to plasma protein, mainly albumin, and this is one of several mechanisms whereby other drugs interact with warfarin. It is distributed to the liver, lungs, spleen, and kidneys but does not appear to be distributed into breast milk in significant amounts. It crosses the placenta and is a known teratogen.
Warfarin is hydroxylated in the liver by hepatic microsomal enzymes to produce inactive metabolites. This mechanism is the basis for other significant drug interactions. There is considerable patient variation in the rate of metabolism of specific preparations. Plasma half-life of warfarin is highly variable and may be less important to the duration of action than the rate of catabolism of activated clotting factors. Inactive metabolites of warfarin are excreted in the bile and are reabsorbed and excreted in the urine.
CONTRAINDICATIONS/PRECAUTIONS: Warfarin is contraindicated during pregnancy. It crosses the placenta and has been shown to cause abnormalities in the fetus, especially when taken during the first trimester. Chondrodysplasia punctata has occurred. Because of this, it is a category X drug. Women who become pregnant while taking the drug should be advised of the potential hazards. Warfarin should be replaced by heparin, especially during the first trimester, because heparin does not cross the placenta. Warfarin should not be used during, or immediately after, childbirth because of the possibility of hemorrhage.
Warfarin can cause uncontrolled hemorrhage and should not be used in any condition in which there may be blood loss or in which uncontrolled bleeding could be a hazard. Examples include surgery, especially involving the eye, brain, or spinal cord; active bleeding; peptic ulcer disease, especially if bleeding is involved; hemophilia; polycythemia vera; idiopathic thrombocytopenic purpura; leukemia; lumbar puncture; pericarditis; pericardial effusion; bacterial endocarditis; or hepatic disease, especially cirrhosis with hypoprothrombinemia.
Warfarin also should be used cautiously in the following conditions because bleeding, should it occur, would be extremely serious during warfarin therapy: vasculitis; polyarthritis; hypertension; cerebral or abdominal aneurysms; visceral carcinoma; bleeding granuloma; and bacterial endocarditis.
Intramuscular injections should not be administered to patients receiving warfarin. IM injections may cause bleeding, bruising, or hematomas due to the anticoagulant effect of warfarin therapy.
Patients with protein C deficiency or protein S deficiency can become transiently hypercoaguable when warfarin is initiated, a condition that can manifest in fatty, subcutaneous tissue as necrosis of the skin and underlying tissue. The initial symptom may be an intense burning in the affected area. Warfarin therapy should be immediately stopped because skin necrosis can be permanently disfiguring. If warfarin therapy is indicated in patients with protein C deficiency, anticoagulation should begin with heparin.
Vitamin C deficiency causes increased capillary fragility. Administration of warfarin can increase the risk of localized bleeding.
Vitamin K deficiency and/or hypoprothrombinemia increase the risk of bleeding during therapy with warfarin. Lower doses may be required.
Because safe use of warfarin depends on good patient compliance, therapy should be carefully evaluated for patients with senility, alcoholism, or psychosis; in an outpatient situation; or during long-term use.
Warfarin should be used with caution in breast-feeding women. Warfarin is not excreted substantially into breast milk, but infants should be carefully observed for possible bleeding.
DRUG INTERACTIONS: NOTE: Warfarin has many drug interactions, some of which are potentially serious. Drugs can interact with warfarin through a variety of mechanisms including: impaired warfarin absorption, displacement of warfarin from plasma protein-binding sites, altered warfarin metabolism, and others. In general, interactions are more likely to be significant if a second drug is added to a patient previously stabilized on warfarin therapy or if the second drug is stopped while warfarin therapy continues.
Cholestyramine can decrease warfarin absorption, thus reducing the effectiveness of warfarin. Staggering the doses of cholestyramine and warfarin is recommended but this may not completely avoid a drug interaction. Inactive metabolites of the more potent warfarin S-isomer are eliminated via the bile and cholestyramine has also been shown to enhance the clearance of IV warfarin (no longer available in the US). Thus, it is theoretically possible that cholestyramine may interfere with the actions of warfarin after warfarin has been absorbed. Colestipol and sucralfate have also been reported to interfere with warfarin absorption, however, a warfarin interaction with either of these two agents appears to be of lesser clinical significance. While isolated reports have shown that sucralfate can inhibit warfarin oral absorption, other studies showed no clinical effect. Colestipol may be an acceptable alternative to cholestyramine in patients receiving warfarin who also require therapy with a bile acid sequesterant, although, both cholestyramine and colestipol can decrease vitamin K absorption from the gut, which may indirectly affect the clinical response to warfarin. Antacids do not appear to affect warfarin absorption significantly.
Many drugs can inhibit warfarin hepatic metabolism, thereby potentiating its anticoagulant effects. These include: cimetidine; ciprofloxacin; co-trimoxazole; disulfiram; erythromycin; fluconazole; influenza virus vaccine; itraconazole; miconazole; metronidazole; omeprazole. Cimetidine and omeprazole inhibit the clearance of the less potent warfarin R-isomer while co-trimoxazole and miconazole inhibit clearance of the more potent S-isomer. The evidence for a drug interaction between warfarin and norfloxacin or ofloxacin appears to be less well documented than for ciprofloxacin although ofloxacin has been associated with hematuria and severe PT prolongation in a single case report. Until more information is available, norfloxacin or ofloxacin should be used cautiously in any patient receiving warfarin. Other macrolides, such as azithromycin or clarithromycin, have not been reported to interact with warfarin to the same degree as erythromycin. At low doses, fluconazole, exerts a slight effect on warfarin metabolism although when fluconazole is administered at higher doses, a significant prolongation of PT may be seen. In a review of warfarin drug interactionsD ketoconazole was determined to not interact with warfarin. Clinicians should keep in mind that ketoconazole has been associated with several other hepatically-mediated drug-drug interactions and should, nevertheless, be used cautiously in patients receiving warfarin. Some evidence suggests that allopurinol interferes with the metabolism of warfarin if administered concomitantly. Although an interaction with warfarin has not been significant, allopurinol has affected the hypoprothrombinemic response to dicumarol, which has resulted in bleeding episodes in some patients. Prothrombin times should be monitored carefully in patients receiving oral anticoagulants when allopurinol therapy is added.
Although data are limited, fluoxetine may potentiate the hypoprothrombinemic effects of warfarin. One case is noted of positive challenge and positive dechallenge with fluoxetine on warfarin action. Clinicians should avoid the concomitant use of these two drugs whenever possible.
Griseofulvin can interfere with the hypoprothrombinemic response of warfarin. Although a drug-drug interaction is well-established,D the mechanism of this interaction is unclear. It is commonly believed that griseofulvin enhances the hepatic metabolism of warfarin, although evidence of this is scant. The effects of griseofulvin may require several weeks to become fully manifest. Clinicians should reassess prothrombin times several weeks after the addition of griseofulvin to warfarin therapy.
Glucagon has been reported to enhance the hypoprothrombinemic response in 8 out of 13 patients receiving warfarin. Clinical bleeding also was reported in 3 patients. These findings -based on data from only 13 patients -were published in 1970 and no subsequent reports have been identified. The mechanism of this interaction is uncertain.
Many drugs can accelerate warfarin hepatic metabolism and possibly decrease its therapeutic effect. Examples include: barbiturates, including primidone which is metabolized to phenobarbital; carbamazepine; ethchlorvynol; glutethimide; griseofulvin; and rifampin. An interaction is possible if any of these drugs are added or deleted during warfarin administration. According to a review of warfarin drug interactions,D the griseofulvin-warfarin drug interaction is one of the most well-documented warfarin drug interactions.
Displacement of warfarin from protein-binding sites enhances warfarin's anticoagulant effect. Because warfarin is very highly bound, small changes in protein binding lead to correspondingly large changes in circulating unbound drug, exaggerating the clinical effect. Examples of drugs that can displace warfarin include: aspirin, chloral hydrate, nalidixic acid, and others. The inhibitory effects of aspirin on platelet function probably contribute more to its interaction with warfarin (see below) than displacement of warfarin from protein binding sites. Although bleeding episodes increase when aspirin and warfarin are administered concomitantly, the combination warfarin with low-dose aspirin has been shown to reduce mortality in patients with heart-valve replacement and, for this reason, these two drugs are sometimes intentionally used together. Diazoxide, fenoprofen, and valproic acid are also highly protein-bound and theoretically could displace warfarin, but interactions between warfarin and these drugs have not been seen clinically.
Although acetaminophen is routinely considered safer than aspirin when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Increases in PT usually occurred after several weeks of acetaminophen administration and both PT prolongation and clinical bleeding have been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe. Clinicians should be alert for an increased PT if acetaminophen is administered daily in large doses for longer than 10 days.
Various antibiotics can affect warfarin's anticoagulant effect. Some antibiotics are known to destroy intestinal flora that synthesize vitamin K and a decrease in the activity level of vitamin K can enhance warfarin's anticoagulant effect. There is, however, no evidence in man that intestinal bacterial forms of vitamin K are absorbed. Further, drugs such as cefoxitin and clindamycin, which achieve high concentrations in the colon and readily reduce intestinal bacteria counts, do not exhibit clinically significant interactions with warfarin. It is unclear if sulfonamides other than sulfamethoxazole interact significantly with warfarin since reports of these interactions are attributed to co-trimoxazole, a 2-drug combination. Sulfonamides may displace warfarin from protein-binding sites. Cefamandole, cefoperazone, and cefotetan have been associated with PT prolongation but do not appear to interact directly with warfarin. Some antibiotics, such as erythromycin, metronidazole, and some fluoroquinolones, inhibit warfarin metabolism. Nafcillin can enhance warfarin metabolism. In a review of warfarin drug interactionsD tetracycline was identified as having a clinically-significant interaction with warfarin, although no mechanism was given.
Some drugs may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Examples of drugs that can cause a reduction in the amount or activity of circulating coagulant proteins thereby enhancing warfarin's anticoagulant effect include: amiodarone; androgens such as anabolic steroids; antibiotics such as cefamandole and cefoperazone; antimetabolites, dextrothyroxine; quinidine; and quinine. Danazol, may also augment the activity of warfarin; its mechanism may be similar to that of the anabolic steroids. Although drug interaction references cite a significant interaction between warfarin and thyroid hormones, a review of warfarin drug interactions did not identify thyroid hormones as causing a significant interaction with warfarin.D
Some drugs may generate a pharmacodynamic interaction with warfarin by independently affecting the level of circulating coagulation proteins. Drugs that increase the activity level of circulating coagulant proteins can decrease warfarin's clinical effect. These include: antithyroid drugs, such as methimazole and propylthiouracil, PTU; estrogens; and phytonadione. Occult sources of vitamin K include multivitamins, enteral feeding solutions, and many foods. Even though the dose of estrogen is very small in estrogen-containing oral contraceptives, these, too, can alter the response to warfarin. In general, it is believed that estrogens, by stimulating hepatic synthesis of procoagulant factors, diminishes the anticoagulant effect of warfarin. Other reports exist, however, of oral contraceptives that augment the action of warfarin. Although the quantity of estrogen in oral contraceptives has been reduced substantially since their introduction, clinicians should be alert to altered anticoagulant response if estrogens or oral contraceptives are added to warfarin therapy. This interaction would not seem to be clinically significant if warfarin was added after hormonal therapy was in effect.
Drugs that can independently cause bleeding may lead to a pharmacodynamic interaction with warfarin if administered together. Examples of drugs that may cause bleeding include: cyclophosphamide, which can cause hemorrhagic cystitis; heparin; and thrombolytic agents. Heparin, especially in high concentrations, can prolong the prothrombin time. While concomitant therapy with heparin and warfarin makes accurate interpretation of the prothrombin time difficult, brief periods of overlapping therapy with heparin and warfarin routinely occur in clinical practice. Clinicians should keep in mind that prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.
One report is noted of a severe interaction between cyclosporine and warfarin.D In this report, cyclosporine concentrations fell after warfarin therapy was begun, and prothrombin times subsequently increased after the cyclosporine dose was increased. Until more information is available, the kinetics of each drug should be monitored carefully when the other is added.
In a review of warfarin drug interactionsD chlordiazepoxide was identified as having a clinically-significant interaction with warfarin. Standard drug interaction reference texts, however, state that no interaction exists between chlordiazepoxide and warfarin.
Clofibrate is well-documented to enhance the hypoprothrombinemic actions of warfarin. The mechanism of this interaction, however, is unclear. Clofibrate does displace warfarin from protein binding sites but the magnitude is slight; several reports state that warfarin plasma concentrations do not increase during concomitant administration of clofibrate. Clofibrate should be used cautiously in any patient receiving warfarin. Lovastatin and simvastatin have also been associated with potentiation of warfarin's effect, although clinical data is limited.
Ethanol is well-known to interact with warfarin. Several mechanisms appear to be involved. Acute ethanol ingestion enhances the hypoprothrombinemic actions of warfarin, while chronic ethanol ingestion (in patients without hepatic disease) reduces warfarin's effects. It is thought that, initially, ethanol inhibits warfarin hepatic metabolism. Stimulation of hepatic metabolism occurs during chronic ethanol ingestion. Patients with severe hepatic disease, however, may have effects which differ from those described above.
Isoniazid, INH is known to inhibit the hepatic metabolism of drugs that undergo oxidation including warfarin. Although only isolated case reports exist of this interaction in humans, according to a review of warfarin drug interactionsD the isoniazid-warfarin interaction is highly significant. Clinicians should be aware of alterations in the actions of warfarin if isoniazid is added or discontinued.
Various NSAIDs may exhibit pharmacokinetic and/or pharmacodynamic interactions with warfarin. In general, all NSAIDs may be problematic if administered to a patient receiving warfarin due to their effects on platelet aggregation and their potential for causing gastritis. The inhibitory action on platelets is most pronounced with aspirin, which may also interact with warfarin by displacing warfarin from protein binding sites. Sulfinpyrazone, in addition to its action on platelets, also inhibits the clearance of the more potent warfarin S-isomer. According to a review of warfarin drug interactionsD the sulfinpyrazone-warfarin drug interaction is one of the most well-documented warfarin drug interactions. This review also cited the piroxicam-warfarin interaction as being highly significant, although the recommendation was based on only a single patient. Phenylbutazone is also known to inhibit warfarin metabolism. In conclusion, all NSAIDs, especially piroxicam and sulfinpyrazone, should be used cautiously in patients receiving warfarin, although even aspirin can be coadministered with warfarin under appropriate circumstances.
At least two mechanisms explain the interaction between phenytoin and warfarin. Initially, phenytoin can increase the hypoprothrombinemic response by displacing warfarin from protein binding sites. After prolonged administration of phenytoin, however, hepatic enzyme induction occurs potentially reducing the effectiveness of warfarin. Warfarin dosage adjustments may be necessary if phenytoin is added or after phenytoin is discontinued.
Propafenone can increase warfarin serum concentrations and augment warfarin-induced hypoprothrombinemia. Although the mechanism of this interaction is unclear, inhibition of warfarin hepatic metabolism by propafenone has been proposed.
Limited data suggest that both azathioprine and mercaptopurine, 6-MP may interfere with the anticoagulant response to warfarin. Although the mechanism is unclear, it has been proposed that these agents potentiate the activity of prothrombin.
According to a comprehensive reviewD of the literature on warfarin drug interactions published in 1994, no clinically-significant drug interactions occur between warfarin and any of the following drugs: allopurinol, cefamandole, diazoxide, valproic acid. The interaction between oral anticoagulants and oral sulfonylureas is complex. Dicoumarol has been reported to inhibit the metabolism of chlorpropamide and tolbutamide, however, warfarin did not exhibit a similar effect on tolbutamide kinetics. Glyburide has been reported to augment the hypoprothrombinemic response to warfarin, although other reports showed no interaction. Warfarin appears less likely to interact than dicoumarol. Nevertheless, it would be wise for clinicians to use warfarin and oral sulfonylureas together cautiously.
ADVERSE REACTIONS: The most common adverse effect of warfarin therapy is bleeding, which can be minor, such as epistaxis or bleeding from the gums, or fatal. The risk of bleeding is higher in older patients, in patients with more intense anticoagulation, and in patients with drug interactions. Intracranial hemorrhage is the most common type of fatal hemorrhage, usually manifest as subdural hematoma. Intracerebral bleeding accounts for only a small fraction of cranial hemorrhage. The gastrointestinal tract is the next most frequent site of bleeding. Although rare, massive intraocular hemorrhage has been reported in patients with pre-existing disciform macular degeneration. All patients should have prothrombin time (PT) evaluations made before and 24 hours after initiation of therapy. Subsequent evaluations should be made every 24-48 hours for the first week of therapy and then once or twice every week for the next few weeks. Long-term therapy requires PT evaluation every month, depending on individual patients.
Skin necrosis is a relatively uncommon adverse reaction to warfarin therapy. When it occurs, however, it can be extremely severe and disfiguring. It occurs more frequently in women than in men and especially in patients with preexisting protein C and S deficiency. These patients initially become hypercoaguable because warfarin depresses anticoagulant proteins C and S more quickly than coagulant proteins II,VII, IX, and X. Subcutaneous fat is most commonly affected. Women will note an intense, painful burning in places such as the thigh, buttocks, waist, and/or breast several days after beginning warfarin. This will be followed by skin necrosis and permanent scarring. Immediate withdrawal of warfarin is indicated, and vitamin K therapy should be given. Heparin can be safely substituted in place of warfarin.
Warfarin is a known teratogen and is classified as category X. It can cause a variety of fetal anomalies including cleft palate, digestive tract abnormalities, chondrodysplasia punctata, and even fetal abortion. Warfarin should not be given during pregnancy (see Contraindications).
Warfarin can produce a purple-toe syndrome. This condition does not involve necrosis and is reversible.
Other adverse reactions that occur infrequently with warfarin include: agranulocytosis, leukopenia, anorexia, diarrhea, nausea/vomiting, exfoliative dermatitis, alopecia urticaria, and pruritus.
PATIENT INFORMATION:
What do warfarin tablets do?
Warfarin (CoumadinTM ) is an anticoagulant, sometimes called a blood thinner. However, it does not thin the blood or dissolve clots that have already formed. Instead it prevents clot formation and existing clots getting bigger, while letting the body's natural processes dissolve the clots. Warfarin helps to treat or prevent clots in the veins, arteries, lungs, or the heart. Generic warfarin tablets are available.
What should my doctor know before I take warfarin?
They need to know if you have any of these conditions:
How should I take this medicine?
Take warfarin tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take your doses at regular intervals. Do not take more often than directed.
What if I miss a dose?
Try not to miss doses. If you do miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not double doses, and do not take two doses in one day unless your doctor tells you to; this can cause excessive bleeding.
What other medicines can interact with warfarin?
Warfarin interacts with many other medicines; some are listed below:
Tell your doctor or pharmacist: about all other medicines you are taking including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These can affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects might I notice from taking warfarin?
Serious side effects with warfarin include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with warfarin include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take warfarin?
Visit your doctor for regular checks on your progress. While you are taking warfarin carry an identification card with your name, name and dose of medicine(s) being used, and name and phone number of your doctor or person to contact in an emergency. After you stop taking warfarin it will be some time before your body recovers its normal blood clotting ability. Ask your doctor how long you need to need to be cautious.
Do not change brands of warfarin without talking to your doctor. Different products can act differently in your body.
Alcohol can affect the way warfarin works. Limit your intake of alcohol to an occasional drink.
Be careful to avoid injury while you are using warfarin. Take special care brushing or flossing your teeth. Report any injuries, bruising, or red spots on the skin to your doctor.
If you are going to have surgery, tell your doctor or dentist that you are taking warfarin.
Do not take aspirin or aspirin-like products while taking warfarin.
Where should I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Protect from light. Throw away any unused medicine after the expiration date.
Parkinsn's Archive Treasures Page
John Cottingham is the webmaster of this site.
