Warfarin

• Warfarin is used in treating patients with deep vein thrombosis (DVT) to prevent extension of the clot, and to reduce the risk of pulmonary embolism.
• Patients with pulmonary embolism are treated with warfarin to prevent further emboli.
• Warfarin also is used in patients with atrial fibrillation or artificial heart valves to reduce the risk of strokes, and after a heart attack.
• It also is helpful in preventing blood clots from forming in certain orthopedic surgeries such as knee or hip replacements.
• Warfarin is used in preventing closure of coronary artery stents due to clotting.

Warfarin is the generic form of the brand-name drugs Coumadin and Jantoven, prescribed to treat blood clots.

Blood clots can occur if you have conditions like deep vein thrombosis (DVT) or pulmonary embolus (PE).

Other conditions that might increase your risk of developing blood clots are an irregular heart rhythm known as atrial fibrillation, a recent heart attack, heart valve replacement, or surgeries like a hip or knee replacement.

Warfarin is also used to prevent new blood clots from forming, helping to reduce your risk of stroke or heart attack.

The anticoagulant is designed to keep blood flowing smoothly in your body by decreasing the amount of clotting proteins present in your blood.

First approved by the Food and Drug Administration (FDA) in 1954, warfarin is available in different strength tablets and injections.

According to the FDA, about two million people in the United States take warfarin to prevent blood clots, heart attack, and/or strokes.

Warfarin Warnings

The FDA has issued a black-box warning for warfarin because the drug can lead to severe bleeding that could be fatal.

The risk of bleeding is more likely when you first begin taking the drug or if you are using a higher dose.

One additional concern with warfarin is that it can be difficult for your doctor to determine the correct dosage, because the right dose will vary depending on your age, diet, and use of other drugs.

In 2007, the FDA updated the labeling of warfarin to explain that a person's genetic makeup might influence how he/she responds to the drug.

Anyone who has a bleeding disorder should not use warfarin.

In addition, you should not use warfarin if you have blood in your urine or stools, bleeding in your brain or stomach, or an infection in the lining of your heart.

You should avoid using warfarin if you need a spinal tap or epidural, if you had a recent surgery, or are anticipating surgery.

During the time you are taking this drug, you'll need to keep track of the time it takes your blood to clot by undergoing occasional blood tests.

If you are planning to have any surgery, including a dental procedure, make sure your doctor/dentist is aware that you are using warfarin as well as all the other drugs and products you are taking.

You should also avoid getting injections in your muscles as much as possible. If you must get one, use your arm so that any potential bleeding will be easy to detect.

In the event you develop an illness that results in vomiting, diarrhea or fever and it lasts longer than two days, let your doctor know right away since this could impact how the drug works.

Pregnancy and Warfarin

Warfarin has been linked to miscarriage, birth defects, and other abnormalities, and the risks of taking warfarin during pregnancy clearly outweigh the benefits.

Don't take this medication if you are pregnant unless your doctor has advised you to do so.

There are no studies showing warfarin is present in the breast milk of women using the drug, though the manufacturer has recommended that caution be used when women who are breastfeeding used warfarin.

Using warfarin in children requires close monitoring.

Warfarin is a prescription medication used to lower the chances of blood clots forming in your body due to various causes. Warfarin belongs to a group of drugs called anticoagulants or "blood thinners". It helps prevent blood clots from forming by decreasing the formation of substances in the blood known as clotting factors. Careful monitoring of side effects is required using regular blood tests.

This medication comes in tablet form. It is also available in an injectable form to be infused into a vein by a healthcare provider at a hospital or other medical facility. Warfarin is usually taken once daily, with or without food. The dosage will vary depending on the results of your PT/INR test (blood test).

Common side effects of warfarin are nausea, vomiting, and an altered sense of taste. Seek medical attention if you experience bruising or bleeding.

Warfarin may be found in some form under the following brand names:

• Coumadin

• Jantoven

Tell your doctor if you are pregnant or planning to become pregnant. Warfarin should not be taken during pregnancy. Warfarin can cause death or birth defects to an unborn baby.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Warfarin falls into 2 categories: D for women with mechanical heart valves, and X for all other pregnant women. It has been shown that use of warfarin in pregnant women caused some babies to be born with problems. However, because women with mechanical heart valves are at a high risk of thromboembolism (blood clot in blood vessel), the benefits of taking warfarin may outweigh the risks.

Talk to your doctor about the risks of taking warfarin during pregnancy.

Studies have shown that warfarin is not excreted in human milk. Caution should be exercised if you are breastfeeding and also taking warfarin.

Warfarin is used to prevent or treat blood clots, including deep venous thrombosis or pulmonary embolism. It is also used for blood clots that may be caused by certain heart conditions, open-heart surgery, or after a heart attack. Warfarin is an anticoagulant (blood thinner) that decreases the clotting ability of the blood.

warfarin is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bleeding gums
• blood in the urine
• bloody stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• confusion
• coughing up blood
• difficulty with breathing or swallowing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• excessive bruising
• headache
• increased menstrual flow or vaginal bleeding
• nosebleeds
• paralysis
• peeling of the skin
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• stomach pain with cramping
• sweating
• unexplained swelling
• unusual tiredness or weakness

• Arm, back, or jaw pain
• blue-green to black skin discoloration
• blue or purple toes
• change in consciousness
• chest tightness or heaviness
• chills
• clay-colored stools
• diarrhea
• dizziness
• fainting or loss of consciousness
• fast or irregular breathing
• fast or irregular heartbeat
• fever
• itching or skin rash
• light-colored stools
• loss of appetite
• nausea and vomiting
• pain in the toes
• pain, redness, or sloughing of the skin
• pale skin
• purplish red, net-like, blotchy spots on the skin
• skin blisters
• small red or purple spots on the skin
• stomach pain
• swelling of the eyes or eyelids
• troubled breathing with exertion
• unpleasant breath odor
• unusual bleeding or bruising
• upper right stomach pain
• vomiting of blood
• yellow eyes and skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Joint pain
• muscle pain

• Bloated
• change in taste, or bad, unusual, or unpleasant (after) taste
• cold intolerance
• excess air or gas in the stomach or intestines
• full feeling
• general feeling of discomfort or illness
• hair loss or thinning of the hair
• hives or welts
• lack or loss of strength
• pain
• passing gas
• red, sore, or itching skin
• sores, welting, or blisters
• unusual drowsiness, dullness, or feeling of sluggishness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Pregnancy

Risk Summary

Warfarin sodium tablets, USP are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of Warfarin sodium may outweigh the risks [see Warnings and Precautions (5.7)]. Warfarin sodium can cause fetal harm. Exposure to Warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of Warfarin sodium and possible risks to the fetus when prescribing Warfarin sodium to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

In humans, Warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to Warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following Warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4)].

Lactation

Risk Summary

Warfarin was not present in human milk from mothers treated with Warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Warfarin sodium and any potential adverse effects on the breastfed infant from Warfarin sodium or from the underlying maternal condition before prescribing Warfarin sodium to a lactating woman.

Clinical Considerations

Monitor breastfeeding infants for bruising or bleeding.

Data

Human Data

Based on published data in 15 nursing mothers, Warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated.

Females and Males of Reproductive Potential

Pregnancy Testing

Warfarin sodium can cause fetal harm [see Use in Specific Populations (8.1)].

Verify the pregnancy status of females of reproductive potential prior to initiating Warfarin sodium therapy.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose of Warfarin sodium.

Pediatric Use

Adequate and well-controlled studies with Warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of Warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered Warfarin sodium should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of Warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing Warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to Warfarin therapy, while human milk-fed infants may be sensitive to Warfarin therapy.

Geriatric Use

Of the total number of patients receiving Warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of Warfarin [see Clinical Pharmacology (12.3)]. Warfarin sodium is contraindicated in any unsupervised patient with senility. Observe caution with administration of Warfarin sodium to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of Warfarin sodium in elderly patients [see Dosage and Administration (2.2, 2.3)].

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 impairment. Instruct patients with renal impairment taking Warfarin to monitor their INR more frequently [see Warnings and Precautions (5.4)].

Hepatic Impairment

Hepatic impairment can potentiate the response to Warfarin through impaired synthesis of clotting factors and decreased metabolism of Warfarin. Use caution when using Warfarin sodium in these patients.

Signs and Symptoms

Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.

Treatment

The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of Warfarin sodium anticoagulation may be obtained by discontinuing Warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K1.

The use of vitamin K1 reduces response to subsequent Warfarin sodium therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of Warfarin sodium administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of Warfarin sodium is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to Warfarin sodium overdosage.

Atrial Fibrillation

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 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was 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 4).

Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with Warfarin sodium [see Dosage and Administration (2.2)].

Mechanical and Bioprosthetic Heart Valves

In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with Warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.

In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus 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 per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.

In a randomized trial in 210 patients comparing two intensities of Warfarin therapy (INR 2.0 to 2.25 vs. INR 2.5 to 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 hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

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. The primary endpoint was a composite 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 Table 7.

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with Warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or Warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in Table 8.

There were approximately four times as many major bleeding episodes in the two groups receiving Warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus Warfarin than among those receiving Warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

Warfarin Sodium Tablets, USP are single-scored, flat, beveled, capsule-shaped tablets, engraved numerically with 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 on one side and engraved with "Warfarin" on top of "TARO" on the other side. They are packaged with potencies and colors as follows:

Protect from light and moisture. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

Store the unit-dose blister packages in the carton until contents have been used.

Special Handling

Procedures for proper handling and disposal of potentially hazardous drugs should be considered. Guidelines on this subject have been published [see References (15)].

Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Specific Populations (8.1)].

NDC 51672-4032-1
100 Tablets

Warfarin Sodium
Tablets, USP Crystalline

5 mg

Dispense with
Medication Guide

PROTECT FROM LIGHT.
HIGHLY POTENT ANTICOAGULANT.

WARNING: Serious bleeding results from overdosage.
Do not use or dispense before reading directions and
warnings in accompanying product information.

Rx only

• Coumadin
• Jantoven

There are no dosage adjustments provided in the manufacturer's labeling. However, the response to oral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis, and cirrhosis. INR should be closely monitored.

Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Monitor therapy

Adalimumab: May decrease the serum concentration of Warfarin. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Alcohol (Ethyl): May decrease the serum concentration of Vitamin K Antagonists. More specifically, this effect has been described in heavy drinking alcoholic patients (over 250 g alcohol daily for over 3 months). The role of alcohol itself is unclear. Monitor therapy

Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Amiodarone: May enhance the anticoagulant effect of Vitamin K Antagonists. Amiodarone may increase the serum concentration of Vitamin K Antagonists. Management: Monitor patients extra closely for evidence of increased anticoagulant effects if amiodarone is started. Consider empiric reduction of 30% to 50% in warfarin dose, though no specific guidelines on dose adjustment have been published. Consider therapy modification

Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Anticoagulants: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Antihepaciviral NS5B RNA Polymerase Inhibitors: May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Aprepitant: May decrease the serum concentration of Warfarin. Monitor therapy

Atazanavir: May increase the serum concentration of Warfarin. Monitor therapy

AzaTHIOprine: May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. An anticoagulant dose increase may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction. Consider therapy modification

Benzbromarone: May increase the serum concentration of Warfarin. Monitor therapy

Bicalutamide: May increase the serum concentration of Vitamin K Antagonists. Specifically, free concentrations of the vitamin K antagonists may be increased. Monitor therapy

Bifonazole: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Vitamin K Antagonists. Monitor therapy

Boceprevir: May decrease the serum concentration of Warfarin. Boceprevir may increase the serum concentration of Warfarin. Monitor therapy

Bosentan: May increase the metabolism of Vitamin K Antagonists. Monitor therapy

Capecitabine: May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased INR and effects of vitamin K antagonists if carbamazepine is initiated/dose increased, or increased INR and effects if carbamazepine is discontinued/dose decreased. Warfarin dose adjustments will likely be required. Consider therapy modification

Cephalosporins: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chenodiol: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Chloral Betaine: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Chloral Hydrate: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Chloramphenicol: May enhance the anticoagulant effect of Vitamin K Antagonists. Chloramphenicol may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Chondroitin Sulfate: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Clopidogrel: May enhance the anticoagulant effect of Warfarin. Consider therapy modification

Cloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Cloxacillin may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Cobicistat: May increase the serum concentration of Warfarin. Monitor therapy

Coenzyme Q-10: May diminish the anticoagulant effect of Vitamin K Antagonists. Coenzyme Q-10 may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Contraceptives (Estrogens): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Consider therapy modification

Contraceptives (Progestins): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Consider therapy modification

Corticosteroids (Systemic): May enhance the anticoagulant effect of Warfarin. Monitor therapy

Cranberry: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May decrease the serum concentration of Warfarin. Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Desvenlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Dexmethylphenidate: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Dicloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Disulfiram: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Dronabinol: May increase the serum concentration of Warfarin. Specifically, dronabinol may displace warfarin from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

Dronedarone: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Econazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Efavirenz: May decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Enzalutamide: May decrease the serum concentration of Warfarin. More specifically, enzalutamide may decrease concentrations of the S-warfarin enantiomer. Management: Avoid concurrent use of warfarin and enzalutamide whenever possible. If the combination must be used, conduct additional INR monitoring as serum concentrations may be decreased. Consider therapy modification

Erlotinib: May increase the serum concentration of Warfarin. Monitor therapy

Erythromycin (Ophthalmic): May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Eslicarbazepine: May decrease the serum concentration of Warfarin. Specifically, S-warfarin serum concentrations may be decreased. Monitor therapy

Esomeprazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Ethacrynic Acid: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Ethotoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Ethotoin. Management: Anticoagulant dose adjustment will likely be necessary when ethotoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Consider therapy modification

Etoposide: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Etoposide Phosphate: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Exenatide: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Fat Emulsion (Fish Oil and Plant Based): May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Fenofibrate and Derivatives: May enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin. Consider therapy modification

Fenugreek: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Seek alternatives to fenugreek in patients receiving vitamin K antagonists. Monitor patients receiving these combinations closely for increases in INR and systemic effects of the vitamin K antagonist (particularly easy bruising and bleeding). Consider therapy modification

Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Flucloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Flucloxacillin may decrease the serum concentration of Vitamin K Antagonists. Monitor therapy

Fluconazole: May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

Fluorouracil (Systemic): May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

Fluorouracil (Topical): May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Fosamprenavir: May increase the serum concentration of Warfarin. Monitor therapy

Fosaprepitant: May decrease the serum concentration of Warfarin. The active metabolite aprepitant is likely responsible for this effect. Monitor therapy

Fosphenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Vitamin K antagonist dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely for evidence of bleeding and to determine appropriate dose. Consider therapy modification

Gefitinib: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Gemcitabine: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Ginkgo Biloba: May enhance the adverse/toxic effect of Vitamin K Antagonists. Management: Consider avoiding the use of this combination of agents. Monitor for signs and symptoms of bleeding if vitamin K antagonists and Ginkgo biloba are used concomitantly. Consider therapy modification

Ginseng (American): May decrease the serum concentration of Warfarin. Monitor therapy

Glucagon: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Glucosamine: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Glutethimide: May increase the metabolism of Vitamin K Antagonists. Consider therapy modification

Green Tea: May enhance the adverse/toxic effect of Warfarin. Particularly, the risk of bleeding may be increased due to possible antiplatelet effects of green tea. Green Tea may diminish the anticoagulant effect of Warfarin. Monitor therapy

Griseofulvin: May decrease the serum concentration of Vitamin K Antagonists. Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

HMG-CoA Reductase Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: AtorvaSTATin. Monitor therapy

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Ifosfamide: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Imatinib: May enhance the anticoagulant effect of Warfarin. Imatinib may decrease the metabolism of Warfarin. Consider therapy modification

Itraconazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Ivermectin (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Lansoprazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Leflunomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

LevOCARNitine: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Levomilnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Lomitapide: May increase the serum concentration of Warfarin. Monitor therapy

Lopinavir: May decrease the serum concentration of Warfarin. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists. Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. Monitor therapy

Menadiol Diphosphate: May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Mercaptopurine: May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Methylphenidate: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Metreleptin: May decrease the serum concentration of Warfarin. Metreleptin may increase the serum concentration of Warfarin. Monitor therapy

MetroNIDAZOLE (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding. Consider therapy modification

Miconazole (Oral): May increase the serum concentration of Warfarin. Monitor therapy

Miconazole (Topical): May increase the serum concentration of Vitamin K Antagonists. Consider therapy modification

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

Milnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Mirtazapine: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the anticoagulant effect of Vitamin K Antagonists. Multivitamins/Minerals (with ADEK, Folate, Iron) may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Nafcillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Management: Consider choosing an alternative antibiotic. Monitor for decreased therapeutic effects and need for dose adjustments of oral anticoagulants if nafcillin is initiated/dose increased, or increased effects if nafcillin is discontinued/dose decreased. Consider therapy modification

Nelfinavir: May decrease the serum concentration of Warfarin. Nelfinavir may increase the serum concentration of Warfarin. Monitor therapy

Neomycin: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Nevirapine: May diminish the anticoagulant effect of Warfarin. Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

NSAID (COX-2 Inhibitor): May enhance the anticoagulant effect of Vitamin K Antagonists. NSAID (COX-2 Inhibitor) may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

NSAID (Nonselective): May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Obeticholic Acid: May diminish the anticoagulant effect of Warfarin. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Omeprazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Oritavancin: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Orlistat: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Oxatomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Avoid combination

Penicillins: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Dicloxacillin; Nafcillin. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Consider therapy modification

Phytonadione: May diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Posaconazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Proguanil: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Propacetamol: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with higher doses (equivalent to acetaminophen doses exceeding 1.3 to 2 g/day) for multiple consecutive days. Monitor therapy

Propafenone: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. Note that the INR/PT might be unchanged in the face of increased bleeding. Monitor therapy

QuiNINE: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Quinolone Antibiotics: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

RaNITIdine: May increase the serum concentration of Warfarin. Monitor therapy

Regorafenib: Warfarin may enhance the adverse/toxic effect of Regorafenib. Specifically, the risk for bleeding may be increased. Monitor therapy

Ribavirin (Systemic): May diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Vitamin K Antagonists. Monitor therapy

Ritonavir: May decrease the serum concentration of Warfarin. Monitor therapy

RomiDEPsin: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Roxithromycin: May enhance the anticholinergic effect of Warfarin. Monitor therapy

Salicylates: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Salsalate. Consider therapy modification

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Salicylates (Topical): May enhance the anticoagulant effect of Warfarin. Monitor therapy

Saquinavir: May increase the serum concentration of Warfarin. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

SORAfenib: May enhance the anticoagulant effect of Warfarin. SORAfenib may increase the serum concentration of Warfarin. Management: Warfarin dose adjustment will likely be necessary. Increase frequency of INR monitoring during sorafenib therapy (particularly when starting or stopping therapy), and increase monitoring for signs and symptoms of bleeding. Consider therapy modification

St John's Wort: May increase the metabolism of Vitamin K Antagonists. Consider therapy modification

Streptokinase: May enhance the anticoagulant effect of Vitamin K Antagonists. Avoid combination

Sucralfate: May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate may decrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfate may decrease the absorption of Vitamin K Antagonists. Management: Administer vitamin K antagonists at least 2 hours before or at least 6 hours after sucralfate. Consider therapy modification

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sulfinpyrazone: May decrease the metabolism of Vitamin K Antagonists. Sulfinpyrazone may decrease the protein binding of Vitamin K Antagonists. Consider therapy modification

Sulfonamide Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Sulfonylureas: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Avoid combination

Tegafur: May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and signs/symptoms of bleeding closely when starting or stopping this combination. Anticoagulant dose adjustment will likely be necessary. Consider therapy modification

Telaprevir: May decrease the serum concentration of Warfarin. Telaprevir may increase the serum concentration of Warfarin. Monitor therapy

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy

Teriflunomide: May decrease the serum concentration of Warfarin. Monitor therapy

Tetracycline Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Thyroid Products: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tigecycline: May increase the serum concentration of Warfarin. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tolterodine: May enhance the anticoagulant effect of Warfarin. Monitor therapy

Toremifene: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Torsemide: May increase the serum concentration of Warfarin. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

TraMADol: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Tranilast (Systemic): May enhance the adverse/toxic effect of Warfarin. Tranilast (Systemic) may diminish the therapeutic effect of Warfarin. Monitor therapy

TraZODone: May diminish the anticoagulant effect of Warfarin. Monitor therapy

Tricyclic Antidepressants: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vemurafenib: May increase the serum concentration of Warfarin. Monitor therapy

Venetoclax: May increase the serum concentration of Warfarin. Monitor therapy

Venlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Monitor therapy

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Voriconazole: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Vorinostat: May enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Zafirlukast: May increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Zileuton: May increase the serum concentration of Warfarin. Monitor therapy

Get emergency medical help if you have signs of an allergic reaction to warfarin: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Warfarin increases your risk of bleeding, which can be severe or life-threatening. Call your doctor at once if you have any signs of bleeding such as:

• sudden headache, feeling very weak or dizzy;

• swelling, pain, unusual bruising;

• bleeding gums, nosebleeds;

• bleeding from wounds or needle injections that will not stop;

• heavy menstrual periods or abnormal vaginal bleeding;

• blood in your urine, bloody or tarry stools; or

• coughing up blood or vomit that looks like coffee grounds.

Clots formed by warfarin may block normal blood flow, which could lead to tissue death or amputation of the affected body part. Get medical help at once if you have:

• pain, swelling, hot or cold feeling, skin changes, or discoloration anywhere on your body; or

• sudden and severe leg or foot pain, foot ulcer, purple toes or fingers.

Bleeding is the most common side effect of warfarin.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Use with caution

No adjustment recommended

• Warfarin may be used to increase the time it takes for the blood to clot, often described as "thinning the blood".
• Warfarin works by blocking the formation of vitamin K-dependent clotting factors, inhibiting a vitamin K dependent enzyme complex, as well as two anticoagulant proteins.
• Warfarin belongs to the class of drugs known as coumarins. Warfarin is also an anticoagulant.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.