Vitamin K Side Effects, Toxicity & Warfarin Interaction

Oral anticoagulants

Vitamin K Side Effects, Toxicity & Warfarin Interaction

Anticoagulants are used for treating and preventing embolic events. The most common oral anticoagulatory agents are vitamin K antagonists such as warfarin and phenprocoumon. Non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran and rivaroxaban have also gained popularity in recent years.

Vitamin K antagonists inhibit the enzyme vitamin K epoxide reductase, thereby blocking hepatic synthesis of the active, reduced form of vitamin K (needed for carboxylation of coagulation factors II, VII, IX, and X, protein C, protein S).

This effect can last for several days, which complicates exact dosing and makes regular monitoring necessary. Vitamin K antagonists are also metabolized by C-P450 (CYP) enzymes and therefore interact with a broad range of foods and drugs.

NOACs act selectively via inhibition of thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban). Because of their comparatively short half-life and fewer interactions, NOACs are easier to control and administer than warfarin and do not require regular monitoring to ensure their efficacy and safety.

For all substances, it is important to consider the dose-dependent risk of bleeding, especially when combining different substances that affect hemostasis (e.g., aspirin, clopidogrel, ticagrelor).

Substances Mechanism of actionAdvantages Disadvantages Vitamin K antagonists (coumarins) PhenprocoumonWarfarinDirect oral anticoagulantsDirect oral thrombin inhibitors DabigatranDirect oral factor Xa inhibitors ApixabanRivaroxabanEdoxabanGeneral notes regarding oral anticoagulationIndications for all oral anticoagulants Expected laboratory changes
  • Well-known effects and side effects
  • Low costs
  • In cases of life-threatening bleeding: direct reversal by replacement (e.g., prothrombin complex concentrate, FFP) or indirect/delayed reversal by increasing production of coagulation factors (e.g., vitamin K)
  • Selective thrombin antagonist
  • Costly
  • Limited clinical experience with these drugs
  • Not recommended, and partially contraindicated, in patients with artificial cardiac valves
  • Not suited for patients with valvular atrial fibrillation
  • Selective and direct inhibition of factor Xa

The most important side effect of all oral anticoagulants is a dose-dependent increase in bleeding risk!

You can memorize the most important oral anticoagulants with DRAW: Dabigatran, Rivaroxaban, Apixaban, and Warfarin.

Individuals with protein C deficiency are at a higher risk of developing warfarin necrosis!

Direct factor Xa inhibitors and direct thrombin inhibitors

We list the most important adverse effects. The selection is not exhaustive.

We list the most important contraindications. The selection is not exhaustive.

Warfarin is metabolized by cytochrome P450 (CYP) enzymes.warfarin

  • Increase of anticoagulant effect

P450 inducers: ↓ warfarin levels (Chronic Alcoholics Steal Phen-Phen and Never Refuse Greasy Carbs): C – Chronic alcohol use, S – St. John's wort, P – Phenytoin, P – Phenobarbital, N – Nevirapine, R – Rifampin, G – Griseofulvin, C – Carbamazepine

P450 inhibitors can be remembered with “ group”: S – Sulfonamides, I – Isoniazid, C – Cimetidine, K – Ketoconazole, F – Fluconazole , A – Alcohol (binge drinking), C – Ciprofloxacin, E – Erythromycin, S – Sodium valproate, C – Chloramphenicol, O – Omeprazole, M – Metronidazole, G – Grapefruit juice

  • 1. Olson KR, Tarabar A. Warfarin and Superwarfarin Toxicity. In: Warfarin and Superwarfarin Toxicity. New York, NY: WebMD. Updated December 12, 2016. Accessed February 21, 2017.
  • 2. Tran HA, Chunilal SD, Harper PL, et al. An update of consensus guidelines for warfarin reversal. Med J Aust. 2013; 198(4): pp. 198–199. doi: 10.5694/mja12.10614.
  • 3. Department of Surgical Education, Orlando Regional Medical Center. Warfarin reversal Guideline. url: Accessed February 21, 2017.
  • 4. Green D. Antidote to Dabigatran Is Approved. Updated February 21, 2017. Accessed February 21, 2017.
  • 5. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013; 369(13): pp. 1206–1214. doi: 10.1056/NEJMoa1300615.
  • 6. Saltzman JR. Approach to acute upper gastrointestinal bleeding in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated November 12, 2015. Accessed February 21, 2017.
  • 7. Nickson C. Warfarin Reversal. Updated February 21, 2017. Accessed February 21, 2017.
  • 8. Vyas R, Oakley A. Warfarin-induced skin necrosis. Updated February 1, 2016. Accessed February 21, 2017.
  • 9. Garcia DA, Crowther M. Management of bleeding in patients receiving direct oral anticoagulants. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated December 19, 2016. Accessed February 21, 2017.
  • 10. Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016; 41(1): pp. 206–232. doi: 10.1007/s11239-015-1310-7.
  • 11. Kakagia DD, Papanas N, Karadimas E, Polychronidis A. Warfarin-induced skin necrosis. Ann Dermatol. 2014; 26(1): p. 96. doi: 10.5021/ad.2014.26.1.96.
  • 12. Ouellette DR. Pulmonary Embolism. In: Pulmonary Embolism. New York, NY: WebMD. Updated June 22, 2016. Accessed February 14, 2017.
  • 13. Christensen B. International Normalized Ratio (INR) Targets: Valvular Disease . In: International Normalized Ratio (INR) Targets: Valvular Disease . New York, NY: WebMD. Updated December 10, 2014. Accessed February 21, 2017.
  • 14. Aurigemma GP, Konkle BA, Gaasch WH. Antithrombotic therapy for prosthetic heart valves: Indications. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated May 23, 2016. Accessed February 21, 2017.
  • 15. Falck-ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(Suppl 2): pp. e278S–325S. doi: 10.1378/chest.11-2404.
  • 16. Pai M, Douketis JD. Prevention of venous thromboembolic disease in surgical patients. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated January 18, 2017. Accessed February 21, 2017.
  • 17. Medscape. warfarin (Rx). In: warfarin (Rx). New York, NY: WebMD. Updated February 21, 2017. Accessed February 21, 2017.
  • 18. Weitz JI. Expanding use of new oral anticoagulants. F1000Prime Rep. 2014; 6: p. 93. doi: 10.12703/P6-93.
  • 19. Ginsberg JS, Crowther MA. Direct oral anticoagulants (DOACs) and pregnancy: A plea for better information. Thromb Haemost. 2016; 116(4): pp. 590–591. doi: 10.1160/TH16-08-0602.
  • 20. Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014.
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  • 23. Investigators TBS. Bridging anticoagulation: is it needed when warfarin is interrupted around the time of a surgery or procedure?. Circulation. 2012; 125(12): pp. e496–e498. doi: 10.1161/CIRCULATIONAHA.111.084517.

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Warfarin – Uses, Dosages, Side Effects & Black Box Warnings

Vitamin K Side Effects, Toxicity & Warfarin Interaction

On This Page Warfarin Facts

  1. Used to TreatPatients at risk of blood clots and stroke, including those diagnosed with atrial fibrillation (AF or AFib)
  2. Related DrugsJantoven, heparin, Pradaxa, Xarelto
  3. ManufacturerBristol-Myers-Squibb
  4. Black Box WarningsBleeding risk
  5. FDA Approval1954

Home Warfarin

Warfarin (brand name Coumadin) is one of the original anticoagulant medications, also referred to as blood thinners. It is used to prevent and treat blood clots and to prevent strokes from atrial fibrillation. Warfarin requires regular blood testing and frequent dosage adjustments. It is also linked to increased bleeding risks, which can sometimes be fatal.

Warfarin (Coumadin) is an anticoagulant (blood thinner) that has been on the U.S. market for over six decades since its initial approval by the U.S. Food and Drug Administration in 1954.

This drug has a black box warning for serious bleeding. Patients taking warfarin must get frequent lab work measuring the International Normalized Ratio (INR), a blood-clotting measurement.

Fact An estimated 2.6 million individuals suffer from arterial fibrillation in the U.S. That’s predicted to jump to 12 million by 2050. Warfarin is used to prevent strokes from AF.

The test helps determine dosage. Changes to diet, starting or stopping other drugs, and certain lifestyle choices, such as alcohol intake or cigarette smoking, can alter a patient’s INR.

Warfarin prevents and treats clots from forming in the blood. The drug prevents problems due to certain types of irregular heartbeats. It is also used in patients who have suffered a heart attack or have prosthetic heart valves.

Warfarin is used to prevent and treat venous thrombosis (a blood clot in a vein), as well as a related condition, pulmonary embolism. A pulmonary embolism happens when part of a blood clot breaks away and becomes lodged in an artery supplying blood to the lungs.

Warfarin is also used to prevent and treat strokes associated with atrial fibrillation (AF or AFib). AF is the most common heart-rhythm abnormality, according to the FDA.

The condition is characterized by an irregular and often rapid heart rate that can increase a patient’s risk of suffering from stroke among other serious and sometimes deadly conditions, such as heart failure and other heart-related complications.

Warfarin may also be prescribed to reduce the risk of death from heart attacks and thromboembolic events, such as stroke or systemic embolization (a blocked artery often caused by a blood clot) after a heart attack.

Warfarin contains a black box warning for major and life-threatening bleeding risks. Since the drug is designed to prevent blood from clotting, it can also take longer than usual for patients to stop bleeding if they are cut or injured.

Bleeding linked to warfarin use can also result in increased menstrual flow or vaginal bleeding in women, nosebleeds and bleeding of the gums from teeth brushing.

The drug label advises patients to report any unusual bleeding, bruising or other signs and symptoms of internal bleeding, such as headache, dizziness or weakness to their health care provider.

Additionally, health care providers should perform regular monitoring of INR levels for patients treated with warfarin.  If the INR level is too high, there is an increased risk of bleeding.

Aside from bleeding, warfarin use is associated with several other side effects. These side effects can range from mild adverse reactions, such as nausea or abdominal pain, to rare but serious complications, such as calciphylaxis (calcium build-up in small blood vessels of the fat and skin tissues) and tissue necrosis (death of body tissue).

Serious side effects of Warfarin

  • Hemorrhage (severe bleeding)
  • Tissue necrosis or gangrene (death of skin or body tissues)
  • Calciphylaxis (calcification of blood vessels) – this condition can lead to blood clots and skin necrosis
  • Acute kidney injury
  • Cholesterol embolism (blockage of an artery, typically by a clot) – this condition occurs when cholesterol is released, usually from plaque build-up in the arteries, and travels through the bloodstream becoming lodged in blood vessels in various parts of the body
  • Decreased blood flow to limbs, tissue death and gangrene in patients with heparin-induced thrombocytopenia (low blood platelet count) (HIT) and HITTS (heparin-induced thrombotic thrombocytopenia syndrome)

The most common side effects reported in patients taking Coumadin include:

  • Hypersensitivity or allergic reaction – can result in hives as well as anaphylaxis. Anaphylaxis requires immediate emergency medical attention
  • Inflammation of the skin (dermatitis), including bullous eruptions (fluid-filled blisters)
  • Elevated liver enzymes
  • Nausea and/or vomiting
  • Diarrhea
  • Changes in the sense of taste
  • Abdominal pain
  • Hepatitis (inflammation of the liver) – cholestatic hepatitis has also been found to occur in patients taking both warfarin and ticlopidine (a drug that also helps to prevent blood clots) together
  • Vasculitis (inflammation and damage to blood vessels, primarily in the skin)
  • Gas and/or bloating
  • Rash
  • Itchy skin
  • Hair loss
  • Feeling cold or chills

The drug works by slowing down the blood-clotting process. Clots form through a process involving various substances, including vitamin K. The drug decreases the amount of vitamin K in the body. The decrease in vitamin K prolongs the time it takes to form clots, which can decrease new clots from forming.

The drug does not dissolve or break down blood clots. However, by slowing down the time for blood to clot, warfarin can help treat an existing clot by stopping the clot from spreading. It also gives the body time to break down the clot on its own.

Vitamin K rich foods kale, above, can impact INR/PT measurements as well as the effectiveness of warfarin

The Prothrombin Time (PT) is a laboratory test showing the time it takes blood to clot.  The PT is reported as a value known as the International Normalized Ratio (INR).

When patients are prescribed warfarin, they are required to undergo regular testing to make sure the INR measurement stays within the desired testing range. Testing occurs at least once a month but may be more frequent.

If the INR is too high, bleeding may occur. If the INR is too low, blood clots may form. Warfarin dosing is INR values.

Vitamin K intake can affect the INR/PT measurement as well as the effectiveness of the drug.

The American Heart Association states that patients should keep vitamin K intake “as consistent as possible.

” Sudden increases of vitamin K foods may decrease the INR and warfarin’s effect, which could cause blood clots. While lowering vitamin K intake can increase INR and the effect of the medication.

One way to keep vitamin K intake consistent is to not make too many dietary changes, or modifications in food choices, and to carefully consider any dietary supplements or herbal products.

Since dosing is dependent on each patient’s INR measurements, patients should not entirely stop eating vitamin K-rich foods that they normally eat, nor should they suddenly add foods or supplements rich in vitamin K to their normal daily diets.

Changes in diet should be reported to a healthcare provider.

Foods rich in vitamin K include:

  • Kale
  • Spinach
  • Collards
  • Swiss chard
  • Mustard greens
  • Turnip greens
  • Parsley
  • Broccoli
  • Brussels sprouts
  • Cabbage
  • Green leaf lettuce
  • Romaine lettuce
  • Prunes
  • Asparagus
  • Avocado
  • Endive
  • Tuna
  • Blueberries
  • Blackberries
  • Peas

Warfarin comes in a tablet form to be taken by mouth. The tablets are available in several different strengths. Health care providers will ly start patients on a lower dose and gradually increase or decrease the dose results of INR blood tests. Drug labeling for warfarin advises patients not to stop taking the medication without first talking to their doctor.

1 milligramPink2 milligramsLavender2.5 milligramsGreen 3 milligramsTan4 milligramsBlue5 milligramsPeach 6 milligramsTeal7.5 milligramsYellow10 milligramsWhite

The dosage and administration of warfarin is individualized for each patient according to their blood tests and conditions.

Lower initial doses are recommended for patients who are elderly, weakened or of Asian descent. Duration of treatment will also vary from one patient to the next with therapy generally being continued until the risk of blood clotting has passed.

Certain dental or surgical procedures may require a temporary interruption or change in warfarin treatment due to bleeding risks.

The primary concern with overdosage in patients taking warfarin is the risk for bleeding. Taking too much of the anticoagulant can result in several signs and symptoms that a dose adjustment is needed. Many of these symptoms can signal life-threatening bleeding and require immediate medical intervention.

Signs and symptoms of Coumadin overdose may include:

  • Excessive bruising or persistent oozing from superficial injuries (any injury that does not affect underlying muscles or organs, typically only affecting the skin)
  • Blood in the stool or urine
  • Excessive menstrual bleeding in women
  • Unexplained fall in hemoglobin (a lab value that may indicate blood loss)
  • Dark, sticky stool containing blood
  • Pinpoint, round spots that appear on the skin
  • Blood in vomit

Treatment of overdose is the patient’s INR level, the presence or absence of bleeding and other clinical circumstances. Reversal of the medication’s effects may be achieved by discontinuing the drug and administering vitamin K.

Certain drugs, and even herbal or dietary supplements, can interact with warfarin. Additionally, more frequent blood monitoring is needed when a patient starts or stops other drugs, including supplements, or when dosages of other drugs are changed.

Certain drugs, such as those belonging to the class of inhibitors of CYP2C9, 1A2 and/or 3A4 (certain enzymes found in the body), have the ability to increase the effect of warfarin.

These medications include certain antifungals, decongestants, Xanax (alprazolam) and caffeine. Other substances that induce these enzymes may have the opposite effect on warfarin.

These include certain anti-seizure drugs and cigarettes.

These can include certain pain medications, such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, serotonin reuptake inhibitors (SRIs) used to treat depression and anxiety disorders, and use of other medications that can thin the blood (antiplatelets and other anticoagulants).

Many dietary supplements and herbal medications interact with warfarin and alter a patient’s INR/PT levels. This may increase or decrease the effect of warfarin.

Dietary supplements and herbal medications that can alter a patient’s INR/PT levels include:

  • Co-enzyme Q10
  • Echinacea
  • Garlic
  • Ginkgo biloba
  • Ginseng
  • Goldenseal
  • St. John’s Wort
  • Any vitamin/mineral supplements that list vitamin K on the label

Some antibiotics can interfere with the effect of warfarin. There have been reports of changes in INR in patients taking warfarin and certain antibiotics or antifungals, according to drug labeling for warfarin.

Alcohol can affect dosing of warfarin. It is best to limit alcohol while taking warfarin and avoid drinking it on a daily basis.

Please seek the advice of a medical professional before making health care decisions.


Poor patient warfarin knowledge may increase risk of deadly side effects: Awareness was lowest on diet and drug interactions and when to call a doctor

Vitamin K Side Effects, Toxicity & Warfarin Interaction

Patients have poor knowledge of warfarin which may increase their risk of serious side effects, according to research presented today at EuroHeartCare 2016 by Dr Kjersti Oterhals, a nurse researcher at Haukeland University Hospital in Bergen, Norway.

“The stroke and bleeding complications from warfarin can be fatal,” said Dr Oterhals. “Worldwide warfarin causes the most deaths from drug-related side effects. Patients need to know what foods and drugs have an impact on how warfarin works, and what to do if they have symptoms of an overdose or underdose.”

Warfarin is given to patients at increased risk of blood clots from conditions such as atrial fibrillation or a mechanical heart valve. Blood clots can travel through the blood to the brain and cause a stroke.

Warfarin 'thins the blood' by slowing down the anticoagulation effect of vitamin K, thereby increasing the time it takes blood to clot and reducing the risk of stroke.

Taking too much warfain raises the risk of bleeding.

Patients on warfarin take an individually tailored dose that depends on their genes, usual diet, drugs and physical activity.

Initially patients have a daily blood test to check their international normalised ratio (INR) which indicates how long it takes the blood to clot.

People not taking warfarin have an INR of around 1 but patients with a mechanical heart valve should have an INR in the range of 2.5 to 3.5 to prevent their body creating a blood clot which could travel to the brain and cause a stroke.

“The goal is to thin the blood enough to prevent a stroke but not too much and cause bleeding,” said Dr Oterhals. “An INR of 3 means it takes 3 times longer to stop a bleeding than it would take someone not on warfarin.

If a patient's INR is below the target range they are at increased risk of thrombosis and above it they are at risk of bleeding complications.

Lack of knowledge on what food and drugs interact with warfarin can lead to INR levels outside the therapeutic range which can be dangerous.”

The study included 404 patients with aortic stenosis who were taking warfarin. Nearly two-thirds (63%) took warfarin because they had a mechanical heart valve to treat aortic stenosis and 24% took the drug because they had atrial fibrillation. Patients were 68 years old on average and 70% were men.

Patients received a postal questionnaire with 28 multiple choice questions about warfarin. They answered 18 questions correctly on average but 22% gave correct answers on less than half of the questions. Questions with the least correct answers concerned food and drug interactions and when to call a doctor.

When asked which of the following foods would interfere with warfarin: celery, carrot, coleslaw or green beans, just 25% correctly said coleslaw and most patients answered green beans.

“Patients often think green vegetables have the most vitamin K but that's not true,” said Dr Oterhals. “Brassica vegetables such as cabbage, broccoli and cauliflower are rich sources.

Patients do not have to avoid these foods but they should eat an equal amount every week because the vitamin K will decrease their INR and put them at increased risk of thrombosis or embolism.

Patients who to eat a lot of vitamin K containing foods can take a higher warfarin dosage but they need to be consistent.”

While 80% knew they should go directly to the emergency room if they had nose bleeding that would not stop, only 45% correctly said diarrhoea for more than one day should trigger a visit to the doctor. Some 86% knew that the INR test tells the pharmacist how thick or thin the blood is while taking warfarin.

The study found that increased age was associated with decreasing correct answers. Dr Oterhals said: “We can only speculate why. Younger people tend to seek out information about how to manage their disease while the older generation wants the doctor to tell them what to do.”

She continued: “Motivated patients should be offered an INR testing kit so that they can monitor their levels and adjust the warfarin dose themselves, just as patients with diabetes who use insulin do.

It enables patients to travel and try new foods without having to find a clinic to get tested.

Patients tell me that hot weather increases their INR while another found out while in Asia that nori decreased his INR.”

Warfarin checklist

  • Diet: keep vitamin K intake consistent and check content of new foods; even small levels eaten in large amounts affect the INR
  • Drugs: antibiotics increase INR; avoid herbal medicines; ask about over the counter drugs
  • Call the doctor: nosebleeds indicate blood is too thin; diarrhoea causes vitamin K loss
  • Exercise: patients who exercise regularly need a higher warfarin dose
  • Be consistent: check how anything the ordinary will affect your warfarin.

Dr Oterhals concluded: “Warfarin is a life saving drug but can be deadly if not used carefully. Health professionals have a responsibility to educate patients but unfortunately even cardiac nurses do not know enough.2 There is an urgent need to improve health professionals' warfarin knowledge so they can educate patients.”

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Coumadin (Warfarin Sodium): Uses, Dosage, Side Effects, Interactions, Warning

Vitamin K Side Effects, Toxicity & Warfarin Interaction

Drugs may interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms.

Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance).

Pharmacokinetic mechanisms for drug interactions with COUMADIN 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.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see BOX WARNING].

Consult the labeling of all concurrently used drugs to obtain further information about interactions with COUMADIN or adverse reactions pertaining to bleeding.

CYP450 Interactions

CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential.

The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

Table 2: Examples of CYP450 Interactions with Warfarin

CYP2C9amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukastaprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileutonmontelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileutonarmodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Drugs That Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Table 3: Drugs that Can Increase the Risk of Bleeding

Drug ClassSpecific Drugs
Anticoagulantsargatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agentsaspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agentscelecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitorscitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Antibiotics And Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

Botanical (Herbal) Products And Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN.

Conversely, some botanicals may decrease the effects of COUMADIN (e.g., co-enzyme Q10, St. John ’s wort, ginseng). Some botanicals and foods can interact with COUMADIN through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St.

John’s wort).

The amount of vitamin K in food may affect therapy with COUMADIN. Advise patients taking COUMADIN to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking COUMADIN should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.


Warfarin Toxicity – What You Need to Know

Vitamin K Side Effects, Toxicity & Warfarin Interaction

This material must not be used for commercial purposes, or in any hospital or medical facility. Failure to comply may result in legal action.

What is warfarin toxicity?

Warfarin toxicity happens when you have too much warfarin in your body. Certain changes to foods and medicines can also increase the effect of warfarin. Warfarin is a medicine that is used to prevent or treat the formation of blot clots. It works by making your blood clot more slowly. Warfarin toxicity can cause bleeding that can become life-threatening.

What increases my risk for warfarin toxicity?

  • You take higher doses of warfarin than is recommended by your healthcare provider.
  • Your risk of warfarin toxicity increases if you do not have your INR checked as recommended. Your healthcare provider adjusts your dose your INR. The INR, or International Normalized Ratio, is a measure of how long it takes your blood to clot. Your risk of bleeding increase over time when your INR is too high.
  • A sudden decrease of vitamin K in your diet can increase your risk of bleeding. Vitamin K changes how your blood clots. Your vitamin K levels affect your INR.
  • You start or stop taking another medicine or supplement that affects the way warfarin works.

What are the signs and symptoms of warfarin toxicity?

  • Red spots on your skin that look a rash
  • Severe headache or dizziness
  • Heavy bleeding after an injury
  • Heavy bleeding during monthly period in women
  • You have severe stomach pain or you vomit blood
  • Pink, red, or dark brown urine
  • Black or bloody bowel movements

How do I safely take warfarin?

  • Go to all your follow-up appointments. Your healthcare provider will need to monitor you closely while you are taking warfarin. He may need to adjust your dose your INR results.
  • Take this medicine exactly as directed. Contact your healthcare provider if you miss a dose or you have any questions about how to take warfarin.
  • Do not start or stop taking medicines or herbal supplements that can affect the way that warfarin works. Some examples include NSAIDs, aspirin, acetaminophen, and certain antacids, antibiotics, and medicines used to lower cholesterol. Some herbal supplements that can affect the way warfarin works are ginkgo biloba, garlic, fish oil, vitamin E, and tumeric. Talk to your healthcare provider before you start or stop any medicines.
  • Eat the same amount of vitamin K daily to help keep your INR stable. Vitamin K is found in green leafy vegetables, broccoli, grapes, and other foods. Ask your healthcare provider for more information about vitamin K.
  • Avoid alcohol. Alcohol increases your INR.

What else should I do while I am taking warfarin?

Wear medical alert jewelry or carry a card that says you take warfarin. Ask where to get these items.

What should I do if I think I or someone I know took too much warfarin?

Call the Poison Control Center at 1-800-222-1222 immediately.

When should I seek immediate care?

  • You have a severe headache or dizziness.
  • You have heavy bleeding that does not stop.
  • You have severe stomach pain or you vomit blood.
  • Your urine is pink, red, or dark brown.
  • You have black or bloody bowel movements.

When should I contact my healthcare provider?

  • You have fever and chills.
  • Your gums bleed when you brush your teeth.
  • You have frequent nosebleeds.
  • You bruise easily.
  • You have red spots on your skin that look a rash.
  • You have heavy bleeding during your period if you are a woman.
  • You have questions or concerns about your condition or care.

Care Agreement

You have the right to help plan your care. Learn about your health condition and how it may be treated. Discuss treatment options with your healthcare providers to decide what care you want to receive. You always have the right to refuse treatment. The above information is an educational aid only. It is not intended as medical advice for individual conditions or treatments.

Talk to your doctor, nurse or pharmacist before following any medical regimen to see if it is safe and effective for you.

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or IBM Watson Health

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

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  • Safe Use of Anticoagulants


Drugs & Medications

Vitamin K Side Effects, Toxicity & Warfarin Interaction
Drugs & Medications

  • Uses
  • Side Effects
  • Precautions
  • Interactions
  • Overdose
  • Images
  • Uses
  • Side Effects
  • Precautions
  • Interactions
  • Overdose
  • Images


Vitamin K is used to treat and prevent low levels of certain substances (blood clotting factors) that your body naturally produces. These substances help your blood to thicken and stop bleeding normally (e.g., after an accidental cut or injury). Low levels of blood clotting factors increase the risk for unusual bleeding. Low levels may be caused by certain medications (e.g., warfarin) or medical conditions (e.g., obstructive jaundice). Vitamin K helps to treat and prevent unusual bleeding by increasing the body's production of blood clotting factors.

This medication is given by injection under the skin or into a muscle or vein as directed by your doctor. If this medication is given into a vein, it should be injected very slowly (no more than 1 milligram per minute) to reduce the risk of serious side effects. (See also Warning section.)

Dosage is your medical condition and response to treatment.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. The solution is normally clear and yellow in color. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

If you are using a certain “blood thinner” drug (warfarin), vitamin K can decrease the effects of warfarin for up to 2 weeks. Therefore, be sure to take your vitamin K and warfarin exactly as directed by your doctor or pharmacist.

If you develop easy bruising or bleeding, seek immediate medical attention. You may need another dose of vitamin K.

Side Effects

Pain, swelling, or soreness at the injection site may occur. Temporary flushing, taste changes, dizziness, rapid heartbeat, sweating, shortness of breath, or bluish lips/skin/nails may also rarely occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US –

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