Side Effects of Coumadin (warfarin)

Coumadin (warfarin) is an oral anticoagulant, a drug that inhibits the clotting of blood. Coumaid is used to do the following: 

• treat deep vein thrombosis (DVT) to prevent extension of the clot, and to reduce the risk of pulmonary embolism;
• to prevent further emboli in patients with pulmonary embolism;
• to reduce the risk of strokes, and after a heart attack in patients with atrial fibrillation or artificial heart valves;
• to prevent blood clots from forming in certain orthopedic surgeries such as knee or hip replacements; and
• to prevent closure of coronary artery stents due to clotting.

Coumadin prevents the formation of blood clots by reducing the production of factors by the liver that promote clotting, factors II, VII, IX, and X, and the anticoagulant proteins C and S. The production of these factors by the liver are dependent on adequate amounts of vitamin K. Warfarin reduces the production of the factors because it antagonizes vitamin K. Coumadin is important in preventing the formation of blood clots, preventing extension of clots already formed, and minimizing the risk of embolization of blood clots to other vital organs such as the lungs and brain.

Common side effects of Coumadin include:

• bleeding,
• rash,
• hair loss,
• bloating,
• diarrhea,
• yellowing of eyes and skin (jaundice), and
• purple, painful toes.

Serious side effects of Coumadin include:

• severe bleeding and necrosis (gangrene) of the skin.
• Bleeding around the brain can cause severe headache and paralysis.
• Bleeding in the joints can cause joint pain and swelling.
• Bleeding in the stomach or intestines can cause weakness, fainting spells, black tarry stools, vomiting of blood, or coffee ground material.
• Bleeding in the kidneys can cause back pain and blood in urine.

Drug interactions of Coumadin which can increase the effect of Coumadin by reducing its breakdown in the body include:

• amiodarone,
• trimethoprim/sulfamethoxazole,
• fluconazole,
• itraconazole,
• fluvastatin,
• fluvoxamine,
• metronidazole miconazole,
• voriconazole,
• zafirlukast,
• ciprofloxacin,
• cimetidine,
• atorvastatin,
• clarithromycin,
• fluoxetine,
• indinavir, and
• ritonavir.

Drugs that may reduce the effect of Coumadin by increasing its breakdown include:

• St. John's wort,
• carbamazepine,
• rifampin,
• bosentan, and
• prednisone.

Bleeding is increased when Coumadin is taken with other anticoagulants, antiplatelet drugs such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and serotonin reuptake inhibitors (SSRIs). Garlic and ginkgo also increase the risk of bleeding because they cause bleeding when taken alone. Foods with high vitamin K content (for example, green leafy vegetables) reduce the effect of Coumadin.

Coumadin should be avoided by pregnant women or women who may become pregnant. Birth defects and fetal bleeding have been reported. Available evidence suggests that Coumadin is not secreted in breast milk. Consult your doctor before breastfeeding. 

The two most serious side effects of warfarin are:

• Bleeding
• Necrosis (gangrene) of the skin

Bleeding can occur in any organ or tissue. Bleeding around the brain can cause severe headache and paralysis. Bleeding in the joints can cause joint pain and swelling. Bleeding in the stomach or intestines can cause weakness, fainting spells, black tarry stools, vomiting of blood, or coffee ground material. Bleeding in the kidneys can cause back pain and blood in urine.

Other side effects include:

• Purple, painful toes
• Rash
• Hair loss
• Bloating
• Diarrhea
• Jaundice (yellowing of eyes and skin)

Signs of overdose include:

• bleeding gums,
• bruising,
• nosebleeds,
• heavy menstrual bleeding, and
• prolonged bleeding from cuts.

The following serious adverse reactions to Coumadin are discussed in greater detail in other sections of the labeling:

• Hemorrhage
• Tissue Necrosis
• Calciphylaxis
• Acute Kidney Injury
• Systemic Atheroemboli and Cholesterol Microemboli
• Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS
• Other Clinical Settings with Increased Risks

Other adverse reactions to Coumadin include:

• Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)
• Vascular disorders: vasculitis
• Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of Coumadin and ticlopidine.
• Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
• Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia
• Respiratory disorders: tracheal or tracheobronchial calcification
• General disorders: chills

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).

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

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

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.