Warfarin resources

Interactions for Warfarin:

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 altered 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.

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response

ENDOGENOUS FACTORS

EXOGENOUS FACTORS

Potential drug interactions with COUMADIN are listed below by drug class and by specific drugs.

also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations

^† increased and decreased PT/INR responses have been reported.

The following factors, alone or in combination, may be responsible for DECREASED PT/INR response

ENDOGENOUS FACTORS

EXOGENOUS FACTORS

Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific drugs.

also: diet high in vitamin K unreliable PT/INR determinations

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

Because a patient may be exposed to a combination of the above factors, the net effect of COUMADIN on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable.

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

Botanical (Herbal) Medicines

Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN. 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. It is good practice to monitor the patient’s response with additional PT/INR determinations when initiating or discontinuing botanicals.

Specific botanicals reported to affect COUMADIN therapy include the following:

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

• Coenzyme Q₁₀ (ubidecarenone) and St. John’s wort are associated most often with a DECREASE in the effects of COUMADIN.

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

Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed.

Effect on Other Drugs

Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.

Special Risk Patients

COUMADIN (Warfarin Sodium) is a narrow therapeutic range (index) drug, and caution should be observed when warfarin sodium is administered to certain patients such as the elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present.

Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.

Caution should be observed when COUMADIN (or warfarin) is administered concomitantly with nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.

Acquired or inherited warfarin resistance should be suspected if large daily doses of COUMADIN are required to maintain a patient’s PT/INR within a normal therapeutic range.

SIDE EFFECTS

Potential adverse reactions to COUMADIN may include:

• Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does not always correlate with PT/INR.

• Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion, e.g., tumor, ulcer, etc.

• Necrosis of skin and other tissues.

• Adverse reactions reported infrequently include: hypersensitivity/allergic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, vasculitis, edema, fever, rash, dermatitis, including bullous eruptions, urticaria, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills.

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown.

Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.