Warfarin (warfarin sodium)

Warfarin dosage is expressed in terms of warfarin sodium.

Nonproprietary (generic) preparations of warfarin sodium are available, and the manufacturers warn that patients should be carefully instructed about the preparation they are receiving so that overdosage from inadvertent simultaneous use of equivalent preparations is avoided.

Warfarin sodium dosage requirements vary greatly among individual patients, and dosage must be carefully individualized based on the patient's INR in order to obtain optimum therapeutic effects while minimizing the risk of hemorrhage. Factors influencing initial dose selection include clinical factors (e.g., age, sex, comorbidities, concomitant medications) and genetic factors (e.g., CYP2C9 and VKORC1 genotypes).

Duration and intensity of anticoagulation (i.e., INR) is based on the indication for use. Pharmacogenomic factors (e.g., genetic variations in enzymes that metabolize warfarin or modulate its effect on clotting factor synthesis) also may be considered in determining the warfarin dosage.

Administer warfarin sodium orally as a single daily dose without regard to food. Adhere strictly to the prescribed dosage and schedule of warfarin. Take warfarin tablets at the same time each day.

If a dose of warfarin is missed at the intended time of day, take the dose as soon as possible on the same day. A double dose of warfarin should not be taken the next day to make up for the missed dose.

Warfarin is discolored by light; warfarin preparations should be stored at controlled room temperature (20-25degreesC) in tight, light-resistant containers.

No dosing information is available for this tab.

No dosing information is available for this tab.

Concurrent administration of numerous drugs or dietary or herbal supplements has been reported to affect patient response to warfarin.

Drugs may increase patient sensitivity to warfarin by decreasing intestinal synthesis or absorption of vitamin K or affecting distribution of the vitamin; decreasing the rate of anticoagulant metabolism by competing for sites of metabolism or inhibiting the function or synthesis of metabolic enzymes; increasing affinity of the anticoagulant for receptor sites; decreasing synthesis and/or increasing catabolism of functional blood coagulation factors II, VII, IX, and X; interfering with other components of normal hemostasis such as platelet function or fibrinolysis; and by producing ulcerogenic effects.

Certain drugs may decrease patient response to warfarin by decreasing absorption of the anticoagulant; increasing the rate of metabolism of the anticoagulant by enzyme induction; or by increasing synthesis of functional blood coagulation factors II, VII, IX, and X.

Some dietary or herbal supplements contain naturally occurring coumarins or salicylates that may have anticoagulant, antiplatelet, or fibrinolytic effects; these supplements would be expected to increase the anticoagulant effects of concomitantly administered warfarin.

Certain dietary or herbal supplements also may decrease response to warfarin, possibly as a result of induction of hepatic microsomal enzymes (e.g., St. John's wort) or because of procoagulant effects (e.g., coenzyme Q10).

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*Pregnancy, except in patients with mechanical heart valves.

*Patients with hemorrhagic tendencies or blood dyscrasias.

*Recent or contemplated surgery of the eye or CNS and in those undergoing traumatic surgery resulting in large open surfaces.

*Bleeding tendencies associated with active ulceration or overt bleeding of the GI, respiratory, or genitourinary tract; CNS hemorrhage; aneurysms (cerebral, dissecting aorta); pericarditis and pericardial effusions; bacterial endocarditis.

*Threatened abortion, eclampsia, and preeclampsia.

*Unsupervised patients with conditions associated with a potential high level of non-compliance with therapy (e.g., dementia/senility).

*Known hypersensitivity (e.g., anaphylaxis).

*Spinal puncture and other diagnostic or therapeutic procedures associated with the potential for uncontrollable bleeding.

*Major regional or lumbar block anesthesia.

*Malignant hypertension.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Most common adverse effects: fatal and nonfatal hemorrhage from any tissue or organ.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

The manufacturer of warfarin states that the optimum dosing, safety, and efficacy in pediatric patients are unknown due to a lack of adequate, well-controlled studies. Pediatric use of warfarin is based on adult data and recommendations, as well as limited pediatric data from observational studies and patient registries. However, the drug has been used in pediatric patients for prevention and treatment of thromboembolic events.

Difficulty achieving and maintaining therapeutic INRs has been reported in pediatric patients, and more frequent assessments of INR are recommended in such patients because of possible changing warfarin requirements due to age, concomitant medications, diet, and comorbid conditions. Variable bleeding rates have been observed in pediatric patients; therefore, such patients should avoid activities or sports that may result in traumatic injury.

Infants may have the highest and adolescents the lowest mg per kg dosage requirements. Human milk-fed children may be more sensitive to warfarin compared to those receiving vitamin-K supplemented nutrition.

Warfarin can cause fetal harm and is contraindicated during pregnancy except in women with mechanical heart valves who are at high risk of thromboembolism and for whom the benefits of warfarin may outweigh the risks.

Major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality may occur as a result of warfarin exposure during pregnancy. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). CNS 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. Teratogenicity risk is highest during the first trimester, at 6-12 weeks of gestation. However, risk of pregnancy loss or fetal hemorrhage still exists for warfarin exposure in the second and/or third trimester.

The risk of valve thrombosis is much higher with mechanical heart valves because of the hypercoagulable state. Pregnant women with mechanical heart valves should receive therapeutic anticoagulation with frequent monitoring during pregnancy. Despite the risks of warfarin to the fetus, the drug has been used in pregnant women with prosthetic heart valves who are at an increased risk for valve thrombosis. The manufacturer states in these situations, the decision to initiate or continue warfarin should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to that individual patient's medical situation, as well as the most current medical guidelines. If warfarin is used during pregnancy, or if the patient becomes pregnant while taking warfarin, the patient should be apprised of the potential hazard to a fetus.

The American College of Cardiology/American Heart Association (ACC/AHA) issued guidelines for the management of patients with valvular heart disease, which includes recommendations for the management of women with mechanical heart valves who are pregnant or plan to become pregnant. Multiple strategies to reduce, as well as balance, the maternal (e.g., valve thrombosis, death) and fetal risks (e.g., fetal loss, teratogenicity) are based on factors such as daily warfarin dosage (<= or >5 mg/day), ability to utilize heparin or low molecular weight heparin (LMWH), ability to conduct frequent laboratory monitoring (e.g., INR, anti-Xa levels), and the patient's values and priorities. No single anticoagulation strategy is optimally safe for both the mother and the fetus; maternal and fetal risks can be reduced, but not eliminated. Options include warfarin continuation throughout pregnancy, dose-adjusted heparin or LMWH with frequent anti-Xa level monitoring throughout pregnancy, or sequential therapy with dose-adjusted heparin or LMWH with frequent anti-Xa level monitoring during the first trimester and warfarin during the second and third trimesters. Heparin and LMWH therapy have been associated with an increased maternal risk for valve thrombosis, death, and major bleeding complications in women with prosthetic heart valves.

Other guidance documents (e.g., American College of Obstetricians and Gynecologists (ACOG), American Society of Hematology (ASH)) should be consulted for the management of other warfarin indications in the context of pregnancy.

The timing of anticoagulation discontinuance in anticipation of labor and delivery is important to reduce the risk of maternal and fetal bleeding; women should have an individualized plan that addresses obstetrical, anesthetic, and thrombotic concerns.

Limited data suggest that warfarin is not significantly distributed into human milk, is not detectable in plasma of nursing infants, and has not produced substantial coagulation abnormalities in such infants. Based on limited available data, it is considered unlikely that maternal warfarin therapy would pose a substantial risk to healthy, full-term infants receiving human milk, and ACOG, ASH, American Academy of Pediatrics (AAP), ACCP and other experts consider maternal warfarin therapy to be compatible with breast-feeding. Women should inform their clinician if they are breast-feeding or plan to breast-feed. The manufacturers state that the decision to breast-feed while receiving warfarin anticoagulation should be made only after careful consideration of the mother's clinical need for warfarin, the developmental and health benefits of breastfeeding, and potential adverse effects.

Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency; monitor infants receiving human milk for bruising and bleeding. The effects of warfarin in premature infants have not been evaluated.

In patients >60 years of age, the manufacturer recommends considering lower initial and maintenance warfarin dosages and more frequent monitoring for bleeding.

Age does not appear to substantially affect the pharmacokinetics of racemic warfarin, and the manufacturer states that the clearance of S-warfarin is similar in geriatric versus younger individuals. However, the clearance of R-warfarin appears to be slightly reduced in geriatric patients compared with that in younger individuals. Patients >60 years of age appear to exhibit a greater than expected INR response to warfarin, and a lower dosage is required to produce a therapeutic level of anticoagulation. Increasing age has been shown to confer a greater risk for bleeding outcomes, and advanced age has been included as a risk factor in both disease and bleeding risk stratification tools. The cause for increased sensitivity in geriatric patients is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients. Conduct more frequent monitoring for bleeding in any situation or with any physical condition where added risk of hemorrhage is present.

A systematic review with meta-analysis of 11 clinical trials involving warfarin and direct oral anticoagulants (DOACs; e.g., dabigatran, apixaban, rivaroxaban, edoxaban) for atrial fibrillation and venous thromboembolism (VTE) compared the benefits and harms of these therapies in patients >=75 years of age. Of the 102,479 patients within the 11 trials, 31,418 were >=75 years of age. In these patients, DOACs were shown to be at least as effective as warfarin in reducing the recurrence of stroke, systemic embolism, and VTE; however, DOAC therapy was associated with a significantly lower risk of intracranial bleeding. When stratified by major bleeding, GI bleeding, and clinically relevant bleeding, comparisons were limited due to trial design and data availability; warfarin or a specific DOAC was favored depending upon the specific bleeding outcome.