WARFARIN SODIUM (warfarin sodium)

There are 20 contraindications. Absolute contraindication.

Contraindication List
Aortic aneurysm with dissection
Calciphylaxis
Cerebral amyloid angiopathy
Deep peripheral nerve block
Deep plexus block
Gastrointestinal hemorrhage
Gastrointestinal ulcer
Genitourinary tract hemorrhage
Hemorrhage
Increased risk of bleeding due to coagulation disorder
Intracranial bleeding
Invasive procedure on spine
Neuraxial anesthesia
Pericardial effusion
Pericarditis
Placement of indwelling epidural catheter
Pregnancy
Respiratory tract hemorrhage
Severe uncontrolled hypertension
Threatened abortion

There are 11 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Bacterial endocarditis
Brain aneurysm
Cholesterol embolism
Gangrene
Heparin-induced thrombocytopenia
Increased risk of bleeding
Invasive surgical procedure
Major traumatic injury
Protein C deficiency disease
Surgical procedure on eye proper
Vitamin K deficiency

There are 14 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Anemia
Biliary obstruction
Bleeding risk associated with vitamin K epoxide reductase (warfarin-sensitive) gene
CYp2c9 poor metabolizer
Disease of liver
Fever
Indwelling vascular catheter
Kidney disease with reduction in glomerular filtration rate (GFr)
Malignancy
Polycythemia vera
Protein-calorie malnutrition
Severe diarrhea
Steatorrhea
Tropical sprue

There are 24 severe adverse reactions.

More Frequent	Less Frequent
Hemorrhage	Leukopenia

Rare/Very Rare
Abnormal hepatic function tests Agranulocytosis Allergic dermatitis Anaphylaxis Anemia Anticoagulant-related nephropathy Calcification of bronchus Calcification of trachea Calciphylaxis Cholestatic hepatitis Cholesterol embolism Dermal necrosis Gangrene Hematuria Hepatitis Hypersensitivity drug reaction Intracerebral hemorrhage Jaundice Pruritus of skin Tissue necrosis Urticaria Vasculitis

There are 13 less severe adverse reactions.

More Frequent	Less Frequent
None.	Abdominal pain with cramps Alopecia Diarrhea Dysgeusia Flatulence Nausea Vomiting

Rare/Very Rare
Abdominal distension Chills Fever Pallor Purpura Skin rash

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.

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.