Included as part of the "PRECAUTIONS" Section
COUMADIN can cause major or fatal bleeding. Bleeding is more likely to occur within the first month.
Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal
to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension,
cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see CLINICAL PHARMACOLOGY], certain concomitant drugs [see DRUG INTERACTIONS], and long duration of
Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit
from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of
therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range
does not eliminate the risk of bleeding.
Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy.
Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or
when changing dosages of other drugs [see DRUG INTERACTIONS].
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and
symptoms of bleeding [see PATIENT INFORMATION].
Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis
may be associated with local thrombosis and usually appears within a few days of the start of
COUMADIN therapy. In severe cases of necrosis, treatment through debridement or amputation of the
affected tissue, limb, breast, or penis has been reported.
Careful clinical evaluation is required to determine whether necrosis is caused by an underlying
disease. Although various treatments have been attempted, no treatment for necrosis has been
considered uniformly effective. Discontinue COUMADIN therapy if necrosis occurs. Consider
alternative drugs if continued anticoagulation therapy is necessary.
Fatal and serious calciphylaxis or calcium uremic arteriolopathy has been reported in patients with and
without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue
COUMADIN and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.
Acute Kidney Injury
In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may
occur with COUMADIN, possibly in relation to episodes of excessive anticoagulation and hematuria
[see Use In Specific Populations]. More frequent monitoring of anticoagulation is advised in patients
with compromised renal function.
Systemic Atheroemboli And Cholesterol Microemboli
Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli.
Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms
depending on the site of embolization. The most commonly involved visceral organs are the kidneys
followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A
distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.”
Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if
continued anticoagulation therapy is necessary.
Limb Ischemia, Necrosis, And Gangrene In Patients With HIT And HITTS
Do not use COUMADIN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and
with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia,
necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was
discontinued and warfarin therapy was started or continued. In some patients, sequelae have included
amputation of the involved area and/or death. Treatment with COUMADIN may be considered after the
platelet count has normalized.
Use In Pregnant Women With Mechanical Heart Valves
COUMADIN can cause fetal harm when administered to a pregnant woman. While COUMADIN is
contraindicated during pregnancy, the potential benefits of using COUMADIN may outweigh the risks
for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual
situations, the decision to initiate or continue COUMADIN should be reviewed with the patient, taking
into consideration the specific risks and benefits pertaining to the individual patient’s medical situation,
as well as the most current medical guidelines. COUMADIN exposure during pregnancy causes a
recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal
fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to a fetus [see Use In Specific Populations].
Other Clinical Settings With Increased Risks
In the following clinical settings, the risks of COUMADIN therapy may be increased:
- Moderate to severe hepatic impairment
- Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
- Use of an indwelling catheter
- Severe to moderate hypertension
- Deficiency in protein C-mediated anticoagulant response: COUMADIN reduces the synthesis of the
naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of
protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin
administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of
therapy with COUMADIN may minimize the incidence of tissue necrosis in these patients.
- Eye surgery: In cataract surgery, COUMADIN use was associated with a significant increase in minor
complications of sharp needle and local anesthesia block but not associated with potentially sightthreatening
operative hemorrhagic complications. As COUMADIN cessation or reduction may lead to
serious thromboembolic complications, the decision to discontinue COUMADIN before a relatively
less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of
anticoagulant therapy weighed against the benefits.
- Polycythemia vera
- Diabetes mellitus
Endogenous Factors Affecting INR
The following factors may be responsible for increased INR response: diarrhea, hepatic disorders,
poor nutritional state, steatorrhea, or vitamin K deficiency.
The following factors may be responsible for decreased INR response: increased vitamin K intake or
hereditary warfarin resistance.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instructions For Patients
Advise patients to:
- Strictly adhere to the prescribed dosage schedule [see DOSAGE AND ADMINISTRATION].
- If the prescribed dose of COUMADIN is missed, take the dose as soon as possible on the same day
but do not take a double dose of COUMADIN the next day to make up for missed doses [see DOSAGE AND ADMINISTRATION].
- Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy
[see DOSAGE AND ADMINISTRATION] .
- Be aware that if therapy with COUMADIN is discontinued, the anticoagulant effects of
COUMADIN may persist for about 2 to 5 days [see CLINICAL PHARMACOLOGY].
- Avoid any activity or sport that may result in traumatic injury [see Use In Specific Populations].
And to tell their physician if they fall often as this may increase their risk for complications.
- Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in
dietary habits, such as eating large amounts of leafy, green vegetables [see DRUG INTERACTIONS].
- Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
- Carry identification stating that they are taking COUMADIN.
Advise patients to
- Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms
of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased
menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding
or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness [see BOX WARNING and WARNINGS AND PRECAUTIONS].
Concomitant Medications And Botanicals (Herbals )
Advise patients to:
- Not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics),
other over-the-counter drugs, and botanical (herbal) products except on advice of your physician
[see DRUG INTERACTIONS].
Pregnancy And Nursing
Advise patients to:
- Contact their doctor
- immediately if they think they are pregnant [see Use In Specific Populations],
- to discuss pregnancy planning [see Use In Specific Populations],
- if they are considering breastfeeding [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.
Use In Specific Populations
COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical
heart valves, who are at high risk of thromboembolism, and for whom the benefits of COUMADIN may
outweigh the risks [see WARNINGS AND PRECAUTIONS]. COUMADIN can cause fetal harm. Exposure to
warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about
5% of exposed offspring. Because these data were not collected in adequate and well-controlled
studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated
incidences in the control group or the U.S. general population and may not reflect the incidences
observed in practice. Consider the benefits and risks of COUMADIN and possible risks to the fetus
when prescribing COUMADIN to a pregnant woman.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Fetal/Neonatal Adverse Reactions
In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal
values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital
malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal
hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation
(including low birth weight). Central nervous system 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 of pregnancy [see CONTRAINDICATIONS].
Warfarin was not present in human milk from mothers treated with warfarin from a limited published
study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant,
consider the developmental and health benefits of breastfeeding along with the mother’s clinical need
for COUMADIN and any potential adverse effects on the breastfed infant from COUMADIN or from
the underlying maternal condition before prescribing COUMADIN to a lactating woman.
Monitor breastfeeding infants for bruising or bleeding.
Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15
full-term newborns, 6 nursing infants had documented prothrombin times within the expected range.
Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have
not been evaluated.
Females And Males Of Reproductive Potential
COUMADIN can cause fetal harm [see Use In Specific Populations].
Verify the pregnancy status of females of reproductive potential prior to initiating COUMADIN
Advise females of reproductive potential to use effective contraception during treatment and for at least
1 month after the final dose of COUMADIN.
Adequate and well-controlled studies with COUMADIN have not been conducted in any pediatric
population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use
of COUMADIN is based on adult data and recommendations, and available limited pediatric data from
observational studies and patient registries. Pediatric patients administered COUMADIN should avoid
any activity or sport that may result in traumatic injury.
The developing hemostatic system in infants and children results in a changing physiology of
thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by
patient age, with infants generally having the highest, and adolescents having the lowest milligram per
kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to
age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to
achieve and maintain in pediatric patients, and more frequent INR determinations are recommended.
Bleeding rates varied by patient population and clinical care center in pediatric observational studies
and patient registries.
Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be
resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.
Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data
were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%)
were 75 years and older. No overall differences in effectiveness or safety were observed between
these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant
effects of warfarin [see CLINICAL PHARMACOLOGY]. COUMADIN is contraindicated in any
unsupervised patient with senility. Observe caution with administration of COUMADIN to elderly
patients in any situation or with any physical condition where added risk of hemorrhage is present.
Consider lower initiation and maintenance doses of COUMADIN in elderly patients [see DOSAGE AND ADMINISTRATION].
Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No
dosage adjustment is necessary for patients with renal impairment. Instruct patients with renal impairment
taking warfarin to monitor their INR more frequently [see WARNINGS AND PRECAUTIONS].
Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting
factors and decreased metabolism of warfarin. Use caution when using COUMADIN in these patients.