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Anticoagulants (Systemic)

This monograph includes information on the following:

1) Acenocoumarol  *
2) Anisindione  
3) Dicumarol  
4) Warfarin

Note: See also individual Antithrombin III (Systemic) , Ardeparin (Systemic) , Dalteparin (Systemic) , Danaparoid (Systemic) , Enoxaparin (Systemic) , and Heparin (Systemic) monographs.



INN:
Dicumarol—Dicoumarol

BAN:
Acenocoumarol—Nicoumalone

VA CLASSIFICATION
Primary: BL114

Commonly used brand name(s): Coumadin4; Miradon2; Sintrom1; Warfilone4.

Other commonly used names are
nicoumalone —acenocoumarol *
and dicoumarol —dicumarol  

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Anticoagulant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
This monograph includes information on two types of anticoagulants—coumarin derivatives (acenocoumarol, dicumarol, warfarin) and indanedione derivatives (anisindione). Warfarin is usually the oral anticoagulant of choice. In general, because of their higher risk of hemorrhage, indanedione derivatives are used only when an oral anticoagulant is indicated but use of coumarin derivatives is not possible {33}0 {05}9. Dicumarol is seldom used because of its unpredictable response and high incidence of gastrointestinal side effects {05}8.

Decisions about whether to use anticoagulants should take into account the balance between potential benefits (prevention of thromboembolism, reduced mortality) and risks (hemorrhage, possible increased mortality) {05}7. The presence or absence of risk factors (e.g., advanced age, history of bleeding or stroke, diabetes, hypertension {05}6) strongly influences both the decision about whether to initiate anticoagulant therapy and the choice of anticoagulant. Multiple indications also may be present (e.g., atrial fibrillation in patients with prosthetic heart valves {05}5) and may affect treatment decisions.

Several of the indications for the oral anticoagulants are identical to those for aspirin, heparin, other antithrombotic agents, other platelet aggregation inhibitors, and thrombolytic agents. Choice of agent may depend on the specific condition, associated risk factors, and desired effect. In some cases, oral anticoagulants may be used in combination with, or sequentially with, one or more of these agents.

Since the full therapeutic effects of oral anticoagulants is delayed for several days, heparin is the agent of choice when an immediate anticoagulant effect is required. Oral anticoagulants are used when treatment is not urgent or for long-term anticoagulant therapy following initial heparin or thrombolytic therapy.

Warfarin injection is used when coumarin anticoagulant therapy is desired in patients who cannot take oral warfarin {05}4.

Accepted

Thrombosis (prophylaxis and/or treatment) or
Thromboembolism (prophylaxis and/or treatment)—Anticoagulants are indicated for prophylaxis and/or treatment of venous [or arterial] thrombosis (and its extension) and pulmonary embolism {05}3 {05}2 {05}1 {05}0 {03}9 {03}8 {03}7 {03}6 {03}5. Deep vein thrombosis (DVT) or pulmonary embolism (treatment)



• Oral anticoagulants are used during and following initial heparin therapy {03}4 {03}3 {03}2 to decrease the risk of extension, recurrence, or death.
Note: Oral anticoagulant therapy is usually initiated at the same time as heparin therapy, or at least overlapped with heparin therapy; heparin therapy is withdrawn when a therapeutic prothrombin time has been maintained for an appropriate period {03}1.


DVT or pulmonary embolism (prophylaxis)



• Oral anticoagulants are used to prevent thromboembolic complications after surgery {03}0 {02}9 {02}8, although low-dose subcutaneous heparin is used more commonly {02}7.
Note: Perioperative warfarin is recommended in selected very-high-risk general surgery patients {02}6.
Warfarin may be started preoperatively in patients undergoing elective total hip replacement or total knee replacement surgery, and continued postoperatively {02}5 {02}4.
Warfarin may be started preoperatively or immediately postoperatively in patients undergoing hip fracture surgery {02}3.
Low-dose warfarin is recommended in patients with long-term indwelling central vein catheters to prevent axillary-subclavian venous thrombosis {02}2 {02}1.


Atrial fibrillation



• Anticoagulants are indicated for prophylaxis and/or treatment of thromboembolic complications (ischemic stroke) associated with atrial fibrillation {02}0 {02}9 {02}8 {02}7 {02}6 {02}5 {02}4 {02}3 {02}2 {02}1 {02}0 {90}9. They are strongly recommended in patients at high risk of stroke (including patients with recent stroke, transient ischemic attack, or systemic embolism; poor left ventricular function; age over 75 years; hypertension; rheumatic mitral valve disease; mechanical or tissue prosthetic heart valves) {90}8.
Note: In patients with one or more lower-risk factors (diabetes mellitus, coronary artery disease, age 65 to 75 years, thyrotoxicosis), the decision about whether to use oral anticoagulants should balance the relative efficacy (compared to aspirin) against the risk of hemorrhage {90}7 {90}6 {90}5.
Oral anticoagulant therapy is strongly recommended for 3 weeks before elective cardioversion of chronic atrial fibrillation, and should be continued until normal sinus rhythm has been maintained for 4 weeks {90}4 {90}3, to reduce the risk of postconversion emboli. Similar antithrombotic therapy may also be considered at the time of cardioversion in atrial flutter {90}2 {90}1, but antithrombotic therapy is not recommended for cardioversion of chronic supraventricular tachycardia {90}0.


Myocardial infarction



• Anticoagulants are indicated after myocardial infarction to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization {01}9 {01}8 {01}7 {01}6 {01}5 {01}4 {01}3.
Note: Anticoagulants are used after initial heparin therapy, primarily in high-risk patients such as those with shock, congestive heart failure, prolonged arrhythmias (especially atrial fibrillation), previous myocardial infarction, or history of systemic or pulmonary thromboembolism {01}2.
The risk of cardioembolic stroke may be decreased by oral anticoagulants, but the risk of hemorrhagic stroke may be increased {01}1. Additional studies are needed to help identify subgroups of patients most likely to benefit from anticoagulant therapy {01}0.


Ischemia, myocardial



• Oral anticoagulants are indicated, alone or in combination with aspirin, for primary prevention of thrombotic complications of coronary artery disease {02}9 {02}8 {02}7 {02}6 {02}5 {02}4 in patients without history of myocardial infarction, stroke, or transient ischemic attacks but with increasing levels of risk {02}3 {02}2.
Note: Because of the risk of cerebral hemorrhage with combined use of aspirin and anticoagulants, as well as the costs and complexity of warfarin therapy, aspirin monotherapy is usually recommended. Low-dose warfarin therapy is recommended as an alternative to aspirin for men at high risk of cardiovascular events, to prevent those events and reduce all-cause mortality {02}1. Combination therapy with aspirin and low-dose warfarin may be considered in men at very high risk {02}0.


Prosthetic heart valves



• Anticoagulants are indicated for prophylaxis and/or treatment of thromboembolic complications associated with tissue and mechanical cardiac valve replacement {03}9 {03}8 {03}7 {03}6 {03}5 {03}4 {03}3 {03}2.
Note: Concurrent use of aspirin may increase effectiveness in patients who experience embolism in spite of adequate anticoagulant therapy {03}1 {03}0 {09}9 {09}8 {09}7 but is associated with an increased risk of hemorrhage if the international normalized ratio (INR) is not kept at a low level {09}6 {09}5 {09}4.


[Valvular heart disease]



• Anticoagulants are used in certain patients with valvular heart disease to prevent systemic embolization {09}3 {09}2 {09}1 {09}0 {48}9.
Note: Warfarin is strongly recommended in rheumatic mitral valve disease in patients who have either a history of systemic embolism or who have paroxysmal or chronic atrial fibrillation {48}8 {48}7 {48}6. Long-term warfarin therapy should be considered in rheumatic mitral valve disease in patients with normal sinus rhythm if the left atrial diameter exceeds 5 centimeters {48}5.
Long-term warfarin therapy is not recommended in aortic valve disease unless there is concomitant mitral valve disease, atrial fibrillation, or a history of systemic embolism {48}4.
Long-term warfarin therapy is strongly recommended in mitral valve prolapse, but only in patients who have documented systemic embolism, chronic or paroxysmal atrial fibrillation, or recurrent transient ischemic attacks despite aspirin therapy {48}3 {48}2 {48}1.
Long-term warfarin therapy is recommended in mitral annular calcification, but only in patients with systemic embolism not documented to be calcific embolism or in patients with associated atrial fibrillation {48}0 {01}9.
Long-term warfarin therapy is strongly recommended in patent foramen ovale (PFO) and atrial septal aneurysm in patients with unexplained systemic embolism or transient ischemic attacks and demonstrable venous thrombosis or pulmonary embolism, unless venous interruption or surgical closure of the PFO is preferable {01}8.
Long-term warfarin therapy may be continued if infective endocarditis occurs in patients with mechanical prosthetic valves, unless there are specific contraindications, because of the high incidence of systemic thromboembolism in these patients {01}7 {01}6; however, the risk of intracranial hemorrhage is significant with this therapy {01}5 {01}4. The therapeutic decision regarding use of anticoagulant therapy when systemic embolism occurs during the course of infective endocarditis involving a native or bioprosthetic heart valve should involve consideration of comorbid factors (atrial fibrillation, evidence of left atrial thrombus, evidence and size of valvular vegetations) as well as the success of antibiotic therapy {01}3 {01}2.


[Vascular disease, peripheral]



• Oral anticoagulants are used, following initial heparinization, to prevent recurrent thromboembolism in peripheral arterial occlusive disease {01}1 {01}0 {02}9. They are not indicated for routine prophylaxis after intrainguinal bypass and other vascular reconstructions but are indicated, usually in combination with aspirin, in patients at high risk of graft thrombosis {02}8.


Acceptance not established
There are insufficient data to evaluate safety and efficacy of oral anticoagulants for prevention of worsening or recurrence of acute ischemic (atherothrombotic) stroke (i.e., noncardioembolic stroke) {02}7 {02}6. At effective INRs, the risk of hemorrhage appears to outweigh the potential benefit {02}5 {02}4.

There are insufficient data to determine efficacy of oral anticoagulants for prevention of occlusion of saphenous veins used in coronary artery bypass grafts; aspirin therapy, however, is well-established {02}3.

Although there is a good theoretical basis for use of anticoagulants in the primary treatment of cancer, efficacy has not been established in clinical trials {02}2.

Unaccepted
Warfarin is no longer recommended for use in the prevention of subacute thrombosis after intracoronary stent placement, because studies have shown that the combination of aspirin and ticlopidine is more effective {02}1.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Coumarin derivatives: Acenocoumarol, dicumarol, warfarin.
    Indanedione derivative: Anisindione.
Molecular weight—
    Acenocoumarol: 353.33 {02}0
    Anisindione: 252.27 {03}9
    Dicumarol: 336.3 {03}8
    Warfarin sodium: 330.32 {03}7

Mechanism of action/Effect:

Both coumarin and indanedione derivatives are indirect-acting anticoagulants {03}6. They prevent the formation of active procoagulation factors II, VII, IX, and X {03}5 {03}4, as well as the anticoagulant proteins C and S {03}3 {03}2 {03}1, in the liver by inhibiting the vitamin K–mediated gamma-carboxylation of precursor proteins {03}0 {09}9. These agents have no direct thrombolytic effect {09}8 and do not reverse ischemic tissue damage, although they may limit extension of existing thrombi and prevent secondary thromboembolic complications {09}7.

Commercially available warfarin is a racemic mixture of R- and S-enantiomers. The S-enantiomer has 2 to 5 times the anticoagulant activity of the R-enantiomer {09}6 {09}5 {09}4 {09}3 but also has more rapid clearance {09}2 {09}1.

Absorption:

Acenocoumarol—Rapid; bioavailability is at least 60% {09}0.

Anisindione—Accumulation does not occur with repeated dosing {48}9.

Dicumarol—Irregular {48}8.

Warfarin—Rapidly and completely absorbed from the gastrointestinal tract {48}7 {48}6 {48}5. The rate, but not the extent, of warfarin absorption is decreased by food {48}4 {48}3.

Protein binding:

Acenocoumarol—Very high (98.7%), primarily to albumin {48}2.

Dicumarol—Very high (approximately 97%), to albumin {48}1.

Warfarin—Very high (approximately 99%), primarily to albumin {48}0 {01}9 {01}8. Affinity of the R-isomer is higher than than of the S-isomer, which could result in stereospecific displacement from binding by other medications {01}7.

Biotransformation:

Hepatic {01}6 {01}5 {01}4 {01}3. Enterohepatic recirculation of warfarin occurs {01}2.

Acenocoumarol—At least two metabolic pathways are involved, oxidation and reduction to pharmacologically inactive metabolites. Oxidation produces two hydroxylated metabolites. Reduction of the ketone produces two different alcohol metabolites; reduction of the nitrite produces an amine metabolite, a major portion of which is further transformed to the corresponding acetamide metabolite. An additional unidentified strongly polar metabolite fraction has also been detected. {01}1

Warfarin—Stereoselective metabolism by hepatic microsomal enzymes to inactive hydroxylated metabolites and by reductases to reduced metabolites (warfarin alcohols), which have minimal anticoagulant activity {01}0 {02}9. The major hepatic isoenzyme involved appears to be CYP 2C9 {02}8 {02}7.

Half-life:


Acenocoumarol:

8 to 11 hours {02}6 {02}5.



Dicumarol:

1 to 2 days {02}4.



Warfarin:

Distribution: 6 to 12 hours {02}3.

Elimination: Approximately 1 week after a single dose; however, the effective half-life is 20 to 60 hours (mean, about 40 hours) {02}2 {02}1. The half-life is 37 to 89 hours for the R-enantiomer and 21 to 43 hours for the S-enantiomer {02}0 {03}9.


Onset of action:


Anisindione:

Effect on prothrombin time (PT): Prolonged, within 6 hours, to 50% of baseline prothrombin activity; prothrombin activity decreases slowly thereafter {03}8.



Dicumarol:

Induction of hypoprothrombinemia: 36 to 48 hours {03}7.

Effect on PT: 1 to 5 days {03}6.



Warfarin (oral):

Effect on PT: Within 24 hours {03}5 {03}4.


Note: Full therapeutic action is delayed until circulating coagulation factors are removed by normal catabolism, which occurs at different rates for each factor {03}3. Although PT may be prolonged when factor VII (which has the shortest half-life) is depleted, it is believed that peak antithrombotic effects are not achieved until all four factors are removed {03}2.
Prolonged PT may reflect early depletion of factor VII rather than peak antithrombotic effects {03}1. Use of an initial loading dose might also produce this effect; however, loading doses currently are not recommended.


Time to peak plasma concentration

Acenocoumarol—Within 1 to 3 hours {03}0.

Dicumarol—1 to 9 hours {14}9.

Warfarin—Oral: Within 4 hours {14}8.

Peak plasma concentration

Acenocoumarol—Following a single dose of 10 mg: 0.3 mcg per mL {14}7. Both peak plasma concentrations and areas under the concentration-time curve (AUCs) are proportional to the size of the dose over a range of 8 to 16 mg {14}6.

Note: Because plasma concentrations achieved are variable among patients, there is no direct correlation between plasma concentration and effect on PT {14}5.


Time to peak effect:


Effect on PT:

Acenocoumarol: 36 to 48 hours {14}4.

Anisindione: 48 to 72 hours, to 15 to 30% of baseline {14}3.

Warfarin: Oral or intravenous—72 to 96 hours {14}2 {14}1 {14}0.


Duration of action:

Acenocoumarol: Within 48 hours {33}9 {33}8.

Anisindione: 1 to 3 days {33}7.

Dicumarol: 5 to 6 days {33}6.

Warfarin: Single dose—2 to 5 days {33}5 {33}4 {33}3.

Elimination:
    Primarily renal, almost entirely as metabolites {33}2 {33}1 {33}0 {14}9, and to a lesser extent biliary {14}8.

• Acenocoumarol—

• Renal, 60% {14}7.


• Fecal, 29% {14}6.



• Warfarin—

• Renal, up to 92% {14}5.



• In dialysis—

• Half-life of warfarin is significantly decreased in hemodialysis {14}4.




Precautions to Consider

Carcinogenicity

Anisindione: Long-term studies have not been done {14}3.

Warfarin: Studies have not been done {14}2 {14}1.

Mutagenicity

Anisindione: No information is available {14}0.

Warfarin: Studies have not been done {14}9 {14}8.

Pregnancy/Reproduction

Pregnancy—
Coumarin- and indanedione-derivative anticoagulants cross the placenta {14}7 {14}6. Concentrations of warfarin in fetal plasma are nearly as high as maternal concentrations {14}5.

Congenital malformations have been reported in infants of mothers who took warfarin during the first trimester, including a syndrome characterized by severe nasal hypoplasia {14}4 {14}3 {14}2 {14}1 {14}0 and stippled epiphyseal calcifications that resemble chondrodysplasia punctata {33}9 {33}8 {33}7 {33}6, as well as central nervous system (CNS) abnormalities, including dorsal midline dysplasia (characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy), and ventral midline dysplasia (characterized by optic atrophy) {33}5. Mental retardation, blindness, and other CNS abnormalities have been reported in infants born to mothers taking these agents during the second and third trimesters {33}4 {33}3 {33}2. Other rare teratogenic effects include urinary tract anomalies, such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly {33}1 {33}0.

Spontaneous abortion and stillbirth have occurred, as well as low birth weight and growth retardation {01}9. In addition, fetal or neonatal hemorrhage {01}8 {01}7 {01}6 {01}5, fetal death from hemorrhage in utero {01}4 {01}3, and increased risk of maternal hemorrhage {01}2 during the second and third trimesters have been reported. There is some evidence that embryopathy occurs only with oral anticoagulant administration between the 6th and 12th weeks of gestation {01}1 {01}0.

The polymorphism in the factor V gene, known as factor V Leiden, that causes activated protein C resistance to anticoagulant therapy is associated with an increased incidence of venous thrombosis cases during pregnancy {01}9 {01}8 {01}7 {01}6 {01}5. Pregnancy is considered a high-risk state, and anticoagulant treatment should be adjusted accordingly, when these genetic factors are present {01}4 {01}3.

In general, clinicians recommend that coumarin- or indanedione-derivative anticoagulants not be used at any time during pregnancy {01}2 {01}1 {01}0 {22}9. Women of childbearing potential should be informed of the risks of becoming pregnant while receiving a coumarin or indanedione derivative {22}8. If the patient becomes pregnant during anticoagulant therapy, the possibility of termination of the pregnancy may be considered {22}7.

If an anticoagulant is required during pregnancy, heparin may be preferred because it does not cross the placenta {22}6. For patients receiving a coumarin or indanedione derivative who wish to become pregnant, some clinicians recommend conversion to heparin therapy prior to conception, while others recommend careful monitoring of the patient and conversion to heparin as soon as pregnancy is confirmed {22}5.

Anisindione: FDA Pregnancy Category X {22}4.

Warfarin: FDA Pregnancy Category X {22}3 {22}2.


Labor and delivery—

If a coumarin or indanedione derivative is used during the third trimester, it should be discontinued after the 37th week of gestation {22}1, and heparin substituted if maternal anticoagulation is required {22}0, to reduce the risk of fetal hemorrhage during labor and of neonatal hemorrhage following delivery. Anticoagulants also increase the risk of maternal hemorrhage during or following delivery {48}9. Anticoagulant therapy may be reinstated 5 to 7 days postpartum {48}8.

Postpartum —
Administration of anticoagulants in the immediate postpartum period may increase the risk of maternal hemorrhage {48}7.

Breast-feeding

Acenocoumarol is distributed into breast milk, but in quantities that are too small for detection {48}6.

Warfarin is distributed into breast milk only in its inactive form {48}5 {48}4; studies in infants who were breast-fed while their mothers were taking warfarin did not find any effect on prothrombin time (PT) {48}3 {48}2 {48}1.

Pediatrics

Safety and efficacy of warfarin in children younger than 18 years of age have not been established in randomized, controlled clinical trials {48}0, although such trials are currently being conducted {03}9. However, use of warfarin in children is well documented for prophylaxis and treatment of thromboembolism {03}8 {03}7 {03}6 {03}5.

Infants, especially neonates, may be more susceptible to the effects of anticoagulants because of vitamin K deficiency {03}4 {03}3. Levels of vitamin K–dependent coagulant factors and inhibitors at birth are approximately 50% of those in adults, similar to the level in adults receiving oral anticoagulant therapy {03}2 {03}1. Levels of vitamin K–dependent proteins increase rapidly after the neonatal period, to within the adult range by the age of 6 months, but average values are approximatley 20% below adult values until the late teenage years {03}0 {05}9. As a result, there is a possibility that the optimal goal of the international normalized ratio (INR) for anticoagulant therapy will be lower in children than in adults {05}8 {05}7.

Breast-fed infants are very sensitive to oral anticoagulants because of the low concentrations of vitamin K in breast milk. Some children are resistant to oral anticoagulant effects because of impaired absorption, use of total parenteral nutrition, or use of nutrient formulas supplemented with vitamin K {05}6 {05}5.

Because there have been reports of difficulty in achieving and maintaining therapeutic PT/INR ranges in pediatric patients, more frequent monitoring is recommended {05}4 {05}3 {05}2 {05}1.

Studies in animals suggest that anticoagulants given during periods of rapid bone growth (i.e., mainly in children) {05}0 {01}9 {01}8 might cause bone abnormalities similar to those that occur in infants whose mothers received anticoagulants during pregnancy (hypoplasia of the nasal bridge and distal phalanges and excessive irregular calcifications in epiphyses and vertebrae) {01}7 {01}6. Studies in humans have not been done {01}5 {01}4.


Geriatrics


Geriatric patients may be more susceptible to the effects of anticoagulants, increasing the risk of hemorrhage {01}3 {01}2. Geriatric patients may have advanced vascular disease that alters hemostatic mechanisms, hepatic function impairment that decreases procoagulant factor synthesis or anticoagulant metabolism {01}1, or they may have renal function impairment {01}0. Lower maintenance doses than those usually recommended for adults may be required for these patients {02}9.

Warfarin—Although there are no age-related differences in pharmacokinetics of racemic warfarin, there is some evidence of a slight decrease in clearance of the R-enantiomer in elderly patients. In addition, elderly patients (60 years of age and over) appear to be more sensitive to the PT/INR effects of warfarin {02}8.


Pharmacogenetics

Certain hereditary or familial conditions that predispose an individual to thrombosis may affect indications for, as well as dose and duration of, anticoagulant therapy {02}7 {02}6. These may include factor V Leiden (a polymorphism in the factor V gene) or a prothrombin gene mutation {02}5, which causes activated protein C resistance, deficiency of protein C or S, deficiency of antithrombin III, hyperhomocysteinemia, and dysfibrinogenemia {02}4 {02}3 {02}2. A study has confirmed a strong association between multiple genetic defects and the risk of venous thrombosis {02}1 {02}0. In addition, patients with hereditary or familial protein C deficiency may be at increased risk of development of skin or tissue necrosis {17}9 {17}8 {17}7 {17}6.

Heterozygosity for the factor V Leiden mutation is between 1 and 8.5% in Causasians (including European) {17}5 {17}4, Jewish, Israeli Arab, and Indian populations, but does not appear to occur in African Blacks, Chinese, Japanese, or Native American populations {17}3. Incidence of the prothrombin gene mutations (G to A transversion of position 20210 in the 3´-untranslated region) has been reported to be 2% in the Netherlands {17}2.

Some patients exhibit resistance to anticoagulant therapy because of genetic variations in the vitamin K receptor site {17}1 {17}0. Doses much higher than those usually recommended may be required to achieve successful anticoagulation in these patients.


Dental

Bleeding from gingival tissue may occur in anticoagulated patients {17}9.

Anticoagulant therapy increases the risk of localized hemorrhage during and following oral surgical procedures. Consultation with the prescribing physician may be advisable prior to oral surgery, to determine whether a temporary dosage reduction or withdrawal of anticoagulant therapy is feasible. Also, local measures to minimize bleeding should be used at the time of surgery. {17}8

Surgical

Careful monitoring and dosage adjustment are required because interruption of anticoagulant therapy may precipitate thromboembolism {17}7, while continuation of full-dose therapy is associated with a risk of hemorrhage {17}6. It is recommended that the operative site be sufficiently limited to permit effective use of local procedures for hemostasis (including absorbable hemostatic agents, sutures, and pressure dressings) if necessary {17}5.

A severe elevation (more than 50 seconds) in activated partial thromboplastin time (aPTT), with PT/INR in the desired range, may be an indication of increased risk of postoperative hemorrhage {17}4.

Drug interactions and/or related problems
The interactions between anticoagulants and other specific medications are complex and sometimes multiple or conflicting, and may vary depending on dose, duration, intermittent versus chronic use, and other factors {17}3. The use of multiple medications with additive or conflicting effects further complicates prediction of the effect. Therefore, the net effect may be unpredictable {17}2 {17}1 {17}0. Decisions regarding dosage adjustment of the anticoagulant should be based on prothrombin time (PT) and/or international normalized ratio (INR) determinations {03}9 {03}8 whenever possible. However, it is important to keep in mind that some medications may increase the risk of bleeding without affecting the PT.

Some medication effects that may increase the risk of bleeding during anticoagulant therapy but that are not associated with an increase in PT include inhibition of platelet aggregation, inhibition of platelet formation, hypoprothrombinemia, effects on vascular integrity, gastrointestinal ulceration or hemorrhage, thrombocytopenia, and direct anticoagulant effects. {03}7

Clinical effects from an interaction may be apparent immediately or may take several days or weeks to appear {03}6. The strength of the effect of interacting medications may be related to a number of factors, including dose, duration of therapy, and even relative effect on the S- or R-isomer of warfarin {03}5 {03}4. The significance and duration of effect also depend on the type of interaction; for example, displacement from plasma protein binding will produce an initial increase in anticoagulant concentration, but a new equilibrium is established within a few days, so the effect is of limited significance {03}3 {03}2.

Only brief information about documented interactions between anticoagulants and other medications has been provided in this monograph. In addition, information regarding the potential mechanism of the interactions is frequently conflicting and incomplete. For additional information about the interactions listed below, please refer to the corresponding USP DI monograph and/or the medical literature.

In addition to the listed interactions, there is a possibility that the risk of hemorrhage may be increased by concurrent use of any medication that may inhibit platelet aggregation or cause hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration. Conversely, there is a possibility that medications that promote blood clotting may interfere with the anticoagulant effect.

Because of the possible serious consequences of interference with anticoagulant therapy, increased monitoring of the PT/INR {03}1 is recommended on addition, dosage change, or withdrawal of any medication from the regimen of a patient stabilized on a coumarin or indanedione derivative, or if the dosage of a concurrently used medication is changed. Anticoagulant dosage must be adjusted as necessary to prevent hemorrhage or loss of effect. Also, substantial alteration of initial anticoagulant dosage may be necessary when anticoagulant therapy is initiated in a patient receiving a medication known to cause significant alteration of anticoagulant effect. {03}0

The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance).

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen, chronic high-dose usage    (effects of anticoagulants may be increased {09}9 {09}8 {09}7 {09}6 {09}5 {09}4; this effect is unlikely to occur with occasional use or chronic use of less than 2 grams of acetaminophen per day {09}3)


Alcohol, acute intoxication    (effects of anticoagulants may be increased {09}2 {09}1 {09}0 {17}9 {17}8 because of inhibition of hepatic metabolism; other acute effects of alcohol on the liver may also be involved)


Alcohol, chronic abuse    (effects of anticoagulants may be decreased {17}7 {17}6 {17}5 {17}4 {17}3 {17}2 because of accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzyme activity {17}1 {17}0 {03}9; however, increased activity is also possible in advance hepatic cirrhosis {03}8 {03}7 {03}6)


Allopurinol    (effects of anticoagulants may be increased {03}5 {03}4 {03}3 {03}2 {03}1 {03}0 {04}9 because of inhibition of hepatic metabolism)


» Amiodarone    (effects of anticoagulants may be increased {04}8 {04}7 {04}6 {04}5 {04}4 {04}3 {04}2 {04}1, possibly because of inhibition of hepatic metabolism {04}0 {03}9; potentiation is reported to occur within 3 to 4 weeks after initiation of amiodarone therapy and persists up to 4 months following withdrawal of amiodarone {03}8)


» Anabolic steroids {03}7 {03}6 {03}5 {03}4 {03}3 {03}2 {03}1 {03}0 , especially 17-alpha-alkylated compounds {04}9 , or
» Androgens {04}8 {04}7 or
» Danazol {04}6 {04}5 {04}4    (effects of anticoagulants are increased within 2 to 3 days; dosage reduction of the anticoagulant may be necessary {04}3)


Anesthetics, inhalation    (effects of anticoagulants may be increased {04}2 {04}1 {04}0)


Antibiotics (see also individual antibiotic entries)    (theoretically, effects of anticoagulants may be increased because of decreased vitamin K synthesis secondary to alterations in intestinal flora {23}9 {23}8 {23}7 {23}6 {23}5 {23}4 {23}3 {23}2 {23}1; however, significant potentiation is very rare if dietary intake of vitamin K is adequate {23}0 {33}9)


Anticonvulsants, hydantoin    (effects of anticoagulants may be increased because of displacement of anticoagulant from protein binding sites {33}8 {33}7 {33}6 {33}5 {33}4 {33}3 {33}2 {33}1)

    (effects of anticoagulants may be decreased with continued concurrent use because of accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzyme activity {33}0 {08}9 {08}8 {08}7 {08}6 {08}5)

    (hepatic metabolism of hydantoin anticonvulsants, especially phenytoin, may be decreased, leading to increased anticonvulsant plasma concentrations, half-life, and risk of toxicity {08}4 {08}3 {08}2 {08}1)


Antidiabetic agents, sulfonylurea, including glimepiride {08}0    (effects of anticoagulants may be increased {23}9 {23}8 {23}7 {23}6 {23}5 initially because of displacement of anticoagulant from protein binding sites)

    (hepatic metabolism of the antidiabetic agent may be decreased, especially by dicumarol, leading to increased plasma concentration and half-life, hypoglycemic effect, and risk of toxicity of the antidiabetic agent {23}4 {23}3 {23}2 {23}1)


» Antifungals, azole    (effects of anticoagulants may be increased {23}0 {33}9 {33}8 {33}7 {33}6 {33}5 {33}4 {33}3)


» Anti-inflammatory drugs, nonsteroidal (NSAIDs)    (effects of anticoagulants may be increased {33}2 {33}1 {33}0 {36}9 {36}8 {36}7 {36}6 {36}5 {36}4 {36}3 because of displacement of anticoagulant from protein binding {36}2 sites by fenoprofen, indomethacin, meclofenamate, mefenamic acid, phenylbutazone, or sulindac, and possibly other NSAIDs {36}1; in addition, phenylbutazone may inhibit hepatic metabolism of the anticoagulant {36}0 {41}9)

    (inhibition of platelet aggregation by NSAIDs {41}8 {41}7 [except meclofenamate and mefenamic acid] may result in increased risk of hemorrhage; risk of gastrointestinal ulceration and hemorrhage caused by NSAIDs may be increased {41}6 {41}5 {41}4; these effects cannot be shown by measurement of PT)


Antineoplastics {41}3 or
Radiation therapy, recent {41}2    (the effect of individual agents is difficult to predict because of the common use of combination therapy {41}1; mechanisms for the observed effects generally have not been determined)

    (effects of anticoagulants may be increased or decreased by cyclophosphamide {41}0 {33}9 or mercaptopurine {33}8)

    (effects of anticoagulants may be increased by bicalutamide {33}7, etoposide {33}6, flutamide {33}5 {33}4 {33}3, fluorouracil {33}2 {33}1 {33}0, ifosfamide {11}9 {11}8 {11}7 {11}6, methotrexate {11}5, nilutamide {11}4, tamoxifen {11}3 {11}2 {11}1 {11}0 {47}9, and vindesine {47}8)

    (effects of anticoagulants may be decreased by aminoglutethimide {47}7 {47}6 {47}5 {47}4, which may induce hepatic enzymes {47}3 {47}2 {47}1)

    (antineoplastics that cause thrombocytopenia may also increase the risk of bleeding [see also Thrombocytopenia-causing medications])

    (imbalances in coagulation factors have been noted with the use of pegaspargase, predisposing the patient to bleeding and/or thrombosis {47}0; caution should be used when administering any concurrent anticoagulant therapy {90}9; it has also been suggested that blood coagulation factor XIII participates in the cross-linking between fibrins and between fibrin and asparaginase)


» Antithyroid agents    (effects of anticoagulants may be increased paradoxically {90}8 {90}7 {90}6 because of decreased hepatic synthesis of procoagulant factors; this effect may depend on antithyroid dosage and subsequent thyroid status of the patient {90}5)


» Cephalosporins, second- and third-generation    (effects of anticoagulants may be increased {90}4 {90}3 {90}2 because of decreased vitamin K synthesis {90}1 {90}0)

    (concurrent use of anticoagulants with cefamandole, cefmetazole, cefoperazone, or cefotetan may increase the risk of bleeding {03}9 because the N-methylthiotetrazole [NMTT] side chain on these medications may inhibit the metabolism of anticoagulants {03}8; however, critical illness, poor nutritional status, and the presence of liver disease may be more important risk factors for hypoprothrombinemia and bleeding {03}7)


Chloral hydrate    (initially, effects of anticoagulants may be increased {03}6 {03}5 {03}4 because of displacement of anticoagulant from protein binding sites {03}3 {03}2 {03}1 {03}0 {04}9 {04}8; however, with continued use, anticoagulant activity may return to baseline level or be decreased as a new equilibrium warfarin concentration is established {04}7 {04}6 {04}5 {04}4 {04}3)


Chloramphenicol    (effects of anticoagulants may be increased {04}2 {04}1 {04}0 because of inhibition of hepatic metabolism)


Cholestyramine    (effects of anticoagulants may be decreased {03}9 {03}8 {03}7 {03}6 {03}5 {03}4 {03}3 {03}2 {03}1 because of decreased absorption from the gastrointestinal tract {03}0 {04}9 and interference with enterohepatic circulation {04}8)

    (effects of anticoagulants may be increased {04}7 {04}6 {04}5 {04}4 {04}3 because of decreased vitamin K absorption or synthesis {04}2)


» Cimetidine    (effects of anticoagulants may be increased {04}1 {04}0 {03}9 {03}8 {03}7 {03}6 {03}5 {03}4 {03}3 because of inhibition of hepatic metabolism )


» Cinchophen    (effects of anticoagulants may be increased {03}2 {03}1 {03}0 {06}9)


Cisapride    (effects of acenocoumarol may be increased because of increased absorption from the gastrointestinal tract {06}8)


» Clofibrate    (effects of anticoagulants may be increased {06}7 {06}6 {06}5 {06}4 {06}3 {06}2 {06}1 {06}0 {03}9 {03}8, possibly because of alteration of procoagulant factor synthesis or catabolism {03}7 or displacement of anticoagulant from protein binding sites {03}6)


Corticosteroids, glucocorticoid, or
Corticotropin    (effects of anticoagulants may be increased {03}5 {03}4 {03}3 or decreased {03}2 {03}1 {03}0 {06}9 {06}8 {06}7 by an unknown mechanism)


» Dextrothyroxine    (effects of anticoagulants may be increased {06}6 {06}5 {06}4 {06}3 {06}2 because of alteration of procoagulant factor synthesis or catabolism and increased receptor affinity for the anticoagulant; this effect may depend on the thyroid status of the patient)


» Diflunisal    (effects of anticoagulants may be increased {06}1 {06}0 {03}9, possibly in part because of displacement of anticoagulant from protein binding sites {03}8)


Disopyramide    (effects of anticoagulants may be increased {03}7 {03}6 {03}5 {03}4 or decreased {03}3 {03}2 by an unknown mechanism)


» Disulfiram    (effects of anticoagulants may be increased {03}1 {03}0 {06}9 {06}8 {06}7 {06}6 {06}5 {06}4 {06}3; disulfiram may act in the liver to directly increase the hypoprothrombinemia-inducing activity of coumarin derivatives {06}2)


Diuretics    (effects of anticoagulants may be decreased {06}1 {06}0 {03}9 {03}8 {03}7 {03}6 because of reduction of plasma volume leading to concentration of procoagulant factors in the blood {03}5)

    (effects of anticoagulants may be increased by ethacrynic acid {03}4 {03}3 {03}2 {03}1 {03}0 {06}9, possibly in part because of displacement of anticoagulant from protein binding sites; clinical significance has not been determined)


Erythromycins    (effects of anticoagulants may be increased {06}8 {06}7 {06}6 because of inhibition of enzymatic metabolism)


Estrogens    (effects of anticoagulants may be decreased because of increased hepatic synthesis of procoagulant factors {06}5)

    (use of estrogens in patients with thrombophilic disorders tends to increase the risk of thrombosis, especially in patients with activated protein C resistance due to factor V Leiden mutation {06}4 {06}3)


Estrogens and progestins (oral contraceptives)    (effects of anticoagulants may be decreased {06}2 {06}1 {06}0 {03}9 because of increased hepatic synthesis of procoagulant factors by estrogens; however, increased effects have also been reported {03}8)

    (use of estrogen-containing oral contraceptives in patients with thrombophilic disorders tends to increase the risk of thrombosis, especially in patients with activated protein C resistance due to factor V Leiden mutation {03}7 {03}6)


Ethchlorvynol    (effects of anticoagulants may be decreased {03}5 {03}4 {03}3 {03}2 {03}1 {03}0 {06}9 because of accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzyme activity)


Fluoroquinolones    (effects of anticoagulants may be increased {06}8 {06}7 {06}6)


Fluoxetine    (effects of anticoagulants may be increased {06}5 {06}4, possibly in part because of displacement of anticoagulant from protein binding sites)


» Fluvoxamine {06}3 {06}2 {06}1    (concurrent use with warfarin for 2 weeks resulted in warfarin plasma concentration increases of up to 98% and prolonged prothrombin time)


Gemfibrozil    (effects of anticoagulants may be increased {06}0 because of inhibition of hepatic metabolism)


Glucagon    (effects of anticoagulants may be increased {03}9 {03}8 {03}7 {03}6 {03}5 {03}4; however, dosage reduction of warfarin is recommended only with glucagon doses above 25 mg per day for 2 or more days {03}3, which are rarely, if ever, used)


» Glutethimide    (effects of anticoagulants may be decreased {03}2 {03}1 {03}0 {08}9 {08}8 {08}7 because of accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzyme activity {08}6 {08}5)


» Griseofulvin    (effects of anticoagulants may be decreased {08}4 {08}3 {08}2 {08}1 {08}0 {08}9 {08}8 because of accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzyme activity {08}7)


Heparin {08}6 {08}5 or
Heparin, low-density, including:
Ardeparin {08}4
Dalteparin {08}3
Danaparoid {08}2
Enoxaparin {08}1    (the anticoagulant activity of heparin or low-density heparins may result in an increased risk of hemorrhage; low-density heparins and low doses of heparin do not prolong PT {08}0 {58} {59})

    (heparin may prolong PT when it is given as an intravenous bolus or if full therapeutic doses are given subcutaneously; to minimize problems, it is recommended that blood for the PT test be drawn just prior to, or 5 hours after, the intravenous bolus dose or 24 hours of subcutaneous injection of a full therapeutic dose of heparin {01} {02} {03} {05})


» Hepatic enzyme inducers (see Appendix II )    (effects of anticoagulants may be decreased {01} {02} {03} {05} {08} {09} {10} {33} {82} because of induction of hepatic microsomal enzymes; the effect of primidone may be caused by a barbiturate metabolite )


Hepatotoxic medications    (effects of anticoagulants may be increased {01} {02} {03} because of slow metabolism and impaired synthesis of clotting factors)


HMG-CoA reductase inhibitors    (concurrent use has been reported to increase bleeding and/or PT {03} {09} {10} {17} {60} {61} {62} {63})


Influenza virus vaccine    (effects of anticoagulants have been reported to be increased {01} {02} {03} {09} {10} {17} {33}; however, recent studies have failed to show a significant impact of influenza virus vaccine on the laboratory or clinical effect of warfarin {09}, and patients taking these medications can be vaccinated safely without special precautions or monitoring {84})


Intrauterine devices (IUDs), copper {64} or progesterone    (administration of anticoagulants during IUD use may increase the risk of abnormal uterine bleeding and anemia secondary to menorrhagia and/or hypermenorrhea {64}; the risk of abnormal uterine bleeding increases around the time of IUD insertion and lessens with continued use, although spotting may persist)


Isoniazid    (effects of anticoagulants may be increased {10} {17} {33} {86} because of inhibition of hepatic metabolism)


» Lepirudin    (effects of anticoagulants may be increased; gradual reduction in dose and/or infusion rate of lepirudin is recommended prior to switching to an oral anticoagulant {80})


» Metronidazole    (effects of anticoagulants may be increased {01} {02} {03} {05} {08} {09} {10} {17} {33} {86} because of inhibition of hepatic metabolism {10} {33})


Nalidixic acid    (effects of anticoagulants may be increased {01} {02} {03} {05} {09} {10} {33}, possibly in part because of displacement of anticoagulant from protein binding sites )


Olsalazine    (may increase the PT {03})


» Omeprazole    (inhibition of the cytochrome P450 enzyme system by omeprazole, especially in high doses, may cause a decrease in hepatic metabolism of anticoagulants, which may result in delayed elimination and increased blood concentrations {03} {17} {66} {86})


Opioid (narcotic) analgesics    (effects of anticoagulants may be increased with prolonged use {01} {02} {03} {10} {17} {33})


» Paroxetine    (a pharmacodynamic interaction may occur that causes an increased bleeding diathesis despite unaltered PT {03} {67}; since there is little clinical experience, caution is advised when these agents are used concomitantly)


Penicillins    (inhibition of platelet aggregation by high-dose parenteral penicillins may result in increased risk of hemorrhage {03} {10}; this effect cannot be shown by measurement of PT)

    (dicloxacillin and nafcillin may decrease {03} {08} {10} {17} {33} the effects of anticoagulants by inducing hepatic enzymes {10} {33})


Pentosan    (because pentosan has weak anticoagulant activity, the risk of hemorrhage may be increased {77})


Pentoxifylline    (pentoxifylline inhibits platelet aggregation and has also caused prolongation of PT and bleeding {69}; concurrent use with any of these medications may increase {01} {02} {03} {69} the risk of bleeding because of additive interference with blood clotting)


» Platelet aggregation inhibitors    (effects of anticoagulants may be increased {01} {02} {03} {05} {08} {10}; the effect will not be reflected in PT)


» Plicamycin {89}    (effects of anticoagulants may be increased because of plicamycin's hypoprothrombinemic effect)

    (interference with platelet formation by plicamycin may result in increased risk of hemorrhage; this effect cannot be shown by measurement of PT)


» Propafenone    (concurrent use results in a significant increase [approximately 39%] in mean steady-state warfarin plasma concentrations, with a corresponding increase in PT of approximately 25% {03} {10} {17} {70} {86})


Propranolol    (effects of anticoagulants may be increased {09} {17} {33} {86})


» Quinidine    (effects of anticoagulants may be increased {01} {02} {03} {05} {09} {10} {17} {33} because of alteration of procoagulant factor synthesis {10}; however, decreased anticoagulant effect has also been reported {09} {10})


Quinine    (effects of anticoagulants may be increased {01} {02} {03} {05} {09} {10} because of decreased hepatic synthesis of procoagulant factors)


Repaglinide    (effects of anticoagulants may be increased because of displacement from plasma protein-binding sites {81})


Rifabutin    (rifampin is structurally related to rifabutin; rifampin is know to decrease the activity of many drugs due to its hepatic enzyme–inducing properties; rifabutin appears to be a less potent enzyme inducer of the hepatic cytochrome P450 system than rifampin; drug interactions data are unavailable for rifabutin itself; therefore, it is recommended that patients taking rifabutin concurrently with anticoagulants be monitored since the significance of possible drug interactions is not known {71})


» Salicylates, including bismuth subsalicylate {55}    (effects of anticoagulants may be increased {01} {02} {03} {09} {10} {33} {55} because of the hypoprothrombinemic effect [with large doses] {01} {10})

    (inhibition of platelet aggregation by aspirin {10} may result in increased risk of hemorrhage; risk of gastrointestinal ulceration or hemorrhage caused by salicylates may be increased {10} {33}; these effects cannot be shown by measurement of PT )


» Sertraline    (caution in concurrent use with anticoagulants is recommended because of possible displacement of either medication from protein-binding sites, leading to increased plasma concentrations of the free [unbound] medications and increased {03} {72} risk of adverse effects)


Smoking, tobacco    (effects of anticoagulants may be decreased {09} {33} because of accelerated metabolism of the anticoagulant secondary to stimulation of hepatic microsomal enzyme activity {33})


Sucralfate    (effects of anticoagulants may be decreased {03} {09} {10} {17} {33} {86})


» Sulfapyridine {87} or
» Sulfasalazine {88}    (anticoagulants may be displaced from protein-binding sites and/or metabolism may be inhibited by sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy)


» Sulfinpyrazone    (effects of anticoagulants may be increased {01} {02} {05} {08} {09} {10} {17} {33} {86} because of inhibition of hepatic metabolism {09} {10} {33} and displacement of the anticoagulant from protein-binding sites {08} {10}; a biphasic response, with decreased anticoagulation occurring following initial potentiation, has been reported {10} {33} {86}; the reason for the effect is unclear since other reports indicate only potentiation of the anticoagulant effect {10})

    (inhibition of platelet aggregation by sulfinpyrazone may result in increased risk of hemorrhage {09}; risk of gastrointestinal ulceration or hemorrhage caused by sulfinpyrazone may be increased; these effects cannot be shown by measurement of PT)


Sulfonamides, long-acting, including co-trimoxazole {17} {86}    (effects of anticoagulants may be increased {01} {02} {03} {05} {09} {10} {17} {33}, possibly in part because of displacement of anticoagulant from protein-binding sites)


Tamsulosin    (caution is recommended when used with warfarin because of inconclusive results from in vitro and in vivo studies {78})


» Thrombocytopenia-causing medications    (effects of anticoagulants may be increased {01} {02})


» Thrombolytic agents    (thrombolytic effect may lead to hemorrhage {01} {03}; concurrent use is not recommended {14}, although sequential use may be indicated {08})

    (anticoagulants are recommended to prevent additional thrombus formation following thrombolytic therapy for most indications {08}; however, following intravenous thrombolytic therapy for acute coronary arterial occlusion, the need for anticoagulant administration should be determined on an individual basis; if an anticoagulant is administered under these circumstances, careful monitoring of the patient is recommended because of the risk of hemorrhage )


» Thyroid hormones    (effects of anticoagulants may be increased {01} {02} {03} {05} {09} {33} because of alteration of procoagulant factor synthesis or catabolism {09} {33} and increased receptor affinity for anticoagulant; this effect may depend upon dosage and subsequent thyroid status of the patient)


» Ticlopidine    (the possibility of additive effects on blood clotting mechanism leading to an increased risk of bleeding cannot be discounted {03}; particularly careful clinical monitoring of the patient is recommended if concurrent use is necessary)

    (in one study, concurrent administration of warfarin and ticlopidine was associated with an increased risk of medication-induced cholestatic hepatitis {03} {10})


Valproic acid or
Divalproex    (effects of anticoagulants may be increased by valproic acid {03} because of decreased hepatic synthesis of procoagulant factors)

    (inhibition of platelet aggregation by divalproex or valproic acid may result in increased risk of hemorrhage; this effect cannot be shown by measurement of PT)


Vitamin E    (effects of anticoagulants may be increased {03} {09} {10} {16} with concurrent use of high doses of vitamin E {10})


» Vitamin K    (effects of anticoagulants may be decreased {03} {08} {09} {10} {17} because of increased hepatic synthesis of procoagulant factors; increased vitamin K intake can occur during weight-reduction diets high in green vegetables, certain vegetable oils, or vitamin K–containing supplements {16} {17} {33} {86})


» Zafirlukast    (the concurrent use of a single 25-mg warfarin dose with multiple doses of zafirlukast resulted in an increase of approximately 35% in the mean PT, due to an inhibition of the cytochrome P450 2C9 isoenzyme {03} {73})


» Zileuton    (concurrent administration of zileuton and warfarin results in a clinically significant increase in the PT {03} {79})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Urinalysis, spectrophotometric {01}    (tests based on color changes may be interfered with because alkaline urine may turn red-orange following administration of anisindione {01}; acidification of the urine to pH 4 eliminates this color {01})

Activated partial thromboplastin time (aPTT)    (may be increased by warfarin, even in the absence of heparin, but interference with heparin anticoagulation during initial combined therapy is of minimal clinical significance {03})


Hepatic enzyme values    (may rarely be increased {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: Many of the conditions listed below are common risk factors that underlie the condition for which the anticoagulant therapy is indicated. The relative effect on the decision to prescribe anticoagulants depends on the specific condition for which anticoagulant therapy is being contemplated. Decisions about whether to use anticoagulants should balance the risk of hemorrhage associated with the condition against the potential clinical benefit of anticoagulant therapy. {02}
For conditions that alter the PT, careful monitoring of PT and/or international normalized ratio (INR) and appropriate adjustment of anticoagulant dose are recommended. For conditions in which the effect on bleeding may not be reflected in the PT/INR, careful monitoring of the patient for indications of bleeding is recommended.
The presence of multliple underlying conditions with additive or conflicting effects may complicate prediction of the effect on response to the anticoagulant. The net effect may be unpredictable {03}. Decisions regarding dosage adjustment of the anticoagulant should be based on PT/INR determinations and observation for possible bleeding {03}.
A strong association has been found between single or multiple genetic defects (e.g., factor V Leiden, prothrombin mutation, antithrombin III deficiency) and risk of thrombosis {13} {15}, which indicates that one or more of these defects may be present in individuals with thrombophilic conditions. However, these effects may also be subclinical and patients may be asymptomatic until their first thrombotic event {14} {15}.
In addition to the specific conditions listed below, caution is recommended with use of anticoagulants in any condition associated with a risk of hemorrhage, necrosis, and/or gangrene {02} {03}.


Except under special circumstances, these medications should not be used when the following medical problems exist:
» Abortion, threatened or incomplete {01} {03}    (increased risk of uncontrollable hemorrhage)


» Aneurysm, cerebral or dissecting aorta {01} {02} {03}    (increased risk of uncontrollable hemorrhage)


» Bleeding, active {01}    (increased risk of uncontrollable hemorrhage)


» Blood dyscrasias, hemorrhagic, such as:
Thrombocytopenia {01} {02} {03} {15} or
» Hemophilia {01} or
» Hemorrhagic tendency, other {01} {02} {03} , including:
Leukemia {01}
Polycythemia vera {01} {02} {03}
Purpura {01}    (increased risk of hemorrhage)

    (in patients with heparin-induced thrombocytopenia, cases of venous limb ischemia, necrosis, and gangrene have occurred when heparin therapy was discontinued and warfarin therapy initiated {03}; sequelae have included amputation of the involved area and/or death {03})


» Cerebrovascular hemorrhage, confirmed or suspected {01} {02} {03}    (increased risk of uncontrollable hemorrhage)


» Eclampsia or pre-eclampsia {01} {02} {03}    (increased risk of hemorrhage)


» Hypertension, severe uncontrolled and/or malignant {01} {02} {03}    (increased risk of cerebral hemorrhage)


» Neurosurgery, recent or contemplated {01} {02} {03} or
» Ophthalmic surgery, recent or contemplated {01} {02} {03} or
» Surgery, major, other, especially if resulting in large open surfaces {02} {03}    (increased risk of uncontrollable hemorrhage)

    (although anticoagulants are generally contraindicated following major surgery, they may be required following orthopedic (hip) surgery to reduce the risk of thromboembolism {08})


» Pericardial effusion {01} {02} {03} or
» Pericarditis {01} {02} {03}    (increased risk of severe hemorrhagic pericardial effusions and pericardial tamponade)


Risk-benefit should be considered when the following medical problems exist
Allergic or anaphylactic disorders, severe {02}
Antiphospholipid syndrome {03} {13} {15} or
Antithrombin III deficiency {13} {14} {15}    (may reduce the effectiveness of the anticoagulant)


Biliary fistula {01}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


Cancer, especially gastrointestinal {02} {03} {13} {15} {33}    (venous thrombosis associated with cancer may be resistant to anticoagulant therapy {13})


» Carcinoma, visceral {01} {02}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


» Childbirth, recent {02}    (increased risk of hemorrhage)


Collagen vascular disease {02} {03}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


Conditions that may result in less compliance by unsupervised outpatients {01} , such as:
Alcoholism, active {02} {03}
Emotional instability
Psychosis, unsupervised {02} {03}
Senility, unsupervised {02} {03}
Uncooperative patient {02} {03}
Congestive heart failure {01} {02} {03} {08} {15}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


Coumarin resistance, hereditary {03}    (response to coumarin anticoagulants may be decreased)


» Diabetes mellitus, severe {02} {03}    (increased risk of hemorrhage)


Diarrhea, prolonged {02} {03}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


Dietary insufficiency, prolonged {01} {02} {03} , especially:
Steatorrhea {02} {03} {16} {33} or low-fat diet {33}
» Vitamin K deficiency or malabsorption {01} {02} {03} {16} {33}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


Diets high in phylloquinone (e.g., green leafy vegetables, certain vegetable oils, supplements)    (may decrease the anticoagulant effect {16})


» Diverticulitis {01}
Edema {02} {03}    (may reduce the effectiveness of the anticoagulant)


» Endocarditis, subacute bacterial {01} {02} {03}    (increased risk of hemorrhage into infarcted area)


Fever {01} {02} {03} {33}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


» Hepatic function impairment {01} {02} {03}    (may increase the patient"s response to the anticoagulant, both through impaired synthesis of clotting factors {08} {33} and decreased metabolism {03}, leading to an increased risk of bleeding)


Hepatitis, infectious {01} {02} {03}    (may increase the patient"s response to the anticoagulant, leading to an increased risk of bleeding)


Hyperhomocystinemia {13} {14} {15}    (may reduce the effectiveness of the anticoagulant)


Hyperlipidemia, including hypercholesterolemia {01} {02} {03}    (may reduce the effectiveness of the anticoagulant)


Hypertension, moderate {01} {02} {03}
Hyperthyroidism {01} {02} {03} {08} {33}    (may increase the patient's response to the anticoagulant, leading to an increased risk of bleeding)


Hypoprothrombinemia {01}    (may increase the patient"s response to the anticoagulant)


Hypothyroidism {01} {02} {03}    (may reduce the effectiveness of the anticoagulant)


Infection {01} {02} {03} or
Disturbances of intestinal flora, such as sprue {01} {02} {03}    (may increase the patient"s response to the anticoagulant)


Procedures (medical or dental) in which the risk of bleeding or hemorrhage is present {02} {03} , such as:
» Anesthetics, regional or lumbar block {01} {02} {03}
Catheters, indwelling {02} {03} {15}
Drainage tubes in any orifice or wound {01} {02}
» Spinal puncture {02} {03}    (increased risk of uncontrollable hemorrhage)


Protein C deficiency, hereditary, familial, or clinical, known or suspected {02} {03} {08} {14} {15} or
Protein S deficiency, hereditary or acquired {03} or
Other conditions predisposing to tissue necrosis {02}    (increased risk of anticoagulant-induced tissue necrosis {01} {02} {03} {08} {14} {37}, although patients with protein C deficiency may require long-term anticoagulant therapy to prevent recurrent thrombus formation {14}; administration of heparin, protein C concentrate, or fresh frozen plasma during the first few days of oral anticoagulant therapy may reduce the risk of tissue necrosis caused by protein C deficiency {02} {03} {14})

    (protein C deficiency should be suspected if there is a history of recurrent episodes of thromboembolic disorders in the patient or the family {02})


Renal function impairment    (possible increased risk of hemorrhage {01} {02} {03}; however, dosage adjustment is usually not required {03} {05} {17})

    (in nephrotic syndrome, decreased half-life and decreased effect may occur as a result of hypoproteinemia {03} {08} {15} {17})


Sensitivity to the anticoagulant prescribed {03}
» Trauma {02} {03} {15} , especially to the central nervous system (CNS)    (increased risk of internal hemorrhage)


Tuberculosis, active {02}    (increased risk of hemorrhage)


» Ulceration or other lesions, active, of:
Gastrointestinal tract {01} {02} {03} , including ulcerative colitis {01}
Respiratory tract {02} {03}
Urinary tract {02} {03}    (increased risk of hemorrhage)


Ulceration or other lesions of gastrointestinal tract, history of {02}    (increased risk of hemorrhage)


» Vasculitis {02} {03}    (increased risk of hemorrhage)


» Wounds, open ulcerative, traumatic, or surgical {01} {02}    (increased risk of hemorrhage)


Caution is also recommended in severely debilitated patients, who may be more sensitive to the effects of anticoagulants {03} .
Caution is also recommended during prolonged hot weather, during which the risk of bleeding may be increased {01} {02} {03} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For all anticoagulants
Blood in urine
Occult blood in stool    (determinations recommended at periodic intervals during therapy)


» Prothrombin time (PT) and/or
International normalized ratio (INR)    (determination of PT/INR is the primary means of establishing correct dose; determinations are recommended prior to initiation of therapy, at 24-hour intervals while maintenance dosage is being established {08} {90}, then gradually less frequently for the duration of therapy {08} {90}; additional PT/INR determinations are recommended when patients are switched to different brands or formulations, and whenever other medications are initiated, changed, taken irregularly, or discontinued {03} {90})

    (PT/INR monitoring generally is not done during fixed low-dose warfarin therapy)

    (the availability of portable PT monitors has made point-of-care self-monitoring by the patient feasible in selected circumstances, following initial dosage stabilization, as an adjunct to regular monitoring by medical professionals {33} {90})

    (PT reflects depression of vitamin K-dependent factors II, VII, and X; PT is often reported by listing the value in seconds along with the control value in seconds; alternately, PT may be reported as the ratio of the prolonged [therapeutic] value to the control value)

    (the one-stage PT test is the usual test used; there is inter-laboratory variability in types [sensitivity] of rabbit brain thromboplastins, as well as one-stage methods, used to determine PT {03} {08}; the appropriate therapeutic PT range used to determine and adjust anticoagulant dosage should be based on the experience of the specific laboratory {03}; a clear understanding of the particular method [e.g., Quick one-stage PT] {02} is important in order to facilitate appropriate anticoagulant dosage adjustment {03})

    (the INR provides a common basis for communication of PT results and interpretation of therapeutic ranges; the INR system is based on a logarithmic relationship between the PT ratios of the test and reference preparation; the International Reference Preparation [IRP] is a sensitive thromboplastin reagent prepared from human brain tissue; the INR is the PT ratio that would be obtained if the IRP, which has an International Sensitivity Index [ISI] of 1.0, were used to perform the test; the INR is calculated as: INR = (observed PT ratio) ISI, where the ISI is the correction factor in the equation that relates the PT ratio of the local reagent to the reference preparation and is a measure of the sensitivity of a given thromboplastin to reduction of vitamin K-dependent coagulation factors; the lower the ISI, the more “sensitive” the reagent and the closer the derived INR will be to the observed PT ratio {03} {08})

    (with the rabbit brain thromboplastins currently commercially available in North America, PT values of 1.2 to 1.5 times the control value are equivalent to INR values of 2 to 3 times the control value {08}, and PT values of 1.5 to 2 times the control value are equivalent to INR values of 3 to 4.5 times the control value; thromboplastins with recombinant tissue factor, which have an IS of approximately 1 [and thus a PT ratio essentially equivalent to the ISR] have recently been introduced {33}; for other thromboplastins, the INR can be calculated using the ISI [available from the manufacturer] as a calibration factor {03} {33})


For anisindione (in addition to the above)
Hematopoietic function {01} and
Hepatic function {01} and
Protein, urinary {01} and
Renal function {01}    (determinations may be advisable at periodic intervals during anisindione therapy because of the risk of blood dyscrasias, hepatotoxicity, and nephrotoxicity associated with phenindione [an anticoagulant chemically related to anisindione that is no longer available] {01})




Side/Adverse Effects

Note: Differences in frequency of side/adverse effects between anticoagulants may reflect either lack of clinical use data or actual pharmacologic distinctions among agents {01}.
Studies in animals suggest that anticoagulants given during periods of rapid bone growth (i.e., mainly in children) might cause bone abnormalities similar to those that occur in infants whose mothers received anticoagulants during pregnancy (hypoplasia of the nasal bridge and distal phalanges and excessive irregular calcifications in epiphyses and vertebrae) {19} {50}. Studies in humans have not been done {19} {50}.
Although not all of the side/adverse effects listed below have been documented with anisindione, they have been reported with phenindione, an indanedione derivative that is no longer commercially available. Other adverse effects or abnormalities reported with phenindione include accommodation paralysis (blurred vision or other problems), aplastic anemia, eosinophilia, leukocytosis, thrombocytopenia, atypical mononuclear cells, red cell aplasia, presence of leukocyte agglutinins, and exfoliative dermatitis. Because anisindione is chemically related to phenindione, these side/adverse effects should be considered potential side/adverse effects of anisindione also. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)–not necessarily inclusive:

Those indicating need for medical attention
Incidence dose-related
Symptoms of minor bleeding
    
Blood in urine {01} {02} {05} {26} {48}
    
epistaxis {01} {03} (nosebleeds)
    
gingival bleeding {03} (bleeding from gums when brushing teeth)
    
petechiae {01} (pinpoint red spots on skin)
    
unusual bleeding or bruising {01}
    
unusually heavy bleeding or oozing from cuts or wounds {03} {26}
    
uterine bleeding, excessive {01} {02} {05} (unusually heavy or unexpected menstrual bleeding )

Symptoms of major or internal bleeding or hemorrhage
    
Adrenal hemorrhage {01} {02} (abdominal or stomach pain ; diarrhea; dizziness or fainting; headache; loss of appetite; nausea with or without vomiting; nervousness ; weakness)
    
bleeding into joints {03} (joint pain, stiffness, or swelling)
    
gastrointestinal bleeding {01} {05} {08} {48} (black, tarry stools; blood in stools; bloody vomit or vomit that looks like coffee grounds; constipation)
    
hepatic hemorrhage {01} {05} (asymptomatic)
    
hypotension or shock {03} (dizziness or fainting)
    
intracranial hemorrhage {08} {22} {34}
including spinal hemorrhage {01} {08} (confusion; dizziness; headache, continuing or severe; nausea and vomiting ; paralysis; paresthesias; weakness)
    
ophthalmic hemorrhage {05} (bleeding in eye; blurred vision)
    
ovarian hemorrhage at time of ovulation {02} (abdominal or stomach pain)
    
pericardial hemorrhage {01} {08} (chest pain)
    
pulmonary bleeding (coughing up blood ; shortness of breath)
    
retroperitoneal bleeding {34} {01} (abdominal pain or swelling ; back pain or backaches)


Note: Fatal or nonfatal bleeding or hemorrhage can occur from any tissue or organ {01} {02} {04} {09}. Signs, symptoms, and severity vary depending on the site and extent of bleeding {01} {02} {03} {04}. Therefore, bleeding should be considered as a potential cause of any sign or symptom not otherwise explainable {04}.
Incidence of bleeding or hemorrhage depends on dose and duration of anticoagulant therapy {01} {02} {03} {24} {33} {34} {49}, as well as age {22} {24} {34} and other medications and underlying conditions {01} {02} {24} {33} {34} {49}. Incidence is increased at an INR over 3 {24} {33} {34} {37} {50}, although bleeding may not always correlate with PT {01} {02}. Incidence of hemorrhage is not increased with use of fixed low-dose warfarin (1 mg per day), which produces an INR of 1.3 to 1.9 {34}.
Adrenal hemorrhage may result in acute adrenal insufficiency {02}. Diagnosis may be difficult because the initial symptoms (abdominal pain, apprehension, diarrhea, dizziness or fainting, headache, loss of appetite, nausea or vomiting, and weakness) are nonspecific and variable.
The occurrence of gastrointestinal or genitourinary hemorrhage during anticoagulant therapy, especially if the prothrombin time (PT) is within the therapeutic range, may indicate the presence of an underlying occult lesion such as a tumor or ulcer {02} {05} {09} {33} {34} {37}.
Gastrointestinal bleeding may also be a symptom of ulceration {01}.
Constipation may be a symptom of hemorrhage-induced paralytic ileus or intestinal obstruction caused by submucosal or intramural hemorrhage {02}.
Intracranial hemorrhage (ICH) includes intracerebral, subdural/epidural, and subarachnoid hemorrhage and commonly results in fatalities {22} {29}. Incidence of ICH appears to be dose-related; however, it has been reported at INRs well within the therapeutic range {22}. Neurologic deficits may evolve rapidly or slowly (over 6 to 24 hours) as the bleeding evolves and expands slowly {22} {29}.
With anisindione, the possibility exists that unusual bleeding or bruising may also indicate thrombocytopenia {01}.


Incidence less frequent
    
Dermatitis, allergic {01} {02} {03} {08} {09} {48} (skin rash, hives, and/or itching)—rare with dicumarol and warfarin {48}
    
fever {01} {02} {08} {09}
    
leukopenia {02} (fever or chills; cough or hoarseness ; lower back or side pain; painful or difficult urination)

Incidence rare
    
Agranulocytosis {01} ( fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—with anisindione
    
calcification, tracheal or tracheobronchial {03} (trouble in breathing)—with long-term warfarin {03}
    
hepatotoxicity {01} {03} {05} {09} (usually asymptomatic and seen on laboratory tests {03}; dark urine ; yellow eyes or skin)
    
lipid emboli
including systemic atheroemboli and cholesterol microemboli {03}
    
necrosis and/or gangrene, hemorrhagic, of skin and other tissues {01} {02} {03} {05} {08} {09} {33} {48} {50} ( sores on skin, especially on thighs, breasts, penis, or buttocks {09} {48})
    
purple toes syndrome {01} {02} {03} {08} {48} (blue or purple toes; pain in toes)
    
renal damage, with resultant edema and proteinuria {01} (bloody or cloudy urine; difficult or painful urination ; sudden increase or decrease in amount of urine; swelling of face, feet, and/or lower legs)
    
sores, ulcers, or white spots in mouth or throat {01} {03}
    
vasculitis {03} ( fever; itching; skin sores or blisters)

Note: Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms, including purple toes syndrome; livedo reticularis; rash; gangrene; abrupt and intense pain in the leg, foot, or toes; foot ulcers; myalgia; penile gangrene; abdominal pain, flank pain, or back pain; hematuria; renal insufficiency; hypertension; cerebral ischemia; spinal cord infarction; pancreatitis; symptoms simulating polyarteritis; or any other sequelae of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are the kidneys, followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. {03}
Necrosis is caused by thrombosis of the venules and capillaries within the subcutaneous fat {01} {03} {08} {33} {50}. It usually occurs on the 3rd to 8th day of therapy {01} {02} {03} {08} {33} {48} and may be more frequent in patients with protein C deficiency {08} {14} {33}. Initial lesions, which are painful, are erythematous or ecchymotic with a sharply demarcated border, subsequently developing bullae with full-thickness skin necrosis {48}. It is important to determine whether necrosis is caused by the anticoagulant or by an underlying disease {01} {02} {03}. In severe cases, debridement or even amputation of affected tissue, limb, breast, or penis may be necessary {01} {02} {03} {08} {09} {48}. Fatalities have occurred {01} {02} {03} {09}.
Purple toes syndrome may develop 3 to 10 weeks after initiation of anticoagulant therapy {03} {08}; it results from systemic cholesterol microembolization {03} {48}. Anticoagulant therapy may enhance the release of atheromatous plaque emboli, which may increase the risk of purple toes syndrome and other complications of systemic cholesterol embolization {03} {08} {48}. Purple spots may blanch with pressure or elevation of the leg {03} {48}. The syndrome is usually reversible but in some cases may progress to gangrene or necrosis {03}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Bloated stomach or gas {03}
    
cold intolerance {03}
    
diarrhea {01} {02} {03} {05} {08} {09} — more frequent with dicumarol {09}
    
loss of appetite {01} {02}
    
nausea or vomiting {01} {02} {03} {05} {08} {09} —more frequent with dicumarol {09}
    
stomach cramps or pain {01} {02} {03}



Those not indicating need for medical attention
Incidence less frequent or rare
    
Alopecia of scalp {01} {02} {03} {05} {08} {09} {48} (loss of hair on scalp)—with long-term use
    
orange-red color in alkaline urine —with anisindione {01}





Overdose
For specific information on the agents used in the management of anticoagulant overdose, see the Vitamin K (Systemic) and Factor IX (Systemic) monographs.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Early signs of overdose
    
Overt or suspected bleeding{03}
including petechiae{01} (pinpoint red spots on skin), unusual bleeding or bruising{01}
unusually heavy bleeding or oozing from cuts or wounds{03}
uterine bleeding, excessive{01}{02}{05} (unusually heavy or unexpected menstrual bleeding)

Possible symptoms of internal bleeding
    
Adrenal hemorrhage{01}{02} (abdominal or stomach pain; diarrhea; dizziness or fainting; headache; loss of appetite; nausea with or without vomiting; nervousness; weakness)
    
bleeding into joints{03} (joint pain, stiffness, or swelling)
    
gastrointestinal bleeding{01}{05}{08}{48} (black, tarry stools; blood in stools; bloody vomit or vomit that looks like coffee grounds; constipation)
    
genitourinary bleeding{01}{05}{48}
including urinary bleeding{01}{02}{05}{48} (blood in urine), or ovarian hemorrhage at time of ovulation{02} (abdominal or stomach pain)
    
hepatic hemorrhage{01}{05} (asymptomatic)
    
hypotension or shock{03} (dizziness or fainting)
    
intracranial hemorrhage{08}{22}{34}
including spinal hemorrhage{01}{08} (confusion; dizziness; headache, continuing or severe; nausea and vomiting; paralysis; paresthesias; weakness)
    
ophthalmic hemorrhage{05} (bleeding in eye; blurred vision)
    
pericardial hemorrhage{01}{08} (chest pain)
    
pulmonary bleeding{01} (coughing up blood; shortness of breath)
    
retroperitoneal bleeding{34} (abdominal pain or swelling; back pain or backaches)


Treatment of overdose
If excessive increases in prothrombin time (PT) and/or international normalized ratio (INR), without bleeding or prospective surgery, occur, the INR should be reduced to a safe level (e.g., less than 5) {03} {33}. If serious bleeding is present, the INR should be reduced to 1 as soon as possible {33}. If elective surgery or urgent surgery is required, the INR can be reduced to 1 to 1.5 at the time of surgery {33}.

Reduction of INR can usually be accomplished by temporarily withdrawing anticoagulant therapy and, if necessary, administering oral or parenteral vitamin K 1 {01} {03} {23} {24} {33}. Reversal of anticoagulation is not maximal for 24 to 48 hours after withholding the anticoagulant, until synthesis of fully carboxylated coagulation proteins is complete {08} {23}. For serious overdose or life-threatening bleeding, when immediate restoration of clotting factors is necessary, transfusion of fresh plasma {01} {03} {24} {33} or prothrombin (factor IX) complex concentrate {03} {23} {24} {33} along with vitamin K 1 may be necessary. Use of these blood products is associated with an increased risk of hepatitis and other viral diseases {03} {24}; use of prothrombin complex is also associated with an increased risk of thrombosis {03}. Use of purified factor IX complex preparations (Coagulation Factor IX [Human or Recombinant]) is not recommended because they will not increase concurrently depressed levels of factor II, factor VII, and factor X {03}. Packed red blood cells may be administered for significant blood loss {03}. Although whole blood may be given if blood loss has been extensive, transfusion of whole blood will not elevate procoagulant factor concentrations sufficiently to eliminate the need for administration of plasma or prothrombin complex concentrate. Caution and careful monitoring are recommended during infusion of blood or plasma to avoid precipitating pulmonary edema in elderly patients or patients with cardiac disease {03} {24}.

Vitamin K 1—Overcomes the anticoagulant effect because it is reduced through a different warfarin-resistant enzyme system {33}. Repeated doses may be necessary {08}. The fact that large doses of vitamin K 1 (5 mg or more) will reduce the response to subsequent anticoagulant therapy for up to a week or longer must be kept in mind {03} {08} {23} {24} {33}. Although resumption of anticoagulant therapy can produce therapeutic PT/INR with careful dosage adjustment, heparin may be preferable for initial therapy and/or if rapid anticoagulation is desired {03} {08}.

Fresh whole blood or plasma—200 to 500 mL may be required {03}.

Prothrombin complex concentrate—A factor IX product (Factor IX Complex USP) that may also contain clinically useful quantities of factors II, VII, and X. May also contain other proteins, including proteins C and S; high molecular weight kininogen; and small quantities of activated clotting factors II, VII, IX, or X {85}. The usual dose is 1500 Units {85}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anticoagulants (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to the anticoagulant prescribed

Pregnancy—Possibility of birth defects or bleeding in the fetus or bleeding in the mother; not becoming pregnant during therapy without first discussing with physician; telling physician immediately if pregnancy is suspected {03}





Use in children—Infants may be more sensitive to the effects of anticoagulants






Use in the elderly—Elderly patients (60 years of age and older) may be more sensitive to the effects of anticoagulants
Other medications of any kind
Other medical problems

Proper use of this medication
» Compliance with therapy; taking at same time each day {08} {09}

» Regular visits to physician or clinic to check progress {01} {03}; possibility of monitoring PT/INR and adjusting dosage at home for some patients {90}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if not remembered until next day; not doubling doses; keeping a record of doses taken to avoid mistakes; keeping record of missed doses to give physician {03} {04}

» Proper storage

Precautions while using this medication
» Informing all physicians, dentists, and/or {90} pharmacists that anticoagulant is being used

» Checking with physician immediately if any signs or symptoms of bleeding occur

» Not taking, stopping, or changing other medications, including over-the-counter (OTC) medications, without first discussing with physician {01} {03}

» Carrying or wearing identification indicating use of anticoagulant {02} {03}

Not engaging in activities that may lead to injury {03}

Caution in activities with risk of cutting or bleeding (e.g., shaving)

Minimizing alcohol consumption {03}

» Eating a normal, balanced diet; caution with weight-loss diets; not changing diet, taking vitamins, or using nutritional supplements without first discussing with physician because of possible alteration of anticoagulant effect by substantial changes in intake of vitamin K {03}

Checking with physician if unable to eat for several days or if continuing gastric upset, diarrhea, or fever occurs {03}

Caution in prolonged hot weather {03}

» Caution when anticoagulant therapy is discontinued, and for several days after withdrawal of therapy, as blood clotting returns to normal {03}


Side/adverse effects
Signs and symptoms of potential side effects, especially bleeding or hemorrhage, allergic dermatitis, fever, leukopenia, agranulocytosis (for anisindione), tracheal or tracheobronchial calcification, hepatotoxicity, lipid emboli including systemic atheroemboli and cholesterol microemboli, necrosis and/or gangrene, purple toes syndrome, renal damage, sores in mouth or throat, and vasculitis

Checking with physician if red-orange color of urine occurs with anisindione; not harmful but may interfere with certain urine tests


General Dosing Information
Dosage should be adjusted to achieve the goal of impeding the coagulation or clotting mechanism to the point that thrombosis will not occur but spontaneous bleeding will be avoided {02}.

Patient compliance is essential to the safe use of these medications. The patient must be responsible and willing to deal with the demands of therapy with these medications. {45}

Determination of dose is complicated by the narrow therapeutic window and wide variability in dose response to warfarin {12} {17}. It has been estimated that 20 to 25% of patients never achieve a stable therapeutic dose {17}. Dosage of anticoagulants must be individualized and should be adjusted according to prothrombin time (PT) and/or international normalized ratio (INR) determinations. {90} Determinations of clotting time, bleeding time, or anticoagulant plasma concentration are not effective measures for monitoring anticoagulant therapy {03}. However, it is important to keep in mind that certain medications or medical conditions may increase risk of hemorrhage without increasing PT (e.g., by causing inhibition of platelet aggregation or thrombolysis). Monitoring of PT/INR must be accompanied by careful monitoring for possible bleeding or hemorrhage, and anticoagulant dosage adjusted accordingly. {17} {90}

Some patients may exhibit resistance to anticoagulant therapy because of genetic predisposition {03} {33}, acquired resistance (e.g., antiphospholipid antibodies) {03} {13}, or an increased rate of anticoagulant metabolism and excretion {08}. Doses much higher than those usually recommended may be required to achieve successful anticoagulation in these patients. The presence of acquired or hereditary coumarin resistance should be considered if large daily doses are required to maintain the patient's PT/INR within a normal therapeutic range {03}.

Some patients may exhibit unusual sensitivity to the effects of warfarin. The cause has been postulated to be vitamin K depletion but this has not been studied. {03}

Manufacturers" dosage recommendations may include administration of an initial large loading dose, which is gradually reduced to the maintenance level according to PT/INR determinations {01} {02}. However, many clinicians do not recommend use of large loading doses because of the increased risk of hemorrhage, {03} and because a more rapid anticoagulant effect can be achieved by initiating therapy with heparin {03}.

The therapeutic value of the PT was previously considered to be 1.5 to 2.5 times the control value {08}. Because the rabbit brain thromboplastins currently used in the U.S. for PT determinations are less sensitive than the human brain thromboplastins used previously, the optimal therapeutic value of the PT is now considered to be 1.3 to 1.5 times the control value. However, in the presence of a very high risk of thromboembolism (e.g., in patients with a history of recurrent systemic embolism or patients with mechanical heart valves), maintaining the PT at 1.5 to 2 times the control value may be necessary.

The target INR for any given indication can be defined in general, but may vary depending on severity of the condition, associated risk factors for thrombosis, risk factors for major hemorrhage, combination therapy with other agents, and other relevant conditions. For specific guidelines concerning INR values in determining the appropriate dose of anticoagulant therapy, the prescriber should refer to the literature or to published guidelines {53}, such as those developed in 1998 by the Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy {52}.

In general, an INR of 2 to 3 is recommended for prevention or treatment of venous thromboembolism {03} {20} {37}, including pulmonary embolism, atrial fibrillation {03} {08} {09} {38} {44}, valvular heart disease {08} {39}, or with bioprosthetic heart valves {08} {09} {40}. An INR of 2.5 to 3.5 is recommended after myocardial infarction {03} {23} {33}, in patients with mechanical prosthetic heart valves {03} {08} {09} {12} {33}, or in certain patients with thrombosis and the antiphospholipid syndrome {12} {33}. Higher INR may be recommended for recurrent systemic embolism {03}. Effectiveness of warfarin is reduced at INRs of less than 2, although some benefit can be obtained in some conditions (e.g., prevention of deep vein thrombosis in patients with indwelling central vein catheters) with fixed low-dose warfarin (1 mg per day) at an INR of 1.3 to 2 {23} {33}.

Increased monitoring of PT/INR is recommended when any new medication, including nonprescription (over-the-counter [OTC]), is added to or withdrawn from the regimen of a patient stabilized on a coumarin or indanedione anticoagulant, or when the dosage of a concurrently used medication is changed. Anticoagulant dosage must be adjusted as necessary to prevent hemorrhage or loss of effect. Also, substantial alteration of initial anticoagulant dosage may be necessary when anticoagulant therapy is initiated in a patient receiving a medication known to cause significant alteration of anticoagulant effect.

When anticoagulant therapy is initiated with heparin and continued with a coumarin or indanedione anticoagulant, it is recommended that both agents be given concurrently until PT/INR determinations indicate an adequate response to the coumarin or indanedione anticoagulant {02} {08}. However, the fact that heparin may prolong the PT must be kept in mind. Subcutaneous or bolus intravenous administration of full therapeutic doses of heparin may prolong the PT considerably because of the high concentrations of heparin achieved in the blood. On the other hand, continuous intravenous infusion of full therapeutic doses or subcutaneous administration of low (prophylactic) doses usually do not increase the PT by more than a few seconds. To minimize problems in interpreting PT test results, it is recommended that blood for the PT test be drawn just prior to, or at least 5 hours after, a bolus intravenous dose or 24 hours after subcutaneous administration of a full therapeutic dose of heparin {01} {02} {03} {05}. Also, the fact that reduction in PT may reflect early depletion of factor VII rather than peak antithrombotic effects of coumarin or indanedione derivatives must be kept in mind {33}. Some clinicians recommend continuation of heparin therapy for up to 4 to 5 days after initiation of therapy with a coumarin or indanedione anticoagulant to ensure that peak antithrombogenic activity has been reached {20}.

Duration of anticoagulant therapy that is appropriate for any given indication can be defined in general, but may vary widely depending on the severity of the condition, associated risk factors for thrombosis, risk factors for major hemorrhage, combination therapy with other agents, and other relevant conditions {03} {13} {14} {37} {40}. For specific guidelines concerning INR values as an aid in determining the appropriate duration of anticoagulant therapy, the prescriber should refer to the literature or to published guidelines {13} {53}, such as those developed in 1998 by the Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy {52}.

Because of the risk of rebound hypercoagulability (which may not be detected by clotting tests) when anticoagulant therapy is discontinued {09} {31}, gradual withdrawal over 3 to 4 weeks is recommended {01} {05} {31}.

Diet/Nutrition
Dietary vitamin K fluctuations are especially important in patients taking low-dose warfarin {16}.

Loss of anticoagulant effect may occur in a previously stabilized patient following increased intake of vitamin K from dietary sources (green leafy vegetables such as broccoli, cabbage, collard greens, kale, lettuce, or spinach and certain vegetable oils) or vitamin K-containing multiple vitamins or nutritional supplements {16} {17} {23} {33}.

Increased anticoagulant effect may occur in a previously stabilized patient if prolonged malnutrition or vitamin C deficiency develops, or if diarrhea, other illness, or changes in diet resulting in decreased intake or absorption of vitamin K occur during therapy {23}.

For parenteral dosage form of warfarin only
It is recommended that parenteral warfarin be administered by slow intravenous injection (over 1 to 2 minutes) into a peripheral vein {03}.

Intramuscular administration of warfarin is not recommended {03}.

For prevention or treatment of adverse effects
If excessive increases in PT/INR, without bleeding or prospective surgery, occur, the INR should be reduced to a safe level (e.g., less than 5) {03} {33}. If serious bleeding is present, the INR should be reduced to 1 as soon as possible {33}. Reduction of INR may be accomplished by temporarily withdrawing anticoagulant therapy, administering vitamin K 1, and, in life-threatening situations, by transfusing fresh plasma or prothrombin complex concentrate {24} {33}. (See Treatment of overdose for more information.) If elective or urgent surgery is required, the INR can be reduced to 1 to 1.5 at the time of surgery {33}.

It is recommended that intramuscular injections of concomitant medications be avoided whenever possible, because of the risk of hematoma {05}, or be administered in the upper extremities to ensure easy access for manual compression, inspections for bleeding, and use of pressure bandages {03}.

If acute adrenal hemorrhage or insufficiency is suspected, anticoagulant therapy should be discontinued, plasma cortisol concentrations measured, and high-dose intravenous corticosteroid therapy (preferably with hydrocortisone, since other glucocorticoids may not provide sufficient sodium retention) instituted immediately {02}. Delay of treatment while laboratory confirmation of the diagnosis is awaited may prove fatal for the patient {02}. It has been proposed that abdominal computerized axial tomographic (CAT) scanning may be useful in diagnosing this condition more rapidly. {90}

It is recommended that coumarin or indanedione anticoagulant therapy be discontinued at the first sign of anticoagulant-induced tissue necrosis {01} {02} {03} {09} {48}. If necessary, anticoagulant therapy can be continued with heparin monotherapy {01} {02} {03} {09} {48}. No uniformly effective treatment for anticoagulant-induced tissue necrosis has been established {01} {02} {03}, although some success has been achieved with reintroduction of warfarin at low doses in combination with therapeutic doses of heparin, with gradual increases in warfarin dose over several weeks {14} {33}, or with use of protein C concentrate or fresh frozen plasma until stable anticoagulation is achieved {14}. This approach may prevent an abrupt fall in protein C concentrations before factors II, IX, and X concentrations can fall {14} {33}.

It is recommended that anticoagulant therapy be withdrawn (and replaced by heparin if necessary) at the first sign of:    • Agranulocytosis {01}
   • Hypersensitivity {01}
   • Intracranial hemorrhage

• (aggressive treatment is necessary because of the slow evolution and growth of the bleeding area in about half of the cases {22})

   • Purple toes syndrome {48}
   • Systemic atheroemboli or cholesterol microemboli {03}.





ACENOCOUMAROL

Summary of Differences
Another commonly used name is nicoumalone.


Physicochemical characteristics:
Coumarin derivative.



Pharmacology/pharmacokinetics:
See Pharmacology/Pharmacokinetics .



Oral Dosage Forms

ACENOCOUMAROL TABLETS

Usual adult dose
Oral, 1 to 10 mg per day, as indicated by PT/INR determinations {05}.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg (Rx) [Sintrom]


4 mg (Rx) [Sintrom (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Do not take other medicines without advice from your doctor.


ANISINDIONE

Summary of Differences


Physicochemical characteristics:
Indanedione derivative.



Pharmacology/pharmacokinetics:
See Pharmacology/Pharmacokinetics .



Precautions:
Laboratory value alterations—Alkaline urine may turn red-orange.



Side/adverse effects:
See Side/Adverse Effects .



Oral Dosage Forms

ANISINDIONE TABLETS

Usual adult dose
Oral, 25 to 250 mg a day, as indicated by PT/INR determinations {01}.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


50 mg (Rx) [Miradon (scored) (lactose )]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Do not take other medicines without advice from your doctor.


DICUMAROL

Summary of Differences


Physicochemical characteristics:
Coumarin derivative.



Pharmacology/pharmacokinetics:
See Pharmacology/Pharmacokinetics .



Side/adverse effects:
See Side/Adverse Effects .

Incidence of gastrointestinal side/adverse effects may be higher.



Oral Dosage Forms

DICUMAROL TABLETS USP

Usual adult dose
Oral, 25 to 200 mg a day, as indicated by PT/INR determinations {02}.

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


25 mg (Rx)[Generic]( lactose)

Canada—
Not commercially available.

Packaging and storage:
Store below 25 °C (77 °F).

Auxiliary labeling:
   • Do not take other medicines without advice from your doctor.


WARFARIN

Summary of Differences


Physicochemical characteristics:
Coumarin derivative.



Pharmacology/pharmacokinetics:
See Pharmacology/Pharmacokinetics .



Side/adverse effects:
See Side/Adverse Effects .



Oral Dosage Forms

WARFARIN SODIUM TABLETS USP

Note: With the recent availability of generic formulations of warfarin, the possibility exists for variations in bioavailability (e.g., tablet dissolution) {17} and thus the activity of different commercial preparations. Switching brands should be avoided whenever possible {17}. If a switch to a different brand occurs, the patient's PT/INR should be monitored and dosage adjusted if necessary {03} {09} {17}.


Usual adult dose
Regular-dose (adjusted) therapy
Initial: Oral, 2 to 5 mg per day, the dosage being adjusted according to PT/INR determinations {03} {04}.
Maintenance: Oral 2 to 10 mg per day, as indicated by PT/INR determinations {03} {04}.

Low-dose (fixed) therapy
Oral, 1 mg per day {23} {33}.

Note: There have been a number of reports of use of fixed low-dose warfarin (1 mg per day) for prophylaxis of deep vein thrombosis (e.g., in patients with indwelling central vein catheters) {08} {23} {33} {36} {41}. However, results of studies do not support use of fixed low-dose warfarin for treatment of patients with acute myocardial infarction or atrial fibrillation {33}.



Usual pediatric dose
Dosage has not been established {11} {47} {90}.

Strength(s) usually available
U.S.—


1 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)


2 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)


2.5 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)


3 mg (Rx) [Coumadin (scored) (lactose )]


4 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)


5 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)


6 mg (Rx) [Coumadin (scored) (lactose )]


7.5 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)


10 mg (Rx) [Coumadin (scored) (lactose )][Generic]( may contain lactose)

Canada—


1 mg (Rx) [Coumadin (scored) (lactose )]


2 mg (Rx) [Coumadin (scored) (lactose )]


2.5 mg (Rx) [Coumadin (scored) (lactose )]


4 mg (Rx) [Coumadin (scored) (lactose )]


5 mg (Rx) [Coumadin (scored) (lactose )] [Warfilone (scored) ( tartrazine)]


10 mg (Rx) [Coumadin (scored) (lactose )]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Do not take other medicines without advice from your doctor.



Parenteral Dosage Forms

WARFARIN SODIUM FOR INJECTION USP

Usual adult dose
Initial
Intravenous (over one to two minutes into a peripheral vein), 2 to 5 mg per day, the dosage being adjusted according to PT/INR determinations {03} {04}.

Maintenance
Intravenous (over one to two minutes into a peripheral vein), 2 to 10 mg per day, as indicated by PT/INR determinations {03} {04}.


Usual pediatric dose
Dosage has not been established.

Size(s) usually available:
U.S.—


5 mg (Rx) [Coumadin (sodium phosphate, dibasic, heptahydrate ) (sodium phosphate, monobasic, monohydrate) (sodium chloride) (mannitol) (sodium hydroxide)]

Canada—


5 mg (Rx) [Coumadin (sodium phosphate, dibasic, heptahydrate ) (sodium phosphate, monobasic, monohydrate) (sodium chloride) (mannitol) (sodium hydroxide)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {03} {06}, unless otherwise specified by manufacturer. Do not refrigerate {03} {06}. Protect from light {03} {06}.

Preparation of dosage form:
Warfarin sodium for injection is prepared for administration by adding 2.7 mL of sterile water for injection to the 5-mg vial, producing a solution containing 2 mg of warfarin sodium per mL {03} {06}.

Stability:
It is recommended that the reconstituted solution be used within 4 hours {03} {06}. Any unused portion should be discarded {03}.

Incompatibilities:
Warfarin sodium solutions are incompatible with amikacin sulfate, epinephrine hydrochloride, metaraminol tartrate, oxytocin, promazine hydrochloride, tetracycline hydrochloride, and vancomycin hydrochloride {08}.

Some adsorption of warfarin sodium by polyvinyl chloride has been demonstrated when the warfarin was dissolved in 0.9% sodium chloride injection or 5% glucose injection {08}.



Revised: 5/18/99



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  1. Panel consensus, 4/99.
  1. Panel comment, 4/99.
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