JANTOVEN

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

Route-Specific Administration

Oral Administration
-Administer dose at the same time every day. May be taken with or without food; food decreases the rate but not the extent of absorption.

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance is not known.

Adverse reactions that occur infrequently with warfarin include abdominal cramping and flatulence, alopecia, anaphylactoid reactions, angina or chest pain (unspecified), anemia, asthenia, cold intolerance, coma or loss of consciousness, diarrhea, dizziness, dysgeusia, edema, elevated hepatic enzymes, cholestatic hepatic injury, exfoliative dermatitis, including bullous eruptions, fatigue, feeling cold and chills, fever, headache, hepatitis, hypotension, jaundice, lethargy, malaise, nausea, paresthesias, syncope, vasculitis, vomiting, and pallor.

Bleeding is the primary adverse reaction to warfarin therapy and is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical disorder, and the use of concomitant drugs that may affect hemostasis or interfere with warfarin's metabolism. Management of bleeding depends on the severity and may include interruption of warfarin therapy and/or the use of vitamin K, fresh frozen plasma, prothrombin complex concentrates, and/or recombinant factor VIIa. The intensity of anticoagulant effect is the most important risk factor for bleeding, with the risk increasing dramatically with an INR more than 5. Serious or major bleeding events have been reported in 0.05% to 12.2% of pediatric patients receiving warfarin in clinical trials and case series. Fatal or nonfatal hemorrhage may occur from any tissue or organ. Bleeding complications may be minor (e.g., ecchymosis, epistaxis, or petechiae) or major (e.g., intracranial bleeding or retroperitoneal bleeding). Bleeding that occurs when the INR is less than 3 is often associated with an obvious underlying cause or an occult GI or renal lesion. Massive hemorrhage most frequently involves the GI tract (i.e., GI bleeding) or genitourinary sites (e.g., hematuria), but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites. Other manifestations of bleeding may include excessive uterine or vaginal bleeding or bleeding from the gums or other mucous membranes. Ocular hemorrhage (anterior chamber, subretinal, and subconjunctival hemorrhage) (3% to 11.4%) has been reported in the literature in adult patients and is usually reported more frequently in patients with preexisting ocular conditions. Acute kidney injury may occur as a result of excessive anticoagulation or hematuria in patients with altered glomerular integrity or a history of renal disease; monitor INR more frequently in this population. In making decisions regarding use of warfarin, the potential decrease in thromboembolism must be balanced against the potential increased bleeding risk. Evaluate prothrombin time (PT)/INR in all patients prior to and after initiation of therapy. Monitor patients closely for signs or symptoms of bleeding. Hemorrhagic complications may be manifested by signs or symptoms that do not indicate obvious bleeding, such as paralysis, paresthesias, dizziness, weakness, shortness of breath, dysphagia, unexplained swelling, headache, unexplained shock, or pain in the chest, abdomen, or other areas.

Anticoagulation therapy with warfarin may enhance the release of atheromatous plaque emboli leading to systemic cholesterol microembolization. Sequelae may include livedo reticularis; rash; gangrene; abrupt and intense pain in the leg, foot, or toes; foot ulcers; myalgia; penile gangrene; abdominal pain; flank or back pain; hematuria; renal insufficiency; hypertension; cerebral ischemia; spinal cord infarction; pancreatitis; symptoms similar to polyarteritis; or any other symptoms of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are kidneys, pancreas, spleen, and liver. Some symptoms have progressed to organ necrosis or death. Purple-toe syndrome is a consequence of cholesterol microembolization and usually occurs between 3 to 10 weeks or later after the initiation of warfarin therapy. It is characterized by a dark purplish or mottled color of the toes or plantar surfaces that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of color over time. While purple-toe syndrome is thought to be reversible, some cases may progress to gangrene or tissue necrosis (less than 0.1%), which may require debridement or may lead to amputation. Discontinuation of warfarin is recommended when any of these conditions occur.

Skin necrosis (less than 0.1%) is a relatively uncommon adverse reaction to warfarin associated with local thrombosis and usually appears within a few days of the start of warfarin therapy. When it occurs it can be extremely severe and disfiguring and may require treatment through debridement or amputation of the affected tissue, limb, breast, or penis. It occurs more frequently in women and in patients with preexisting protein C deficiency and, less commonly, with protein S deficiency. Patients initially become hypercoagulable because warfarin depresses anticoagulant proteins C and S more quickly than coagulant proteins II, VII, IX, and X. Extensive thrombosis of the venules and capillaries occurs within the subcutaneous fat. Women will note an intense, painful burning in places such as the thigh, buttocks, waist, and/or breast several days after beginning warfarin; skin necrosis and permanent scarring may follow. Immediate withdrawal of warfarin therapy is indicated. Heparin can be safely substituted in place of warfarin; however, the treatment of patients who require long-term anticoagulant therapy remains problematic. It may be reasonable to restart warfarin therapy at a low dose while therapeutic heparin is used to prevent an abrupt fall in protein C levels before there is a reduction in the levels of factors II, IX, and X. The dosage of warfarin can be increased gradually over several weeks.

Although rare, maculopapular rash, pruritus, and urticaria have been reported in patients taking warfarin, usually within 28 days of drug initiation. Discontinuation of warfarin typically resolves the allergic-type reaction, but it often recurs after rechallenge. Consensus on whether or not cross-sensitivity between warfarin and other coumarin anticoagulants such as dicumarol, acenocoumarol, or phenprocoumon occurs is not available as both cross-sensitivity on rechallenge with a different coumarin anticoagulant and successful use of a different coumarin anticoagulant has been described. A case report also describes the successful initiation of long-term anisindione (an indanedione anticoagulant) in a patient with a history of maculopapular rash to warfarin. If such a reaction occurs in a patient taking warfarin, consideration should be given to using other anticoagulants such as low molecular weight heparins.

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

Fatal and serious calciphylaxis, or calcium uremic arteriolopathy, has been reported with the use of warfarin in patients with and without end-stage renal disease. If calciphylaxis is diagnosed, discontinue warfarin and treat the calciphylaxis as appropriate. Consider alternative anticoagulant therapy in patients who develop calciphylaxis during warfarin therapy.

Warfarin should be used with caution in patients with a history of coumarin anticoagulants hypersensitivity. Consensus on whether or not cross-sensitivity between warfarin and other coumarin anticoagulants such as dicumarol, acenocoumarol, or phenprocoumon occurs is not available as both cross-sensitivity on rechallenge with a different coumarin anticoagulant and successful use of a different coumarin anticoagulant has been described. A case report also describes the successful initiation of long-term anisindione (an indanedione anticoagulant) in a patient with a history of maculopapular rash to warfarin.

Warfarin can cause major or fatal bleeding. Warfarin is contraindicated in patients with conditions in which therapy with warfarin may result in uncontrolled bleeding including certain hematological disease; GI bleeding, genitourinary bleeding, respiratory tract bleeding, retinal bleeding, or intracranial bleeding; head trauma; hemorrhagic stroke; aneurysm; aortic dissection; pericarditis or pericardial effusion; bacterial endocarditis; recent or planned surgery of the central nervous system, eye, or following trauma/surgery that results in large open surfaces; diagnostic or therapeutic procedures with potential for uncontrolled bleeding including epidural anesthesia, spinal anesthesia, spinal puncture and lumbar puncture; and malignant hypertension. Due to the risk of bleeding, warfarin should be used only with extreme caution in patients with hemophilia, leukemia, peptic ulcer disease, and polycythemia vera. Usually, warfarin therapy is stopped 4 to 5 days prior to surgery. In patients with an intermediate- or high-risk for thromboembolism, give either heparin or low molecular weight heparin (LMWH) as the INR falls. Administration of vitamin K 24 to 48 hours prior to surgery will shorten the duration of heparin or LMWH prior to surgery; however, it may make it more difficult to reinstitute warfarin postoperatively. In situations with a low risk of bleeding, another option is to lower the dose of warfarin and operate at an INR of 1.3 to 1.5. This INR level has shown to be safe in randomized trials of gynecologic and orthopedic surgery patients. A severe elevation (more than 50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as a risk factor for postoperative hemorrhage. Use warfarin cautiously in the following conditions because bleeding, should it occur, would be extremely serious during warfarin therapy: vasculitis; polyarthritis; moderate to severe hypertension; or indwelling catheters. The risk of major bleeding with warfarin therapy is increased during the drug initiation phase, in patients with highly variable INRs, in patients requiring long-term treatment, in patients with certain genetic polymorphisms of CYP2C9 and/or VKORC1, and in patients with a history of cerebrovascular disease (e.g., stroke), GI bleeding, or in the presence of serious comorbid conditions such as cardiac disease, malignancy (neoplastic disease), renal disease including renal impairment or renal failure, or anemia. An INR more than 3 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Acute kidney injury, possibly related to excessive anticoagulation or hematuria, may occur in patients with altered glomerular integrity or a history of renal disease; monitor INR more frequently in patients with renal impairment. Warfarin therapy must be individualized for the patient. Warfarin has a narrow therapeutic range and may be affected by factors such as other drugs, dietary vitamin K, and other disease states. Monitor INR response and for signs of bleeding during warfarin therapy; consider more frequent monitoring in patients that have risk factors for major bleeding. Determination of whole blood clotting or bleeding times is not an effective measure to monitor warfarin therapy.

Although genetic polymorphisms of CYP2C9 and VKORC1 have been shown to account for some of the variance associated with warfarin dosing in adult patients, the effects of these polymorphisms on dosing in pediatric patients has not been determined. In a prospective cohort study of 34 White pediatric patients receiving warfarin, CYP2C9 and VKORC1 genotype accounted for only 0.5% and 2.8% of the variation in warfarin dose, respectively. Age was the most important factor influencing dose, accounting for 31.2% of the variation. Another study in 48 Japanese pediatric patients found that patients with VKORC1 1173TT genotype received warfarin doses 28% lower than patients with 1173CT or 1173CC genotypes; however, mean INR values were significantly higher in patients with the 1173TT genotype compared to patients with the 1173CT or 1173CC genotype (1.9 vs. 1.65). Around 30% of the variance associated with warfarin dosing in adults can be attributed to the presence of a VKORC1 variant allele and 40% of the variance in dose can be attributed to the presence of both a CYP2C9 and a VKORC1 variant allele. This is supported by the fact that in Chinese patients, who express a high frequency of variant alleles of the VKORC1 gene, a relatively low maintenance dose of only 3.3 mg +/- 1.4 mg is necessary to achieve an INR of 2 to 2.5. Accordingly, the manufacturer of warfarin indicates that Asian patients may require lower initiation and maintenance doses of warfarin. Several dosing regimens for the initiation of warfarin in adults have been developed based on the presence of polymorphisms, concomitant use of interacting drugs, age, height, weight, and comorbid conditions in patients already stabilized on warfarin therapy. Such dosing regimens may be beneficial in patients to minimize adverse events, especially bleeding. However, these dosing regimens have not been validated in randomized clinical trials. Currently, genetic testing for these polymorphisms is not recommended prior to initiating warfarin therapy; furthermore, in patients where genetic testing is desired, delaying warfarin initiation until the results are known is not recommended. Differences in the frequencies of these variant alleles in people with different ethnic backgrounds exist; for example, in White patients, the frequency of the CYP2C9*2 variant is 8% to 20%, while the frequency of the CYP2C9*3 variant is 6% to 10%. In Black patients, the frequencies are 2% to 4% and 1% to 2% for the presence of CYP2C9*2 or CYP2C9*3 variant alleles, respectively. In Asians, the CYP2C9*2 variant allele does not occur, and the frequency of the CYP2C9*3 variant allele is 1% to 4%. Similarly, ethnicity plays a role in the presence of polymorphisms in the VKORC1 gene. There are several VKORC1 variants that are known to affect warfarin dosing including -1639G>A, 1173C>T, and 3730G>A. Approximately 82%, 89%, and 13% of Asian patients carry variants in these alleles, respectively. In contrast, approximately 14%, 42%, and 45% of White patients, and 0%, 9%, and 49% of Black patients carry variants in these alleles, respectively. In addition, adult patients with CYP2C9 variant alleles may be at increased risk of bleeding compared to patients without these genetic mutations; an increased risk of bleeding in patients with mutations in the VKORC1 gene has not been consistently demonstrated.

In patients at high-risk of bleeding, warfarin should be discontinued prior to dental work. However, patients not at high-risk may continue warfarin therapy in most cases. During dental procedures that require local bleeding control, administer a mouthwash acid or aminocaproic acid mouthwash, without interrupting anticoagulant therapy.

Caution should be observed when warfarin is administered to patients at risk for tissue necrosis and/or gangrene (e.g. patients with diabetes mellitus). Anticoagulations therapy with warfarin may enhance the release of atheromatous plaque emboli, increasing the risk of complication from cholesterol microembolization. Discontinuation of warfarin is recommended when this occurs.

Warfarin should be used with caution in patients with heparin-induced thrombocytopenia (HIT) and deep venous thrombosis. The prothrombotic effects of HIT combined with the procoagulant effects of early warfarin therapy (reduced protein C activity) can result in complications including warfarin-induced skin necrosis and limb gangrene. Cases of venous limb ischemia, necrosis, and gangrene have occurred in these patients when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, amputation of the involved area and/or death occurred. Patients who develop limb gangrene while receiving warfarin often have a high INR (usually more than 4) after starting warfarin therapy. The pathogenesis of warfarin-associated limb gangrene in patients with HIT appears to be insufficient protein C activity (has natural anticoagulant properties) to control the increased thrombin generation seen in these patients. Warfarin can be given safely if thrombin generation is adequately controlled with the use of danaparoid, hirudin, or argatroban, or if warfarin is initiated following resolution of the HIT. Warfarin should not be given alone or in combination with ancrod in patients with acute HIT.

Patients with congestive heart failure may exhibit greater than expected responses to warfarin. These patients require more frequent monitoring and, possibly, reduced doses of warfarin.

Hepatic disease, including infectious hepatitis and cholestasis with symptoms of jaundice, potentiates the response to warfarin therapy by impairing the synthesis of coagulation factors or altering the metabolism of warfarin. In these patients, small doses of warfarin may cause a pronounced hypoprothrombinemic effect; thus, caution is required. Monitor for bleeding more frequently when warfarin is used in hepatically impaired patients.

Intramuscular injections of other drugs should be avoided if possible in patients receiving warfarin. IM injections may cause bleeding, bruising, or hematomas due to the anticoagulant effect of warfarin therapy. If required and appropriate for the administered drug, IM injections should be given to the upper extremities, which permits easy access for manual compression, inspection for bleeding, and use of pressure bandages.

Patients with protein C deficiency or protein S deficiency can become transiently hypercoagulable when warfarin is initiated and may result in necrosis of the skin and underlying tissue. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be consistent for all patients. The initial symptom may be an intense burning in the affected area. If symptoms appear, stop warfarin therapy immediately because skin necrosis can be permanently disfiguring. If warfarin therapy is indicated in patients with protein C deficiency, give heparin with warfarin for the first 5 to 7 days to decrease the risk of tissue necrosis.

Vitamin K deficiency enhances the response to warfarin and may lead to an increased risk of bleeding. The effects of warfarin can be potentiated in patients with poor nutritional status and decreased vitamin K intake (especially if they are treated with antibiotics and IV fluids without vitamin K supplementation) or in states of fat malabsorption. In addition, patients with eating disorders such as anorexia nervosa or bulimia nervosa may have poor or fluctuating vitamin K intake.

Because safe use of warfarin in the outpatient setting depends on good patient compliance, warfarin is contraindicated in unsupervised patients with conditions associated with high levels of non-compliance such as dementia, alcoholism, or psychosis.

Hypermetabolic states produced by fever or hyperthyroidism can increase the responsiveness to warfarin, probably by increasing the catabolism of vitamin K-dependent coagulation factors. Infection or disturbances of intestinal flora due to sprue (Celiac disease) or antibiotic therapy may alter responses to warfarin. Monitor warfarin therapy closely in these situations.

Numerous factors alone or in combination, including travel or changes in diet, environment, physical state, and medication may influence the response to warfarin. It is considered good practice to monitor the patient's response with additional PT/INR determinations in the period immediately after discharge from the hospital and whenever other medications are initiated, discontinued, or taken irregularly. The following conditions, alone or in combination, may be responsible for increased INR responses to warfarin: collagen vascular disease, diarrhea or steatorrhea, and neoplastic disease. Peripheral edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism and nephrotic syndrome, alone or in combination, have been associated with decreased responses to warfarin.

Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden tobacco smoking cessation may reduce the clearance and increase the therapeutic effects of warfarin despite the initiation of a nicotine replacement product. However, the decreased warfarin clearance may not always result in a clinically significant change in the PT or INR. Monitor to assess the need for warfarin dosage adjustment when changes in smoking status occur.

Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. The use of warfarin in neonates and infants is particularly difficult due to rapidly changing physiologic values of the vitamin K dependent clotting factors and frequent changes in diet. Concentrations of the vitamin K dependent clotting factors are decreased in neonates to levels similar to those seen in adults on therapeutic warfarin doses. Also, infant formula is supplemented with vitamin K while breast milk contains very low levels of vitamin K. These factors can increase the sensitivity of neonates and infants to warfarin. The manufacturer recommends more frequent PT/INR determinations due to the possibility of changing warfarin requirements.

Use warfarin with caution in females who may become pregnant. Counsel adolescents about the necessity of the prevention of pregnancy and about using effective contraception during treatment. Warfarin has been shown to cause major congenital malformations (warfarin embryopathy), especially when taken during the first trimester after the 6th week of gestation, and may cause fetal hemorrhage and an increased risk of spontaneous abortion and fetal mortality.

Description: Warfarin is an oral coumarin anticoagulant used to prevent and treat thromboembolic disease in patients with various clinical conditions. Warfarin is a racemic mixture of two active isomers; the S-isomer is 3 to 5 times as potent as the R-isomer. In October 2006, a black box warning was added to the prescribing information concerning the risk of major and sometimes fatal bleeding associated with warfarin therapy. By adopting the International Normalized Ratio (INR) method of monitoring warfarin therapy and decreasing the intensity of anticoagulation for most indications, the major hemorrhagic risks of warfarin therapy have decreased substantially. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported due to developmental changes in vitamin K dependent clotting factors, frequent changes in diet and medications, issues with vascular access, and lack of a liquid preparation. The FDA-approved product labeling recommends more frequent PT/INR determinations due to the possibility of changing warfarin requirements. Specific dosing recommendations for warfarin in pediatric patients are not available in the FDA-approved product labeling; however, it is used in pediatric patients as young as neonates.

General dosing information for systemic anticoagulation
-Pediatric patients should receive up to 3 months of anticoagulation therapy for secondary venous thromboembolism (VTE) and 6 to 12 months of therapy for idiopathic VTE. In patients with ongoing risk factors (e.g., active nephrotic syndrome, asparaginase therapy), anticoagulant therapy should continue beyond 3 months until the risk factor has resolved. In those with recurrent idiopathic VTE, indefinite treatment with warfarin is recommended.

For general dosing information in patients requiring warfarin anticoagulation including patients requiring anticoagulation for deep venous thrombosis (DVT)*, pulmonary embolism*, primary pulmonary hypertension*, cardiomyopathy*, prosthetic heart valves*, cerebral sinovenous thrombosis*, arterial ischemic stroke*, and ventricular assist device*:
Oral dosage:
Neonates: Individualize dose to achieve target INR based on indication. The following is recommended to maintain an INR 2 to 3 in pediatric patients: LOADING DOSE: DAY 1 (baseline INR 1 to 1.3): 0.2 mg/kg/dose PO once; reduce to 0.1 mg/kg/dose in patients with Fontan circulation or hepatic impairment. DAYS 2 thru 4: INR 1.1 to 1.3 = repeat initial load; INR 1.4 to 3 = 50% of initial load; INR 3.1 to 3.5 = 25% of initial load; INR more than 3.5 = hold until INR less than 3.5 then restart at 50% of previous dose. MAINTENANCE DOSE: INR 1.1 to 1.4 = increase dose 20%; INR 1.5 to 1.9 = increase dose 10%; INR 2 to 3 = maintain current dose; INR 3.1 to 3.5 = decrease dose 10%; INR more than 3.5 = hold until INR is less than 3.5 then restart at 20% decreased dose. Max dose is not defined; however, most adult patients are maintained on a dose of 2 to 10 mg/day. Weight-based dosage requirements for warfarin have been determined to be age-dependent. In a large cohort of pediatric patients (n = 263), infants required an average daily dose of 0.33 mg/kg while adolescents required an average daily dose of 0.09 mg/kg to maintain the INR between 2 and 3. Specific dosing recommendations for use in pediatric patients are not available in the FDA-approved product labeling; dosage initiation and adjustments must be made carefully to prevent subtherapeutic or excessive anticoagulation.
Infants, Children, and Adolescents: Individualize dose to achieve target INR based on indication. The following is recommended to maintain an INR 2 to 3 in pediatric patients: LOADING DOSE: DAY 1 (baseline INR 1 to 1.3): 0.2 mg/kg/dose PO once; reduce to 0.1 mg/kg/dose in patients with Fontan circulation or hepatic impairment. DAYS 2 thru 4: INR 1.1 to 1.3 = repeat initial load; INR 1.4 to 3 = 50% of initial load; INR 3.1 to 3.5 = 25% of initial load; INR more than 3.5 = hold until INR less than 3.5 then restart at 50% of previous dose. MAINTENANCE DOSE: INR 1.1 to 1.4 = increase dose 20%; INR 1.5 to 1.9 = increase dose 10%; INR 2 to 3 = maintain current dose; INR 3.1 to 3.5 = decrease dose 10%; INR more than 3.5 = hold until INR is less than 3.5 then restart at 20% decreased dose. Max dose is not defined; however, most adult patients are maintained on a dose of 2 to 10 mg/day. Weight-based dosage requirements for warfarin have been determined to be age-dependent. In a large cohort of pediatric patients (n = 263), infants required an average daily dose of 0.33 mg/kg while adolescents required an average daily dose of 0.09 mg/kg to maintain the INR between 2 and 3. Specific dosing recommendations for use in pediatric patients are not available in the FDA-approved product labeling; dosage initiation and adjustments must be made carefully to prevent subtherapeutic or excessive anticoagulation.

Therapeutic Drug Monitoring:
The response to warfarin is influenced by pharmacokinetic factors (e.g., differences in absorption or metabolism) and pharmacodynamic factors (e.g., differences in hemostatic response to given concentrations of warfarin). Base warfarin dosing on the degree of change from baseline of each patient's individual International Normalized Ratio (INR). The target INR goals are specific to each indication based on the most recent American College of Chest Physicians (ACCP) antithrombotic guidelines.

Target INR
The target therapeutic INR is 2.5 (range 2 to 3) for most pediatric indications. Exceptions include lower target INR of 1.5 to 1.9 for prophylaxis in patients with venous thromboembolism secondary to a central venous access device and higher target INR of 3 (range 2.5 to 3.5) in patients with ventricular assist devices and certain types of mechanical prosthetic heart valves. Pediatric pulmonary hypertension guidelines recommend a goal INR of 1.5 to 2 in young children. For most indications, an INR greater than 3 provides no additional therapeutic benefit and is associated with a higher risk of bleeding.

Frequency of INR Monitoring
ACCP guidelines do not address the frequency of initial INR monitoring specifically for pediatric patients; however, in adult patients in the institutional setting, the INR is usually monitored daily until the therapeutic range has been achieved for at least 2 consecutive days. In the outpatient setting, initial monitoring may be less frequent (e.g., every few days) until a stable INR is reached. INR monitoring in pediatric patients is recommended at a minimum of every 4 weeks once a stable dose is reached, with more frequent monitoring recommended with any change in dose, diet, concomitant medication, or during illness. The use of point-of-care monitoring devices in pediatric patients is recommended when possible; studies comparing these devices to venipuncture INRs have confirmed their accuracy and reliability.

Management of single out-of-range INR
For patients with stable INRs who present with a single INR less than or equal to 0.5 below or above the therapeutic range, the ACCP recommends continuing the current dose and test the INR within 1 to 2 weeks (Grade 2C Recommendation). The ACCP also recommends against routinely administering bridging therapy with heparin for patients with stable therapeutic INRs who present with a single subtherapeutic INR (Grade 2C Recommendation).

Elevated INR/Warfarin-induced Bleeding/Warfarin Reversal Management
Data are limited in pediatric patients. Algorithms for the reversal of warfarin in pediatric patients with elevated INRs, bleeding, or requiring warfarin reversal are extrapolated from adult studies; the ACCP states that in the presence of excessively prolonged INR (more than 8) without significant bleeding, vitamin K may be used. In the presence of significant bleeding, reversal of warfarin using vitamin K, fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa may be required.

Maximum Dosage Limits:
Warfarin has a narrow therapeutic index. The maximum dosage is individualized based on INR monitoring and assessment of efficacy and safety parameters.

Patients with Hepatic Impairment Dosing
Although specific guidelines for dosage adjustment are not available, patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors. Monitor for bleeding frequently.

Patients with Renal Impairment Dosing
No dosage adjustment is necessary in patients with renal failure. Monitor INR more frequently in those with renal impairment to maintain the therapeutic range.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Warfarin inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S. Specifically, warfarin inhibits the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme, which reduces the regeneration of vitamin K epoxide. Vitamin K is a cofactor for the carboxylation of glutamate residues to gamma-carboxyglutamates on the N-terminal regions of vitamin K-dependent proteins. Carboxylation allows the coagulation proteins to undergo a conformational change, which is necessary for their activation. Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase and possibly vitamin K reductase. This results in depletion of the reduced form of vitamin K (vitamin KH2) and limits the gamma-carboxylation of the vitamin K-dependent coagulant proteins. The degree of effect on the vitamin K-dependent proteins is dependent upon the dose of warfarin and, to some extent, the patient's VKORC1 genotype. The anticoagulant effects of warfarin are stereoselective; the S-isomer of warfarin is 2 to 5 times more potent than the R-isomer. Therapeutic doses of warfarin decrease the total amount of active vitamin K-dependent clotting factors produced by the liver by 30% to 50%.

Since warfarin does not affect the activity of synthesized coagulation factors, depletion of these mature factors through normal catabolism and replacement by newly synthesized dysfunctional vitamin K-dependent clotting factors must occur before therapeutic effects of warfarin are seen. Each factor differs in its degradation half-life; factor II 60 hours, factor VII 4 to 6 hours, factor IX 24 hours, and factor X 48 to 72 hours. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively. As a result, 3 to 4 days of therapy may be required before a complete clinical response to any one dosage is seen. Since warfarin reduces the activity of anticoagulant proteins C and S, a hypercoagulable state may be induced for a short period of time after treatment with warfarin is started. The rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.

Warfarin prolongs the prothrombin time (PT), which is responsive to depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X). These factors are reduced by warfarin at a rate proportionate to their respective half-lives. During the first 2 to 5 days of warfarin therapy, the PT primarily reflects the depression of factor VII. With subsequent warfarin treatment, the PT is prolonged by depression of factors II and X. Prothrombin time ratio results can be affected by the responsiveness of the thromboplastin to warfarin. The International Normalized Ratio (INR) has been developed and adopted as a method to standardize monitoring of oral anticoagulant therapy. The PT and INR are related based upon the ISI value (International Sensitivity Index value). The ISI is a measure of the responsiveness of a given thromboplastin to reduction of the vitamin K-dependent coagulation factors compared to the first World Health Organization international reference preparation (IRP). At an ISI value of 0.1, the PT ratio is identical to the INR. As the ISI value of the thromboplastin increases, the INR for a given PT ratio also increases. Therefore, a lower ISI is associated with a more responsive reagent. The INR is less reliable as a measure of anticoagulation in the early course of warfarin therapy; however, it is more reliable than the PT or PT ratio for clinical management.

Warfarin does not affect established thrombus and does not reverse ischemic tissue damage. Warfarin therapy prevents further extension of the clot and prevents secondary thromboembolic complications. The antithrombotic effect of warfarin is generally thought to reflect its anticoagulant effects, mediated through its ability to inhibit thrombin generation by reducing levels of vitamin K-dependent coagulation factors. However, there is evidence that the reduction of prothrombin (factor II), and possibly factor X, is more important than the reduction of factors VII and IX for the antithrombotic effect of warfarin. Reduction in prothrombin levels may result in a decrease in the amount of thrombin that can be generated and bound to fibrin, thereby reducing the thrombogenicity of the clot. If the antithrombotic effect of warfarin is reflected by its ability to lower prothrombin levels, this provides a rationale for overlapping heparin with warfarin in the treatment of patients with thrombotic disease until the prothrombin level is lowered into the therapeutic range. In contrast to heparin, warfarin has no anticoagulant effect in vitro. Warfarin does not affect prostaglandin-mediated platelet aggregation.

The action of warfarin may be overcome by the administration of vitamin K or by transfusion of plasma proteins that contain clotting factors. Hereditary resistance to warfarin has been described. Affected patients may require doses that are 5- to 20-fold higher than average to achieve an anticoagulant effect. This is thought to be due to altered affinity of the receptor for warfarin. There are also anecdotal reports of acquired resistance to warfarin. Acquired resistance to warfarin could be due to poor patient compliance, drug interactions that alter the response to warfarin, exogenous consumption of vitamin K, decreased absorption of warfarin, or increased clearance of warfarin.

Pharmacokinetics: Warfarin is primarily administered orally; however, it can also be administered intravenously. Although warfarin plasma concentrations are detectable within 1 hour of oral administration, anticoagulation effects are dependent on the gradual catabolism of circulating activated clotting factors requiring up to 4 days for complete clinical effect. Therefore, loading doses do not provide more rapid complete anticoagulation and may be associated with the development of a hypercoagulable state. It takes roughly 4 days to return to normal blood coagulation parameters after discontinuation of the drug.

Warfarin is highly bound (about 99%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP) isoenzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). Warfarin alcohols have minimal anticoagulant activity.

The terminal half-life of warfarin after a single dose is 7 days; however, the clinically effective half-life ranges from 20 to 60 hours (mean 40 hours) depending upon the rate of catabolism of activated clotting factors. The clearance of R-warfarin is generally half that of S-warfarin, and thus, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Inactive metabolites of warfarin are excreted in the urine and to a lesser extent in the bile. Up to 92% of orally administered warfarin is recovered in the urine, primarily as metabolites.

Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4
CYP2C9 is the primary enzyme that metabolizes S-warfarin and modulates the in vivo activity of warfarin. CYP1A2 and CYP3A4, and to a lesser extent CYP2C19, metabolize the R-isomer. Although genetic polymorphisms of CYP2C9 have been shown to account for some of the variance associated with warfarin dosing in adult patients, the effects of these polymorphisms on dosing in pediatric patients has not been determined. In a prospective cohort study of 34 White pediatric patients receiving warfarin, CYP2C9 genotype accounted for only 0.5% of the variation in warfarin dose. ACCP does not recommend the routine use of pharmacogenetic testing for patients initiating warfarin therapy. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased hydroxylation of S-warfarin and decrease S-warfarin clearance in adults; the presence of more than 1 of the CYP2C9 variant alleles further decreases clearance. For example, adult patients with CYP2C9 genotypes *1/*2 or *1/*3 have a clearance of 0.041 mL/kg/minute vs. 0.065 mL/kg/minute in patients with CYP2C9 genotypes *1/*1. Additionally, patients with CYP2C9 genotypes *2/*2, *2/*3, or *3/*3 have a clearance of 0.02 mL/kg/minute. In White patients, the frequency of the CYP2C9*2 variant is 8% to 20%, while the frequency of the CYP2C9*3 variant is 6% to 10%. The presence of CYP2C9*2 and *3 variant alleles in Black and Asian patients are much lower (0% to 4%); other CYP2C9 alleles that may decrease warfarin metabolism occur at lower frequencies in all races. Poor CYP2C9 metabolizers are more dependent on the metabolism of S-warfarin via the CYP3A4 pathway. Drugs that affect any of the enzymes involved in the metabolism of warfarin may alter the anticoagulation response. As a result, drugs that preferentially induce the metabolism of S-warfarin impair coagulation to a greater extent than those that induce R-warfarin metabolism.


-Route-Specific Pharmacokinetics
Oral Route
Orally administered warfarin is well absorbed from the GI tract. Administration with food may delay the rate but not the extent of absorption.


-Special Populations
Pediatrics
Children and Adolescents
The body weight adjusted clearance of the pharmacologically active isomer of warfarin, S-warfarin, is faster in younger pediatric patients compared to older pediatric patients and adults and decreases toward adult values throughout childhood. In a pharmacokinetic study in Japanese patients, prepubertal children (n = 38, 1 to 11 years) were shown to have a significantly faster mean clearance of unbound S-warfarin normalized to body weight when compared to pubertal children and adolescents (n = 15, 12 to 18 years) and adults (18.1 vs. 12.6 and 11.6 mL/kg/minute, respectively). The mean clearance of unbound S-warfarin when normalized to body surface area was also significantly faster in prepubertal children compared to adults (574 vs. 438 mL/m2/minute). There were no significant differences between pediatric and adult patients in the mean clearance of unbound R-warfarin.

Hepatic Impairment
Warfarin metabolism may be altered in the presence of hepatic dysfunction. Patients with hepatic impairment may have increased half-lives of warfarin.