(WAR-far-in SO-dee-um)
Coumadin
Anticoagulant (vitamin K antagonist)
pH 8.1 to 8.3
Usual dose
Used primarily for patients on Coumadin when oral dosing is not feasible. IV and oral doses are the same, and administration of the IV formulation should not provide any increased effect or an earlier onset of action. ■ Dose must be individualized and adjusted based on PT/international normalized ratio (INR) and the condition being treated. Consult the latest evidence-based clinical practice guidelines regarding the duration and intensity of anticoagulation for the indicated condition. For most conditions, the warfarin dose should be adjusted to achieve a target INR of 2.5 (INR range of 2 to 3). A higher INR (target INR of 3, with a range of 2.5 to 3.5) may be indicated in select patients with specific types of heart valves. An INR of greater than 4 appears to provide no additional benefit in most patients and is associated with a higher risk of bleeding. Routine use of loading doses is not recommended because this practice may increase the incidence of complications and does not offer more rapid protection against clot formation. ■ Heparin is preferred in situations requiring prompt anticoagulation because the onset of anticoagulant action for warfarin is 24 to 72 hours, and full therapeutic effect is not reached for 5 to 7 days. Conversion to warfarin therapy may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, overlap therapy until warfarin has produced a therapeutic response as determined by PT/INR. Discontinue heparin when therapeutic response is achieved. ■ Duration of treatment is individualized. In general, it should continue until the danger of thrombosis and embolism has passed. See prescribing information and the latest evidence-based clinical practice guidelines for suggested durations of therapy for different indications and/or risk factors. Aspirin may or may not be a component of therapy depending on indication and risk factors. ■ Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by clinical factors that include age, race, body weight, gender, concomitant medications, comorbidities, and genetic factors (CYP2C9 and VKORC1 genotypes). See prescribing information and Dose Adjustments for dosing related to specific genotypes.
Initial dose:
Select the starting dose based on the expected maintenance dose, taking into account the above factors. If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose is usually 2 to 5 mg/day. Adjust dose based on patient-specific clinical factors and PT/INR determination.
Maintenance dose:
2 to 10 mg/day. Adjust dose to maintain desired INR.
Pediatric dose
Safety for use in pediatric patients under 18 years of age not established, but is used. Usually given PO. See Maternal/Child.
Dose adjustments
Use low initial doses in elderly, debilitated, or Asian patients and in patients with expected increased PT/INR responses. ■ Patients with genetic factors (CYP2C9 and VKORC1 genotypes) may require a reduced dose because these alleles may be associated with reduced clearance of warfarin. ■ Use lower end of dose range in patients at increased risk of bleeding or those on aspirin therapy. ■ Reduced dose may be required in impaired hepatic function due to the impaired synthesis of clotting factors and the decreased metabolism of warfarin. ■ No dose adjustment is required in impaired renal function. ■ Higher doses may be required in selected situations (e.g., patients with recurrent systemic embolism or mechanical prosthetic valves).
Dilution
Available as a 5-mg lyophilized powder in a single-use vial. Reconstitute the 5-mg vial with 2.7 mL of SWFI to obtain a solution with a final concentration of 2 mg/mL.
Storage:
Protect from light by storing in carton at CRT. Store reconstituted solution at room temperature and use within 4 hours. Do not refrigerate; discard any unused solution.
Compatibility (underline indicates conflicting compatibility information)
Consider any drug NOT listed as compatible to be INCOMPATIBLE until consulting a pharmacist; specific conditions may apply.
Some adsorption may occur in PVC containers and tubing when diluted in D5W or NS.
One source suggests the following compatibilities:
Y-site:
Amikacin, ammonium chloride, ascorbic acid, bivalirudin (Angiomax), cefazolin (Ancef), ceftriaxone (Rocephin), dopamine, epinephrine (Adrenalin), heparin, lidocaine, morphine, nitroglycerin IV, oxytocin (Pitocin), potassium chloride (KCl), ranitidine (Zantac), vancomycin.
Rate of administration
A single dose as an injection into a peripheral vein over 1 to 2 minutes.
Actions
An anticoagulant that acts by inhibiting the synthesis of vitamin K–dependent coagulation factors (e.g., factor II, VII, IX, and X) and the anticoagulant proteins C and S in the liver, resulting in a depression of their activities. An anticoagulant effect occurs within 24 hours; however, peak anticoagulant effect may be delayed for 72 to 96 hours. Approximately 99% bound to plasma proteins. Effective half-life ranges from 20 to 60 hours, with a mean of 40 hours. Effects may be more pronounced as daily maintenance doses overlap. Well-established clots are not dissolved, but growth is prevented. Metabolized by hepatic microsomal enzymes (cytochrome P450 system) to inactive metabolites and reduced metabolites. Excreted primarily in urine. Crosses the placental barrier.
Indications and uses
Prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism (PE). ■ Prophylaxis and treatment of the thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement. ■ Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction. ■ Treatment of patients receiving oral warfarin who are unable to take oral medication.
Limitation of use:
Warfarin has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.
Contraindications
Pregnancy, except in women with mechanical heart valves, who are at high risk of thromboembolism; see Maternal/Child. ■ Patients with (1) hemorrhagic tendencies or blood dyscrasias; (2) recent or contemplated surgery of the CNS or eye or traumatic surgery resulting in large open surfaces; (3) bleeding tendencies associated with active ulceration or overt bleeding of GI, GU, or respiratory tracts; central nervous system hemorrhage; cerebral aneurysm; dissecting aorta; pericarditis; pericardial effusions; and bacterial endocarditis; (4) threatened abortion, eclampsia, or pre-eclampsia; (5) conditions associated with a potentially high level of noncompliance (unsupervised patients); (6) spinal puncture and other diagnostic or therapeutic procedures with the potential for uncontrollable bleeding; (7) hypersensitivity to warfarin; (8) major regional or lumbar block anesthesia; (9) malignant hypertension.
Precautions
For IV use only; do not administer IM. ■ Warfarin can cause major or fatal bleeding. Hemorrhage in any tissue or organ is one of the most serious risks associated with warfarin therapy. Bleeding is more likely to occur within the first month of therapy and with higher doses (resulting in a higher INR). Risk factors for hemorrhage include an INR greater than 4 or a history of highly variable INRs, elderly patients age 65 or older, history of GI bleed, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors, concomitant drugs that affect hemostasis, and a long duration of therapy. ■ Necrosis and/or gangrene is an uncommon but serious risk associated with warfarin therapy. Necrosis appears to be associated with local thrombosis and usually appears within a few days of initiation of therapy. In severe cases, débridement or amputation may be required. ■ Anticoagulation with warfarin may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of S/S depending on the site of embolization. S/S may include abdominal, back, or flank pain; abrupt and intense pain in the leg, foot, or toes; cerebral ischemia; foot ulcers; gangrene; hematuria; hypertension; livedo reticularis (reddish blue mottling of skin on exposure to cold); myalgias; pancreatitis; “purple toes syndrome”; rash; and renal insufficiency. The kidney is the most commonly involved visceral organ, followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis and death. ■ Do not use warfarin as initial therapy in patients with heparin-induced thrombocytopenia (HIT) or in patients with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients with HIT or HITTS when heparin was discontinued and warfarin was started or continued. Treatment with warfarin can be considered after the platelet count has normalized. ■ Warfarin may increase the aPTT, even in the absence of heparin. A severe aPTT elevation (greater than 50 seconds) with a PT/INR in the normal range is an indicator of increased risk of postoperative hemorrhage. ■ Use caution in elderly or debilitated patients or in patients with moderate to severe hepatic impairment, moderate to severe hypertension, diabetes mellitus, indwelling catheters, infectious diseases or disturbances of the intestinal flora (e.g., sprue, antibiotic therapy), polycythemia vera, vasculitis, or known or suspected deficiency in protein C anticoagulant response. ■ Increased PT/INR response may occur in patients with diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency. ■ Decreased PT/INR response may occur with increased vitamin K intake or in patients with hereditary warfarin resistance. ■ If dental procedures or other minor surgical procedures are necessary, the PT/INR should be adjusted to the lower end of the therapeutic range. Monitor PT/INR just before treatment. Operative site should be limited so local procedures for hemostasis can be used. Warfarin therapy may have to be interrupted; consider risks versus benefits. ■ Limit IM injections of concomitant medications to the upper extremities to permit easy access for manual compression, inspection for bleeding, and the use of pressure bandages.
Monitor:
Obtain baseline PT/INR. Frequent monitoring of PT/INR is required. Usually repeated daily during initiation of therapy and then every 1 to 4 weeks after PT/INR has stabilized in the therapeutic range. Monitor with any change in patient regimen that may affect treatment (e.g., diet, illness, change in drug regimen). Draw blood for prothrombin just before a heparin dose being given concomitantly. If heparin is given as a continuous infusion, PT/INR may be drawn at any time; see Precautions. ■ Because heparin may affect the PT/INR in patients receiving both heparin and warfarin, PT/INR determinations should be drawn 5 hours after the last IV bolus dose of heparin, 4 hours after a heparin infusion has been discontinued, or 24 hours after the last SC injection of heparin. ■ Patients at high risk for bleeding may benefit from more frequent monitoring of INR, careful dose adjustments to desired INR, and a shorter duration of therapy. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. ■ Monitor for S/S of hemorrhage, necrosis, cholesterol microembolization, and the possible sequelae; see Precautions. ■ Has a narrow therapeutic range that can be affected by other drugs and dietary vitamin K. See Drug/Lab Interactions. ■ Determinations of whole blood clotting and bleeding times are not effective measures for monitoring warfarin therapy. ■ See Maternal/Child.
Patient education:
Read manufacturer’s medication guide. ■ Effective contraception is required during treatment and for at least 1 month after the final dose of warfarin. ■ Adhere to dose schedule; do not take or discontinue any prescription or over-the-counter medication, including herbal products, without physician’s approval. ■ Confirm procedure for missed dose. ■ Avoid alcohol. Eat a normal balanced diet, maintaining a consistent vitamin K intake. Avoid cranberry products. ■ Avoid any activity or sport that may result in traumatic injury. ■ Regular PT/INR testing and physician visits are imperative. ■ Notify physician of unusual bleeding (e.g., increased menstrual flow, nosebleeds, tarry stools), any illness (e.g., diarrhea, infection, fever), headache, dizziness, or weakness. ■ Carry an ID stating that warfarin is being taken.
Maternal/child:
Warfarin is contraindicated in women who are pregnant, except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism and for whom the benefits of warfarin may outweigh the risks to the fetus. Warfarin can cause fetal harm. Exposure during pregnancy caused a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. ■ Verify the pregnancy status of females of reproductive potential before initiating warfarin therapy. ■ Limited data suggest that warfarin is not present in breast milk. However, because of the potential adverse effects on the breast-fed infant, caution is advised. Monitor breast-feeding infants for bruising or bleeding. ■ Safety and effectiveness for use in pediatric patients not established; however, use is well documented for prevention and treatment of thromboembolic events. Dosing of warfarin in pediatric patients varies with age, with infants generally having the highest and adolescents having the lowest mg/kg dose requirements to maintain target INRs. Difficulty in achieving and maintaining a therapeutic PT/INR in pediatric patients has been reported. More frequent PT/INR determinations are recommended. ■ Infants and children receiving vitamin K–supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, whereas infants fed human milk may be sensitive to warfarin therapy.
Elderly:
No overall differences in effectiveness or safety were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Less warfarin is required to produce a therapeutic level of anticoagulation in patients over 60 years of age; may have a greater-than-expected PT/INR response; see Dose Adjustments and Precautions. ■ Not recommended for use in an unsupervised patient with senility.
Drug/lab interactions
Drugs, dietary changes, and other factors affect INR levels achieved with warfarin. Monitor PT/INR carefully when drugs are added or discontinued or diet is modified. Interactions are numerous and potentially life threatening. Review of drug profile by pharmacist is imperative. ■ Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms include synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions are mainly enzyme induction or inhibition and reduced plasma protein binding. Some drugs may interact by more than one mechanism. ■ Some of the most significant drug interactions are listed in the following chart. This list is not all-inclusive. See manufacturer’s prescribing information for additional medications that may interact with warfarin, and consult the labeling of all concurrently used drugs to obtain further information. ■ The three more important CYP450 isozymes involved in the metabolism of warfarin are CYP2C9, CYP1A2 and CYP3A4. Inhibitors of these enzymes have the potential to increase the effect (increase the INR) of warfarin. Inducers of these enzymes have the potential to decrease the effect (decrease the INR) of warfarin. The following chart lists examples of inhibitors and inducers of these enzymes.
| Examples of CYP450 Interactions with Warfarin | ||
| Enzyme | Inhibitors | Inducers |
| CYP2C9 | Amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | Aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | Acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | Montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | Alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | Armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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