General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

**BEERS Drug**

Genetic Implications:

Pronunciation:
war-fa-rin

Trade Name(s)

• Coumadin
• Jantoven

Ther. Class.

anticoagulants

Pharm. Class.

coumarins

Indications

• Prophylaxis and treatment of:

  • Venous thrombosis,
  • Pulmonary embolism,
  • Atrial fibrillation with embolization.
• Management of MI
• Prevention of thrombus formation and embolization after prosthetic valve placement.

Action

Interferes with hepatic synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X).

Therapeutic Effect(s):

Prevention of thromboembolic events.

Pharmacokinetics

Absorption: Well absorbed from the GI tract after oral administration.

Distribution: Minimally distributed to tissues.

Protein Binding: 99%.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP2C9 isoenzyme, with some metabolism via the CYP3A4 isoenzyme;  the CYP2C9 isoenzyme exhibits genetic polymorphism (intermediate or poor metabolizers may have significantly ↑ (S)-warfarin concentrations and an ↑ risk of adverse reactions).

Half-life: 42 hr.

TIME/ACTION PROFILE (effects on coagulation tests)

Contraindication/Precautions

Contraindicated in:

• Uncontrolled bleeding;
• Open wounds;
• Active ulcer disease;
• Recent brain, eye, or spinal cord injury or surgery;
• Severe hepatic impairment;
• Uncontrolled hypertension;
• OB:  Pregnancy.

Use Cautiously in:

• Malignancy;
• History of ulcer, liver disease, or acute kidney injury;
• History of poor compliance;
•  Asian patients or those who carry the CYP2C9*2 allele and/or the CYP2C9*3 allele, or with the VKORC1 AA genotype (↑ risk of bleeding with standard dosing; lower initial doses should be considered);
• Rep:  Women of reproductive potential;
• Pedi:  Has been used safely in children, but may require more frequent PT/INR assessments;
• Geri:  Appears on Beers list. ↑ risk of major bleeding when compared to direct acting oral anticoagulants (DOACs) in older adults. Avoid starting as initial therapy for treatment of nonvalvular atrial fibrillation or venous thromboembolism unless alternative options (DOACs) are contraindicated or there are significant barriers to their use. If already using warfarin, it may be reasonable to continue treatment, especially if INR is well controlled (i.e., >70% time in therapeutic range) and no adverse effects.

Adverse Reactions/Side Effects

Derm: dermal necrosis

GI: cramps, nausea

GU: CALCIPHYLAXIS

Hemat: BLEEDING

Misc: fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Androgens,  capecitabine,  cefotetan,  chloramphenicol,  clopidogrel,  disulfiram,  fluconazole,  fluoroquinolones,  itraconazole,  metronidazole  (including vaginal use),  thrombolytics,  eptifibatide,  tirofiban,  sulfonamides,  quinidine,  quinine,  NSAIDs,  valproates, and  aspirin  may ↑ the response to warfarin and ↑ the risk of bleeding.
• Chronic use of  acetaminophen  may ↑ the risk of bleeding.
• Chronic  alcohol  ingestion may ↓ action of warfarin; if chronic  alcohol  abuse results in significant liver damage, action of warfarin may be ↑ due to ↓ production of clotting factor.
• Acute  alcohol  ingestion may ↑ action of warfarin.
•  Barbiturates,  carbamazepine,  rifampin, and  hormonal contraceptives containing estrogen  may ↓ the anticoagulant response to warfarin.
•  Many other drugs  may affect the activity of warfarin.

Drug-Natural Products:

•  St. John's wort  ↓ effect.
• ↑ bleeding risk with  anise,  arnica,  chamomile,  clove,  dong quai,  fenugreek,  feverfew,  garlic,  ginger,  ginkgo,  Panax ginseng,  licorice , and others.

Drug-Food:

Ingestion of large quantities of foods high in vitamin K content (see list in food sources for specific nutrients) may antagonize the anticoagulant effect of warfarin.

Route/Dosage

 PO (Adults): 2–5 mg/day for 2–4 days; then adjust daily dose by results of INR. Initiate therapy with lower doses in older adults or in  Asian patients or those with CYP2C9*2 and/or CYP2C9*3 alleles or VKORC1 AA genotype.

PO (Children >1 mo): Initial loading dose:  0.2 mg/kg (maximum dose: 10 mg) for 2–4 days then adjust daily dose by results of INR, use 0.1 mg/kg if hepatic impairment is present.  Maintenance dose range:  0.05–0.34 mg/kg/day.

Availability (generic available)

Tablets: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Assessment

• Assess for signs of bleeding and hemorrhage (bleeding gums; nosebleed; unusual bruising; tarry, black stools; hematuria; fall in hematocrit or BP; guaiac-positive stools, urine, or nasogastric aspirate).
• Assess for evidence of additional or increased thrombosis. Symptoms depend on area of involvement.

Lab Test Considerations:

Monitor PT, INR, and other clotting factors frequently during therapy; monitor more frequently in patients with renal impairment. Therapeutic PT ranges 1.3–1.5 times greater than control; however, the INR, a standardized system that provides a common basis for communicating and interpreting PT results, is usually referenced. Normal INR (not on anticoagulants) is 0.8–1.2. An INR of 2.5–3.5 is recommended for patients at very high risk of embolization (for example, patients with mitral valve replacement and ventricular hypertrophy). Lower levels are acceptable when risk is lower. Heparin may affect the PT/INR; draw blood for PT/INR in patients receiving both heparin and warfarin at least 5 hr after the IV bolus dose, 4 hr after cessation of IV infusion, or 24 hr after SUBQ heparin injection.  Asian patients and those who carry the CYP2C9*2 allele and/or the CYP2C9*3 allele, or those with VKORC1 AA genotype may require more frequent monitoring and lower doses.

• Geri:  Patients over 60 yr exhibit greater than expected PT/INR response. Monitor for side effects at lower therapeutic ranges.
• Pedi:  Achieving and maintaining therapeutic PT/INR ranges may be more difficult in pediatric patients. Assess PT/INR levels more frequently.
• Monitor hepatic function and CBC before and periodically throughout therapy.
• Monitor stool and urine for occult blood before and periodically during therapy.

Withholding 1 or more doses of warfarin is usually sufficient if INR is excessively elevated or if minor bleeding occurs. If overdose occurs or anticoagulation needs to be immediately reversed, the antidote is vitamin K (phytonadione). Administration of whole blood or plasma also may be required in severe bleeding because of the delayed onset of vitamin K.

Implementation

• High Alert: Do not confuse Jantoven with Janumet or Januvia .
• Because of the large number of medications capable of significantly altering warfarin's effects, careful monitoring is recommended when new agents are started or other agents are discontinued. Interactive potential should be evaluated for all new medications (Rx, OTC, and herbal products).
• PO Administer medication at same time each day. Medication requires 3–5 days to reach effective levels; usually begun while patient is still on heparin.
  • Do not interchange brands; potencies may not be equivalent.

Patient/Family Teaching

• Instruct patient to take medication as directed. Take missed doses as soon as remembered that day; do not double doses. Inform health care professional of missed doses at time of checkup or lab tests. Inform patients that anticoagulant effect may persist for 2–5 days following discontinuation. Advise patient to read  Medication Guide  before starting therapy and with each Rx refill in case of changes.
• Review foods high in vitamin K (see food sources for specific nutrients). Patient should have consistent limited intake of these foods, as vitamin K is the antidote for warfarin, and alternating intake of these foods will cause PT levels to fluctuate. Advise patient to avoid cranberry juice or products during therapy.
• Caution patient to avoid IM injections and activities leading to injury. Instruct patient to use a soft toothbrush, not to floss, and to shave with an electric razor during warfarin therapy. Advise patient that venipunctures and injection sites require application of pressure to prevent bleeding or hematoma formation.
• Advise patient to report any symptoms of unusual bleeding or bruising (bleeding gums; nosebleed; black, tarry stools; hematuria; excessive menstrual flow) and pain, color, or temperature change to any area of your body to health care professional immediately.  Patients with a deficiency in protein C and/or S mediated anticoagulant response may be at greater risk for tissue necrosis.
• Instruct patient not to drink alcohol or take other Rx, OTC, or herbal products, especially those containing aspirin or NSAIDs, or to start or stop any new medications during warfarin therapy without advice of health care professional.
• Rep:   May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 1 month after last dose. Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding.
• Instruct patient to carry identification describing medication regimen at all times and to inform all health care personnel caring for patient on anticoagulant therapy before lab tests, treatment, or surgery.
• Emphasize the importance of frequent lab tests to monitor coagulation factors.

Evaluation/Desired Outcomes

Prolonged PT (1.3–2.0 times the control; may vary with indication) or INR of 2–4.5 without signs of hemorrhage.