Warfarin (Coumadin)

Emergency & Prehospital

• Warfarin-associated bleeding: On any bleed in a patient taking warfarin, the INR comes first. Reversal is in Overdose & Toxicity
• Medication history: confirm warfarin use, the last dose, the last INR and any new antibiotic, antifungal or supplement

ED / ICU / Transport

• Venous thromboembolism: treatment and prevention of DVT and PE, and prevention of their extension (see pulmonary embolism). Current guidance generally prefers a DOAC for most VTE. Warfarin is the fallback when a DOAC is unsuitable
• Non-valvular atrial fibrillation: prevention of thromboembolic complications (stroke, systemic embolism). For eligible patients, guidelines prefer a DOAC. Warfarin is the fallback when a DOAC is unsuitable
• Rheumatic mitral stenosis with AF: the label names warfarin as the anticoagulant. DOACs are not recommended in moderate-to-severe rheumatic mitral stenosis
• Mechanical or bioprosthetic heart valves: Prevents valve thrombosis and thromboembolism. Valve type and risk factors set the INR target (see the Dosing table). Don't use a DOAC with a mechanical valve
• Myocardial infarction: Fewer deaths, recurrent MI and thromboembolism. High-risk patients take warfarin with low-dose aspirin for at least 3 months (label)
• LVAD recipients: thromboprophylaxis and reversal planning (see the LVAD page)

Other Uses

• Antiphospholipid syndrome: vitamin K antagonist therapy is the usual choice. That is off-label for warfarin labeling, per EULAR 2019 recommendations
• Heparin-induced thrombocytopenia: warfarin starts only after platelets recover, never during the acute phase (see Contraindications)

Doses vary by protocol; follow local protocols and medical direction.

Available Forms

• Oral tablets, US labeling: 1 mg (pink), 2 mg (lavender), 2.5 mg (green), 3 mg (tan), 4 mg (blue), 5 mg (peach), 6 mg (teal), 7.5 mg (yellow), 10 mg (white) per the Teva label; tablet colors are manufacturer-specific
• Brand products: Jantoven (Upsher-Smith) has a current US label. Coumadin (brand) has no current US prescribing information on openFDA and is treated as discontinued, but older records still show it. Many manufacturers dispense generic equivalents
• No parenteral form in US labeling: warfarin is given by mouth only; IV reversal uses vitamin K and 4-factor PCC or plasma (see Overdose & Toxicity)

Adult Dosing

Pediatric Dosing

Preparation & Administration

• Route: oral only in US labeling (tablets)
• Monitoring schedule: daily INR until stable in the therapeutic range, then every 1 to 4 weeks (label 2.1 and 2.4)
• Dose changes: adjust by INR for each new drug, antibiotic, botanical or diet change; recheck INR after any change
• Storage: 20–25 °C (68–77 °F), controlled room temperature (label)

Contraindications

• Pregnancy (except pregnant women with mechanical heart valves at high thromboembolic risk, after risk-benefit review)
• Hemorrhagic tendencies or blood dyscrasias; active ulceration or overt bleeding of the GI, genitourinary or respiratory tract
• CNS hemorrhage, cerebral aneurysm, dissecting aorta, pericarditis or pericardial effusion, bacterial endocarditis
• Recent or planned surgery of the CNS or eye, or traumatic surgery with large open surfaces; spinal puncture or other procedures with uncontrollable bleeding risk; major regional or lumbar block anesthesia
• Malignant hypertension; threatened abortion, eclampsia or preeclampsia
• Known hypersensitivity to warfarin or any product component
• Unsupervised patients with a high risk of non-adherence (label)

Precautions

• Older adults: the INR responds more strongly from age 60, and bleeding risk rises from 65
• Heparin-induced thrombocytopenia: warfarin started during HIT has caused limb ischemia, amputation and death. Start only once platelets have recovered
• Tissue necrosis and calciphylaxis: skin or tissue necrosis and fatal calciphylaxis have happened. Discontinue and consider another anticoagulant
• Label-listed settings with increased bleeding risk (label 5.8): moderate to severe hepatic impairment; infectious disease or intestinal flora disturbance (including antibiotic therapy); indwelling catheter; severe hypertension; protein C deficiency

Hold / Reassess If

• INR above the target range for the indication: hold or reduce the dose, recheck INR, and follow protocol
• INR above target to 10 without bleeding: hold or reduce the dose and recheck INR; routine vitamin K is not given
• INR above 10 without bleeding: hold warfarin; oral vitamin K 2.5–5 mg PO per protocol (see Overdose & Toxicity)
• Any bleeding or hemoglobin fall of 2 g/dL or more: stop warfarin and assess for major bleeding
• Planned surgery or procedure: hold timing and bridging per the procedural team and protocol. Routine heparin bridging is not advised for most AF patients. Mechanical valves and recent VTE need specialist planning

Common

• Bleeding (most common): bruising, petechiae, gum or nose bleeding, blood in urine or stool, excessive menstrual bleeding, persistent oozing from minor injury
• Other reactions (label section 6): hypersensitivity and urticaria, vasculitis and hepatobiliary disorders. The reviewed label section does not state frequencies

Serious / Life-Threatening

Overdose & Toxicity Management

• Signs: bleeding (as above) with an INR above the target range. The label lists bleeding as how excessive anticoagulation presents
• Immediate management: stop warfarin; define bleeding severity (major: critical site, instability, hemoglobin fall of 2 g/dL or more, or 2 or more units of red cells); control the source
• No bleeding: INR above target to 10: hold or reduce warfarin and recheck INR; routine vitamin K is not given. INR above 10: oral vitamin K 2.5–5 mg per protocol (see the vitamin K page)
• Vitamin K: 5–10 mg IV, diluted and infused no faster than 1 mg/min, for major bleeding; give with PCC. Boxed warning (phytonadione): fatal and severe hypersensitivity or anaphylactoid reactions have occurred with IV use, even when diluted and infused slowly. IV use is limited to situations where the subcutaneous route is not feasible and the serious risk is justified. Adult and pediatric detail sits on the vitamin K page
• 4-factor PCC (Kcentra): dose in Factor IX units per kg by pretreatment INR: 25 units/kg for INR 2 to under 4 (max 2,500 units), 35 units/kg for INR 4–6 (max 3,500 units), 50 units/kg for INR above 6 (max 5,000 units); weight capped at 100 kg; give concurrently with vitamin K; repeat dosing not recommended (manufacturer dosing guide). Boxed warning: arterial and venous thromboembolic complications. Contraindicated in disseminated intravascular coagulation, known heparin-induced thrombocytopenia (it contains heparin) and known anaphylactic reactions to its components. Not studied within 3 months of a thromboembolic event, MI or stroke. The warfarin label (section 10.2) limits PCC to exceptional or life-threatening bleeding. Weigh the thrombotic risk (mechanical valve, recent VTE) against the bleed. See prothrombin complex concentrate
• Intracranial hemorrhage: the 2022 AHA/ASA guideline favors fast INR correction with 4F-PCC over plasma, given with IV vitamin K. Involve neurosurgery per protocol
• Plasma: a fallback when PCC is unavailable. Volume, infection and thrombosis risks apply (label). The vitamin K page lists 10–15 mL/kg
• Extracorporeal and surgical: for life-threatening bleeding that does not respond, involve the surgical or neurosurgical team (protocol)

Clinically Significant Interactions

• Pediatrics: controlled trials have not established use in children. Dosing is INR-guided and specialist-directed. See the Pediatric Dosing table. Avoid traumatic-injury activity (label 8.4)
• Neonates: infants may be resistant on vitamin K-supplemented formula and sensitive on human milk (label 8.4). This is a specialist decision only
• Pregnancy: warfarin crosses the placenta. First-trimester exposure produced a pattern of malformations in about 5% of exposed offspring: warfarin embryopathy, with nasal hypoplasia, stippled epiphyses, and CNS and eye anomalies. Fetal hemorrhage and miscarriage are also risks (label 8.1). It is contraindicated, except for pregnant women with mechanical valves at high thromboembolic risk, where the benefit may outweigh the risk. The treating specialist makes that call
• Lactation: in one limited published study, warfarin was not detected in human milk. Weigh the benefit of breastfeeding against the maternal need. Watch breastfed infants for bruising or bleeding (label 8.2)
• Older Adults: the INR responds more strongly from age 60, and age 65 and older is a bleeding risk factor. Consider lower starting doses and more frequent bleeding checks (label 8.5). AGS Beers Criteria status not confirmed in this revision (see editorFlags)
• Renal Impairment: renal impairment raises bleeding risk, and label 8.6 directs frequent INR monitoring. The label gives no creatinine clearance cut-off, so titrate by INR
• Hepatic Impairment: moderate to severe hepatic impairment is a listed bleeding risk setting (label 5.8). Monitor the INR closely
• Obesity / Dosing Weight: warfarin is dosed by INR, not by a weight formula. Body weight is one of several factors in the initial dose (label 2.3)
• Genetic factors: CYP2C9 and VKORC1 variants lower warfarin requirements. Genotype-guided initial dosing is in the label (2.3, Table 1). Asian patients may need lower doses

Mechanism of Action

• Target: inhibits vitamin K epoxide reductase complex 1 (VKORC1), reducing regeneration of reduced vitamin K
• Effect: you get fewer working vitamin K-dependent factors II, VII, IX and X, and fewer active proteins C and S
• Consequence: PT and INR prolong. The effect tracks the half-lives of the factors (factor VII 4–6 hr, factor IX 24 hr, factor X 48–72 hr, factor II about 60 hr; label 12.2)
• Clinical meaning: it does not dissolve a clot that already exists or reverse ischemic injury (label indications)

Pharmacokinetics

• Half-life: terminal half-life about 1 week after a single dose; effective half-life 20–60 hr (label 12.3)
• Metabolism: almost entirely hepatic. The S-enantiomer, 2–5 times more anticoagulant, is cleared by CYP2C9. The R-enantiomer is cleared by CYP1A2 and 3A4
• Active metabolites: reduced metabolites have minimal anticoagulant activity
• Elimination: as inactive metabolites, almost entirely by metabolism
• Protein binding and volume: about 99% plasma protein bound; volume of distribution about 0.14 L/kg

Generic Name

Warfarin sodium (racemic mixture of R- and S-enantiomers)

Brand Names

Coumadin (brand; no current US prescribing information found, treat as discontinued; still seen in older records); Jantoven (Upsher-Smith); many generic manufacturers

Pharmacologic Class

Vitamin K antagonist (VKORC1 inhibitor)

Therapeutic Class

Oral anticoagulant

Controlled Substance

Not controlled

ISMP High-Alert

Yes: antithrombotic agent on the ISMP acute-care list (per secondary reproductions; confirm)

Look-Alike / Sound-Alike

None commonly reported; brand and generic names both appear on prescriptions

Error-Prone Abbreviations to Avoid

None specific to warfarin