Unifarin

Approved Indications:

• Venous Thromboembolism (VTE):
• Treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE).
• Thromboembolic Complications:
• Prevention and treatment of thromboembolism in patients with:
• Atrial fibrillation (AF)
• Mechanical or bioprosthetic heart valves
• Post-myocardial infarction (MI) at risk for systemic embolism
• Stroke Prevention:
• In patients with non-valvular atrial fibrillation who are not candidates for direct oral anticoagulants (DOACs)

Clinically Accepted Off-Label Uses:

• Antiphospholipid Syndrome (APS): Long-term anticoagulation to prevent recurrent thrombosis.
• Left Ventricular (LV) Thrombus: To prevent embolization in patients with LV dysfunction.
• Intracardiac Thrombi: In dilated cardiomyopathy or severe heart failure.
• Portal Vein Thrombosis: In non-cirrhotic or selected cirrhotic patients with preserved platelet count and no varices.
• Hypercoagulable States: Including protein C/S deficiency, factor V Leiden, and malignancy-associated thrombosis (when DOACs are contraindicated).

Route of Administration: Oral
Frequency: Once daily, preferably at the same time
Monitoring Required: INR (International Normalized Ratio) regularly

Adults:

• Initial Dose: 5–10 mg once daily for 1–2 days;
  Lower starting dose (2–5 mg) recommended in elderly, debilitated, liver disease, or malnourished patients.
• Maintenance Dose: Typically 2–10 mg/day based on INR response.
• Target INR:
• Most indications: 2.0–3.0
• Mechanical heart valves: 2.5–3.5 (depending on valve type and position)

Pediatrics:

• Initial Dose: 0.2 mg/kg/day (lower if liver impairment or other risk factors)
• INR Target: 2.0–3.0 (or individualized)
• Adjustment: Based on INR and clinical response

Elderly:

• Start at lower doses (2–5 mg daily); more sensitive to anticoagulant effects.

Renal Impairment:

• No specific dose adjustment, but enhanced monitoring advised due to increased bleeding risk.

Hepatic Impairment:

• Caution required; dose reduction and close INR monitoring necessary.

Perioperative Use:

• Discontinue 5 days before surgery; bridge with heparin if high thrombotic risk.
• Resume post-operatively once hemostasis is achieved.

Warfarin inhibits vitamin K epoxide reductase complex 1 (VKORC1) in the liver, which is responsible for recycling vitamin K. Vitamin K is essential for the activation (gamma-carboxylation) of clotting factors II, VII, IX, and X, and anticoagulant proteins C and S. By preventing vitamin K regeneration, warfarin reduces the synthesis of active clotting factors, resulting in impaired coagulation and prevention of thrombus formation. The anticoagulant effect develops gradually as existing clotting factors are depleted over 2–3 days.

• Absorption: Rapid and nearly complete after oral administration
• Bioavailability: ~100%
• Protein Binding: >99% (primarily to albumin)
• Distribution: Small volume of distribution; does not cross the blood-brain barrier
• Metabolism: Hepatic via cytochrome P450 enzymes (mainly CYP2C9; also CYP1A2 and CYP3A4)
• Metabolites: Inactive hydroxylated derivatives
• Half-Life: Average ~40 hours (range 20–60 hours)
• Excretion: Renal (as inactive metabolites), <1% unchanged
• Onset of Action: 24–72 hours
• Peak Effect: 72–96 hours
• Duration of Effect: 2–5 days after discontinuation

Pregnancy:

• Category X: Contraindicated in pregnancy (except rare high-risk conditions such as mechanical heart valves under specialist care)
• Risks Include: Warfarin embryopathy (nasal hypoplasia, stippled epiphyses), CNS defects, fetal hemorrhage, stillbirth, miscarriage

Lactation:

• Warfarin is considered safe during breastfeeding
• Not detected in breast milk in significant amounts
• No adverse effects on infants reported
• Caution in neonates with bleeding disorders

• Primary Class: Anticoagulant
• Subclass: Vitamin K Antagonist (VKA)

• Known hypersensitivity to warfarin or any excipients
• Active major bleeding
• Severe hepatic impairment
• Recent surgery with high bleeding risk (e.g., CNS, ocular)
• Pregnancy (except with high-risk mechanical valves)
• Unsupervised or non-compliant patients
• Hemorrhagic tendencies or blood dyscrasias
• Severe uncontrolled hypertension
• Bacterial endocarditis with cerebral embolism risk

• Boxed Warning: May cause major or fatal bleeding; regular INR monitoring is mandatory.
• Monitoring: INR, complete blood count (CBC), liver function tests
• Risk Factors for Bleeding: Age >65, history of GI bleeding, stroke, malignancy, anemia, renal/liver impairment
• Dietary Vitamin K: Maintain consistent intake; sudden changes may alter INR
• Genetic Variants (CYP2C9, VKORC1): May require dose adjustment
• Purple Toe Syndrome: Rare cholesterol embolization; discontinue if suspected
• Skin Necrosis: Early-onset; more common in protein C/S deficiency

Common Adverse Effects:

• Minor bleeding (epistaxis, bruising, gum bleeding)
• Nausea
• Fatigue
• Abdominal discomfort

Serious Adverse Effects:

• Major bleeding (intracranial, GI, retroperitoneal)
• Warfarin-induced skin necrosis
• Purple toe syndrome
• Cholesterol microembolization
• Hypersensitivity reactions (rash, urticaria)

Rare Effects:

• Alopecia
• Elevated liver enzymes
• Eosinophilia

Onset & Severity:

• Bleeding risk increases with high INR, drug interactions, or comorbidities
• Skin necrosis typically occurs within 3–8 days of initiation

Increased Warfarin Effect (↑ INR):

• Antibiotics (e.g., metronidazole, TMP-SMX, macrolides)
• Antifungals (e.g., fluconazole, ketoconazole)
• Amiodarone, SSRIs, statins (e.g., simvastatin)
• NSAIDs (also increase bleeding risk)
• Acetaminophen (in high doses)

Decreased Warfarin Effect (↓ INR):

• Rifampin, carbamazepine, barbiturates
• Vitamin K supplementation
• Chronic alcohol consumption

Food Interactions:

• High vitamin K foods (e.g., spinach, kale, broccoli) may decrease warfarin effect
• Grapefruit juice may enhance anticoagulation

Alcohol:

• Acute use ↑ INR; chronic use ↓ INR or causes unpredictable effects

Enzyme Pathways:

• Metabolism: Mainly via CYP2C9
• Other pathways: CYP1A2, CYP3A4

• 2023 ACC/AHA Guidelines:
• Recommend DOACs over warfarin for non-valvular AF and VTE in most patients
• Warfarin preferred in patients with mechanical valves, severe mitral stenosis, or antiphospholipid syndrome
• FDA Safety Communication:
• Reaffirmed black box warning
• Encouraged patient education and proper INR monitoring
• Genetic Testing (CYP2C9, VKORC1):
• Recommended in select cases for dose prediction and safety

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Allowable excursions: 15°C to 30°C (59°F to 86°F)
• Humidity & Light: Protect from moisture and light
• Container: Keep in tightly closed original container
• Handling: Avoid splitting or crushing tablets unnecessarily
• No refrigeration or reconstitution required