Bedside Snapshot
  • Essential Cofactor: Essential for hepatic synthesis of vitamin K–dependent clotting factors II, VII, IX, X and proteins C/S
  • Primary Uses: In ICU/ED, used mainly for reversing warfarin effect (elevated INR), and for vitamin K deficiency from malnutrition, cholestasis, or prolonged antibiotics
  • Route Matters: IV for life-threatening bleeding; oral for non-emergent INR correction; SC is less reliable and generally avoided for warfarin reversal
  • Delayed Effect: Effect is not immediate; production of new clotting factors takes 6–24 hours, so emergent reversal usually combines vitamin K with PCC or FFP
  • Warfarin Resistance: Reversing warfarin with high-dose vitamin K may make patients temporarily resistant to re-anticoagulation, important in mechanical valves or high thrombotic risk
Brand & Generic Names
  • Generic Name: Phytonadione (vitamin K1)
  • Brand Names: Mephyton (oral), generics
Medication Class

Fat-soluble vitamin; cofactor for clotting factor γ-carboxylation; warfarin reversal agent

Pharmacology

Mechanism of Action:

  • Acts as an essential cofactor for γ-carboxylation of glutamic acid residues on factors II, VII, IX, X and proteins C/S, enabling calcium binding and full activity
  • Warfarin inhibits vitamin K epoxide reductase; phytonadione bypasses this by replenishing reduced vitamin K, restoring clotting factor synthesis
  • In deficiency states, replacement restores hepatic production of functional clotting factors

Pharmacokinetics:

  • Onset: INR begins to decline within 6–12 hours; maximal effect typically 12–24 hours after administration
  • Absorption: Oral absorption variable, requires bile salts (fat-soluble); better absorption with food
  • Distribution: Concentrates in liver; crosses placenta minimally
  • Metabolism: Hepatic metabolism
  • Duration: Effects last several days; sufficient to overcome warfarin's anticoagulant effect
Indications
  • Warfarin reversal: For elevated INR with or without bleeding, depending on severity (see dosing table)
  • Vitamin K deficiency: From malnutrition, prolonged antibiotic use (disrupts gut flora), cholestatic liver disease, or malabsorption syndromes
  • Hemorrhagic disease of newborn: Prophylaxis and treatment (pediatric dosing not covered here)
  • Coagulopathy assessment: Trial in liver disease to distinguish vitamin K deficiency from synthetic failure (though often limited benefit in severe cirrhosis)
Dosing & Administration

Available Forms:

  • Oral tablets: 5 mg (most common)
  • IV injection: 1 mg/0.5 mL or 10 mg/mL ampules (must be diluted and infused slowly)
  • SC/IM injection: available but less preferred for warfarin reversal due to variable absorption

Adult Dosing - Warfarin Reversal:

Scenario Vitamin K Dose Route Notes
Life-threatening bleeding on warfarin (e.g., ICH, massive GI bleed) 5–10 mg IV Give with 4-factor PCC (or FFP if PCC unavailable); effect within 6–12h
Serious but non-life-threatening bleeding 2.5–5 mg IV Plus PCC or FFP depending on severity and INR
INR ≥10, no significant bleeding 2.5–5 mg PO Hold warfarin; recheck INR in 24–48h
INR 4.5–10, no bleeding 0–2.5 mg PO Often just hold warfarin; low-dose vitamin K in high-risk patients
Vitamin K deficiency without warfarin 2.5–10 mg PO/IV Route per severity; consider malabsorption
Liver disease with coagulopathy 10 mg IV Only helpful if actual vitamin K deficiency; often limited benefit in severe cirrhosis
IV Administration: IV phytonadione must be infused slowly (e.g., over ≥30 minutes) to reduce risk of anaphylactoid reactions. Never give IV push.
Contraindications

Contraindications:

  • Hypersensitivity to phytonadione or formulation components (e.g., some IV preparations contain polyoxyethylated castor oil)

Major Precautions:

  • IV phytonadione has been associated with rare but serious anaphylactoid reactions; infuse slowly (e.g., over ≥30 minutes)
  • Reversing warfarin with high-dose vitamin K may make patients temporarily resistant to re-anticoagulation, important in mechanical valves or high thrombotic risk
  • In liver failure, vitamin K will not correct coagulopathy if the liver cannot synthesize factors; avoid repeated high doses without clear deficiency
Anaphylactoid Risk: Rare but serious reactions with IV administration. Monitor closely during infusion. Infuse slowly over ≥30 minutes.
Warfarin Resistance: High doses can make re-anticoagulation difficult. Use lowest effective dose, especially in patients with mechanical valves or recent VTE.
Adverse Effects

Common:

  • Pain or irritation at injection site
  • Flushing or taste disturbances (IV)
  • Transient resistance to warfarin anticoagulation

Serious (rare):

  • Anaphylactoid reactions with IV administration (hypotension, bronchospasm, cardiac arrest)
  • Hemolysis in G6PD deficiency (rare, more with synthetic vitamin K analogs)
Special Populations

Elderly Patients:

  • No specific dose adjustment required
  • May be more sensitive to warfarin reversal effects

Renal Impairment:

  • No dose adjustment required

Hepatic Impairment:

  • May have reduced clotting factor synthesis even with vitamin K
  • Trial dose reasonable to assess for deficiency, but limited benefit in severe cirrhosis

Pregnancy:

  • Category C: Generally considered safe when needed
  • Crosses placenta minimally

Lactation:

  • Excreted in breast milk in small amounts
  • Generally considered compatible with breastfeeding
Monitoring

Clinical Monitoring:

  • INR before and after vitamin K dosing (usually 12–24h post-dose)
  • Clinical bleeding vs thrombosis risk, especially in anticoagulated patients with mechanical valves or recent VTE
  • Signs of hypersensitivity during and shortly after IV administration
  • Reassess need for re-anticoagulation and appropriate timing
Clinical Pearls
Not Immediate: Vitamin K alone takes 6–24 hours to work. For life-threatening bleeding, always give PCC or FFP along with vitamin K for immediate reversal.
Dosing Strategy: Use the lowest effective dose to avoid warfarin resistance. In patients who need to resume warfarin (mechanical valves), prefer 2.5–5 mg over 10 mg when possible.
Oral vs IV: Oral vitamin K works well for non-emergent INR correction and avoids the anaphylactoid risk of IV. Reserve IV for serious or life-threatening bleeding.
Liver Disease Limitation: In severe cirrhosis, the liver may not be able to synthesize clotting factors even with vitamin K. A trial dose can help distinguish deficiency from synthetic failure, but don't expect miracles.
Slow IV Infusion: Always dilute and infuse IV vitamin K slowly (over ≥30 minutes). Rapid infusion increases anaphylactoid risk.
Recheck INR: INR should be rechecked 12–24 hours after vitamin K administration to assess response and guide further management.
References
  • 1. Lexicomp. (2024). Phytonadione (vitamin K1): Drug information. Wolters Kluwer.
  • 2. Holbrook, A., Schulman, S., Witt, D. M., et al. (2012). Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141(2 Suppl), e152S–e184S. https://doi.org/10.1378/chest.11-2295
  • 3. Dezee, K. J., Shimeall, W. T., Douglas, K. M., et al. (2006). Treatment of excessive anticoagulation with phytonadione (vitamin K): A meta-analysis. Archives of Internal Medicine, 166(4), 391–397. https://doi.org/10.1001/archinte.166.4.391
  • 4. Ageno, W., Gallus, A. S., Wittkowsky, A., et al. (2012). Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141(2 Suppl), e44S–e88S. https://doi.org/10.1378/chest.11-2292
  • 5. Goldstein, J. N., Refaai, M. A., Milling, T. J., et al. (2015). Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: A phase 3b, open-label, non-inferiority, randomised trial. The Lancet, 385(9982), 2077–2087. https://doi.org/10.1016/S0140-6736(14)61685-8
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