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Introduction

  1. Pharmacology. Vitamin K1 is an essential cofactor in the hepatic synthesis of coagulation factors II, VII, IX, and X. In adequate doses, vitamin K1 reverses the inhibitory effects of warfarin and its derivatives on the synthesis of these factors. Note: Vitamin K3 (menadione) and K4 (menadiol sodium diphosphate) are not effective in reversing excessive anticoagulation caused by these agents. After parenteral vitamin K1 administration, there is a 6- to 8-hour delay before vitamin K-dependent coagulation factors begin to achieve significant levels, and peak effects are not seen until 1-2 days after the initiation of therapy. The duration of effect is 5-10 days. The response to vitamin K1 is variable, and the optimal dosage is unclear; it is influenced by the route of administration, the potency and amount of the ingested anticoagulant, vitamin K1 pharmacokinetics, and the patient's hepatic biosynthetic capability.
  2. Indications
    1. Excessive anticoagulation caused by warfarin and its derivatives, as indicated by an elevated prothrombin time (Warfarin and Superwarfarins). Vitamin K1 is not indicated for empiric treatment of anticoagulant ingestion, as most cases do not require treatment.
    2. Vitamin K deficiency (eg, malnutrition, malabsorption, or hemorrhagic disease of the newborn) with coagulopathy.
    3. Hypoprothrombinemia resulting from salicylate intoxication.
  3. Contraindications. Do not use in patients with known hypersensitivity to vitamin K1 or its preservatives.
  4. Adverse effects
    1. Black box warning. Anaphylactoid reactions have been reported after intravenous administration and have been associated with fatalities. Although these are rare (incidence of 3 cases per 10,000 doses), intravenous use should be restricted to true emergencies; the patient must be monitored closely in an intensive care setting, and reducing the infusion rate may reduce the risk. Severe reactions and fatalities have also been associated with IM administration and resembled hypersensitivity reactions. Note: New liposomal preparations of IV vitamin K1 are currently under development and may carry lower risks of hypersensitivity reactions.
    2. Intramuscular administration in patients receiving anticoagulants may cause large, painful hematomas. This can be avoided by using the oral or subcutaneous route.
    3. Patients receiving anticoagulants for medical reasons (eg, deep vein thrombosis or prosthetic heart valves) may experience untoward effects from complete reversal of their anticoagulation status. Therapy in such patients should be based on the INR and presence or risk of bleeding.
    4. Use in pregnancy. FDA Category C (indeterminate). Vitamin K1 crosses the placenta readily. However, this does not preclude its acute, short-term use in a seriously symptomatic patient (Introduction).
  5. Drug or laboratory interactions. Empiric use of vitamin K1 after an acute anticoagulant overdose will delay (for up to several days) the onset of elevation of the prothrombin time, and may give a false impression of insignificant ingestion in a case of serious “superwarfarin” overdose.
  6. Dosage and method of administration.
    1. Oral.
      1. Reversal of therapeutic warfarin effect:
        1. If INR <4.5 and no significant bleeding: hold warfarin dose. No vitamin K1 needed.
        2. If INR 4.5-10 and no bleeding: hold 1-2 warfarin doses. Consider oral vitamin K1 1-2.5 mg.
        3. If INR >10 and no bleeding, or only minor bleeding present regardless of INR: hold warfarin and administer 2.5-5 mg of oral vitamin K1.
        4. If serious hemorrhage is present (regardless of INR): hold warfarin and give 5-10 mg of vitamin K1 via slow IV infusion (see warning above). May need to repeat dose every 12 hours. Note: For more rapid restoration of active clotting factors, use fresh frozen plasma or clotting factor replacement products (see Clotting Factor Replacement Products).
        5. Adjunctive anticoagulation with heparin may be required until the desired prothrombin time is achieved.
      2. Long-acting anticoagulant rodenticide poisoning. The usual dose of vitamin K1 (not menadione or vitamin K3) is 10-50 mg two to four times a day in adults and 5-10 mg (or 0.4 mg/kg per dose) two to four times a day in children. Recheck the prothrombin time after 48 hours and increase the dose as needed. Note: Very high daily doses of 50-250 mg (typical daily dose is 100 mg) and up to 800 mg have been required in adults with brodifacoum poisoning; in addition, treatment for several weeks or months may be needed because of the long duration of effect of the “superwarfarin.” Because the only available oral vitamin K1 formulation is 5 mg, high-dose treatment may require patients to ingest up to 100 pills per day, and long-term compliance with the regimen is often problematic.
    2. Parenteral injection is an alternative route of administration for patients with life-threatening or serious bleeding but is not likely to result in more rapid reversal of anticoagulant effects and is associated with potentially serious side effects. Subcutaneous administration is preferred over IM injection, although both can cause hematomas. The maximum volume is 5 mL or 50 mg per dose per injection site. The adult dose is 10-25 mg, and that for children is 1-5 mg; this may be repeated in 6-8 hours. Switch to oral therapy as soon as possible. Intravenous administration is used only rarely because of the risk for an anaphylactoid reaction. The usual dose is 10-25 mg (0.6 mg/kg in children younger than 12 years), depending on the severity of anticoagulation, diluted in preservative-free dextrose or sodium chloride solution. Give slowly at a rate not to exceed 1 mg/min or 5% of the total dose per minute, whichever is slower.