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- Methylphytyl Napthoquinone
- Vitamin K
- Vitamin K1
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, aqueous colloidal: 1 mg/0.5 mL (0.5 mL); 10 mg/mL (1 mL)
Injection, aqueous colloidal [preservative free]: 1 mg/0.5 mL (0.5 mL)
Tablet, oral: 100 mcg
Mephyton®: 5 mg [scored]
Brand Names: U.S.
- Vitamin, Fat Soluble
Promotes liver synthesis of clotting factors (II, VII, IX, X); however, the exact mechanism as to this stimulation is unknown. Menadiol is a water soluble form of vitamin K; phytonadione has a more rapid and prolonged effect than menadione; menadiol sodium diphosphate (K4) is half as potent as menadione (K3).
Oral: From intestines in presence of bile; SubQ: Variable; IM: Readily
Urine and feces
Onset of Action
Onset of action: Increased coagulation factors: Oral: 6 to 10 hours; IV: 1 to 2 hours
Peak effect: INR values return to normal: Oral: 24 to 48 hours; IV: 12 to 14 hours
Use: Labeled Indications
Prevention and treatment of hypoprothrombinemia caused by vitamin K antagonist (VKA)-induced (eg, warfarin-induced) or other drug-induced vitamin K deficiency, altered activity, or altered metabolism; hypoprothrombinemia caused by malabsorption or inability to synthesize vitamin K; prophylaxis and treatment of hemorrhagic disease of the newborn
Off Label Uses
Hypoprothrombinemia due to long-acting anticoagulant rodenticides (LAARs)
Data from a few case reports suggest that phytonadione may be beneficial in the treatment of hypoprothrombinemia caused by long-acting anticoagulant rodenticides (brodifacoum) [Bruno 2000], [Gunja 2011], [Olmos 2007]. Data from a limited number of patients (case series) also suggest that phytonadione may be beneficial in this setting [Chua 1998]. Additional data may be necessary to further define the role of phytonadione in the treatment of this condition.
Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin)
Based on the Neurocritical Care Society and the Society of Critical Care Medicine guideline for reversal of antithrombotics in intracranial hemorrhage, phytonadione, with 4-factor prothrombin complex concentrate (PCC), is recommended as soon as possible for vitamin K antagonist-associated intracranial hemorrhage and INR ≥1.4. Three-factor PCC may be given with phytonadione but 4-factor PCC is preferred [NCS/SCCM [Frontera 2016]].
Hypersensitivity to phytonadione or any component of the formulation
Note: SubQ is the preferred parenteral route; IM route should be avoided due to the risk of hematoma formation; IV route should be restricted for emergency use only. The American College of Chest Physicians (ACCP) recommends the IV route in patients with major bleeding secondary to use of vitamin K antagonists (VKAs). Oral route is more effective than the SubQ route in the treatment of nonbleeding patients with warfarin-associated coagulopathy; SubQ route has therefore fallen out of favor due to erratic and unpredictable absorption (Crowther 2002).
Adequate intake (AI): Oral: Males: 120 mcg/day; Females: 90 mcg/day
Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis: Oral, SubQ, IV: Initial: 2.5 to 25 mg (rarely up to 50 mg)
Acute liver failure coagulopathy: SubQ, IV: 5 to 10 mg (at least one dose) (AASLD [Lee 2011]; Pereira 2005)
Vitamin K deficiency (supratherapeutic INR) secondary to VKAs (eg, warfarin) (off-label dose):
If INR above therapeutic range to <4.5 (no evidence of bleeding): Lower or hold next VKA dose and monitor frequently; when INR approaches desired range, resume VKA dosing with a lower dose (Patriquin 2011).
If INR 4.5 to 10 (no evidence of bleeding): The 2012 ACCP guidelines recommend against routine phytonadione (aka, vitamin K) administration in this setting (Guyatt 2012). Previously, the 2008 ACCP guidelines recommended if no risk factors for bleeding exist, to omit next 1 or 2 VKA doses, monitor INR more frequently, and resume with an appropriately adjusted VKA dose when INR in desired range; may consider administering vitamin K orally 1 to 2.5 mg if other risk factors for bleeding exist (Hirsh 2008). Others have recommended consideration of vitamin K 1 mg orally or 0.5 mg IV (Patriquin 2011).
If INR >10 (no evidence of bleeding): The 2012 ACCP guidelines recommend administration of oral vitamin K (dose not specified) in this setting (Guyatt 2012). Previously, the 2008 ACCP guidelines recommended to hold warfarin, administer vitamin K orally 2.5 to 5 mg, expect INR to be reduced within 24 to 48 hours, monitor INR more frequently and give additional vitamin K at an appropriate dose if necessary; resume warfarin at an appropriately adjusted dose when INR is in desired range (Hirsh 2008). Others have recommended consideration of vitamin K 2 to 2.5 mg orally or 0.5 to 1 mg IV (Patriquin 2011).
If minor bleeding at any INR elevation: Hold warfarin, may administer vitamin K orally 2.5 to 5 mg, monitor INR more frequently, may repeat dose after 24 hours if INR correction incomplete; resume warfarin at an appropriately adjusted dose when INR is in desired range (Patriquin 2011).
If major bleeding at any INR elevation: The 2012 ACCP guidelines recommend administration of four-factor prothrombin complex concentrate (PCC) and IV vitamin K 5 to 10 mg in this setting (Guyatt 2012). The only available four-factor PCC in the US is Kcentra. Other four-factor PCCs not available in the US include Beriplex P/N, Cofact, and Octaplex. Bebulin VH and Profilnine SD do not contain adequate levels of factor VII and are considered three-factor PCCs. Previously, the 2008 ACCP guidelines recommended to hold warfarin, administer vitamin K 10 mg by slow IV infusion and supplement with PCC depending on the urgency of the situation; IV vitamin K may be repeated every 12 hours (Hirsh 2008).
Note: Use of high doses of vitamin K (eg, 10 to 15 mg) may cause warfarin resistance for ≥1 week. During this period of resistance, heparin or low-molecular-weight heparin (LMWH) may be given until INR responds (Ansell 2008).
Preprocedural/surgical INR normalization in patients receiving warfarin (routine use): Oral: 1 to 2.5 mg once administered on the day before surgery; recheck INR on day of procedure/surgery (Douketis 2012). Others have recommended the use of vitamin K 1 mg orally for mild INR elevations (ie, INR 3.0 to 4.5) (Patriquin 2011).
Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin) (off-label use): IV: Initial: 10 mg once given as soon as possible and concomitantly with 4-factor prothrombin complex concentrate (PCC) for INR ≥1.4 (3-factor PCC may be given concomitantly with phytonadione but 4-factor PCC is preferred). Subsequent phytonadione administration is guided by follow-up INR; if subsequent INR ≥1.4 within the first 24 to 48 hours after the initial dose, give a repeat dose of phytonadione 10 mg IV (NCS/SCCM [Frontera 2016]).
Refer to adult dosing.
Note: According to the manufacturer, SubQ is the preferred parenteral route; IM route should be avoided due to the risk of hematoma formation; IV route should be restricted for emergency use only. The American College of Chest Physicians (ACCP) recommends the IV route in patients with major bleeding secondary to use of vitamin K antagonists (VKAs).
Adequate intake (AI): Oral:
0 to 6 months: 2 mcg/day
7 to 12 months: 2.5 mcg/day
1 to 3 years: 30 mcg/day
4 to 8 years: 55 mcg/day
9 to 13 years: 60 mcg/day
14 to 18 years: 75 mcg/day
Hemorrhagic disease of the newborn:
Prophylaxis: IM: 0.5 to 1 mg within 1 hour of birth
Treatment: IM, SubQ: 1 mg/dose/day; higher doses may be necessary if mother has been receiving oral anticoagulants
Vitamin K deficiency (supratherapeutic INR) secondary to vitamin K antagonists (VKAs) (eg, warfarin) (off-label use): Infants and Children: Excessively prolonged INR (usually INR >8; no significant bleeding): Note: Limited data available: IV: 0.03 mg/kg/dose; maximum dose: 1 mg (Bolton-Maggs, 2002); if significant bleeding, consider use of fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa (Monagle, 2012).
Dosing: Renal Impairment
No dosage adjustment provided in manufacturer’s labeling.
Dosing: Hepatic Impairment
No dosage adjustment provided in manufacturer’s labeling.
Dilute injection solution in preservative-free NS, D5W, or D5NS. To reduce the incidence of anaphylactoid reaction upon IV administration, dilute dose in a minimum of 50 mL of compatible solution and administer using an infusion pump over at least 20 minutes (Ageno, 2012).
A 1 mg/mL oral suspension may be made with tablets. Crush six 5 mg tablets in a mortar and reduce to a fine powder. Add 5 mL each of water and methylcellulose 1% and mix to a uniform paste. Mix while adding sorbitol in incremental proportions to almost 30 mL; transfer to a calibrated bottle, rinse mortar with sorbitol, and add quantity of sorbitol sufficient to make 30 mL. Label "shake well" and "refrigerate". Stable for 3 days.Nahata MC and Hipple TF, Pediatric Drug Formulations, 3rd ed, Cincinnati, OH: Harvey Whitney Books Co, 1997.
Note: The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed (Crowther, 2000; O’Connor, 1986); may administer undiluted or diluted in a beverage (eg, orange juice) (Vanier 2006).
IV administration: Infuse slowly; rate of infusion should not exceed 1 mg/minute. Alternatively, dilute dose in a minimum of 50 mL of compatible solution and administer using an infusion pump over at least 20 minutes (Ageno 2012). The injectable route should be used only if the oral route is not feasible or there is a greater urgency to reverse anticoagulation.
Oral: The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed (Crowther 2000; Crowther 2002; O’Connor 1986); may administer undiluted or diluted in a beverage (eg, orange juice) (Vanier 2006).
Injection: Store at 15°C to 30°C (59°F to 86°F). Protect from light. Note: Store Hospira product at 20°C to 25°C (68°F to 77°F).
Oral: Store tablets at 15°C to 30°C (59°F to 86°F). Protect from light.
Mineral Oil: May decrease the serum concentration of Phytonadione. Specifically, mineral oil may decrease the absorption of phytonadione. Monitor therapy
Orlistat: May decrease the serum concentration of Vitamins (Fat Soluble). Management: Administer oral fat soluble vitamins at least 2 hours before or after the administration of orlistat. Similar precautions do not apply to parenterally administered fat soluble vitamins. Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Phytonadione may diminish the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification
Frequency not defined.
Cardiovascular: Flushing, hypertension, hypotension
Central nervous system: Dizziness
Dermatologic: Diaphoresis, erythematous rash, pruritus
Hypersensitivity: Anaphylactoid reaction (non-immunologic anaphylaxis), hypersensitivity reaction
Local: Fibrosis at injection site, injection site reaction
Respiratory: Cyanosis, dyspnea
Concerns related to adverse effects:
• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Severe reactions resembling hypersensitivity reactions (eg, anaphylaxis) have occurred rarely during or immediately after IV administration (even with proper dilution and rate of administration); some patients had no previous exposure to phytonadione. Anaphylactoid reactions typically occurred when patients received large IV doses administered rapidly with formulations containing polyethoxylated castor oil (also called polyoxyethylated castor oil); proper dosing, dilution, and administration will minimize risk (Ageno 2012; Riegert-Johnson 2002). Limit IV administration to situations where an alternative route of administration is not feasible and the benefit of therapy outweighs the risk of hypersensitivity reactions. Allergic reactions have also occurred with IM and SubQ injections, albeit less frequently.
• Anticoagulant-induced hypoprothrombinemia: In patients receiving a therapeutic vitamin K antagonist (VKA) (eg, warfarin), administer a dose of phytonadione that will quickly lower the INR into a safe range without causing resistance to warfarin. High phytonadione doses may lead to warfarin resistance for at least one week.
• Liver disease induced hypoprothrombinemia: If initial doses do not reverse coagulopathy, then higher doses are unlikely to have any effect. Note: Ineffective in hereditary hypoprothrombinemia.
• Long-acting anticoagulant rodenticide (LAAR) ingestion: Patients with LAAR-induced coagulopathy require much larger doses and longer treatment durations (up to months) after exposure compared to that needed to reverse VKA-induced coagulopathy.
• Neonates: Use with caution in neonates, especially premature infants; severe hemolytic anemia, jaundice, and hyperbilirubinemia have been reported with larger than recommended doses (10 to 20 mg).
Dosage form specific issues:
• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturer’s labeling.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.
• Polyoxyethylated castor oil: Some injectable dosage forms contain polyoxyethylated castor oil (Cremophor EL) which is associated with hypersensitivity reactions.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.
• Appropriate route: Oral administration is the safest and requires the presence of bile salts for absorption. In obstructive jaundice or with biliary fistulas, concurrent administration of bile salts would be necessary for proper absorption. Manufacturers recommend the SubQ route over other parenteral routes, however, SubQ is less predictable when compared to the oral route, and efficacy may be delayed. The American College of Chest Physicians recommends the IV route in patients with major bleeding secondary to use of VKAs such as warfarin. The IV route should be restricted to emergency situations only where oral phytonadione cannot be used. Efficacy (eg, control of bleeding, decrease in INR) is delayed regardless of route of administration; patient management may require other treatments in the interim.
PT, INR; monitor for hypersensitivity reactions if administering IV.
Pregnancy Risk Factor
Animal reproduction studies have not been conducted. Phytonadione crosses the placenta in limited concentrations (Kazzi, 1990). The dietary requirements of vitamin K are the same in pregnant and nonpregnant women (IOM 2000). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience injection site pain, edema, or irritation, change in taste, or flushing. Have patient report immediately to prescriber tachycardia, abnormal heartbeat, dizziness, passing out, shortness of breath, sweating a lot, or skin discoloration (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
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- Drug class: anticoagulant reversal agents