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Phytonadione

Pronunciation

Pronunciation

(fye toe na DYE one)

Index Terms

  • Methylphytyl Napthoquinone
  • Phylloquinone
  • Phytomenadione
  • Vitamin K
  • Vitamin K1

Dosage Forms

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.

  • Mephyton

Pharmacologic Category

  • Vitamin, Fat Soluble

Pharmacology

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).

Absorption

Oral: From intestines in presence of bile; SubQ: Variable; IM: Readily

Metabolism

Rapidly hepatic

Excretion

Urine and feces

Onset of Action

Onset of action: Increased coagulation factors: Oral: 6-10 hours; IV: 1-2 hours

Peak effect: INR values return to normal: Oral: 24-48 hours; IV: 12-14 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

Use: Unlabeled

Treatment of hypoprothrombinemia caused by long-acting anticoagulant rodenticides (LAARs)

Contraindications

Hypersensitivity to phytonadione or any component of the formulation

Dosing: Adult

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: Males: 120 mcg/day; Females: 90 mcg/day

Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis: Oral, SubQ, IM, IV: Initial: 2.5-25 mg (rarely up to 50 mg)

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 4.5-10 (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 1-2.5 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 2.5-5 mg, expect INR to be reduced within 24-48 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 2-2.5 mg orally or 0.5-1 mg IV (Patriquin, 2011).

If minor bleeding at any INR elevation: Hold warfarin, may administer vitamin K orally 2.5-5 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 5-10 mg in this setting (Guyatt, 2012). The only available four-factor PCC in the U.S. is Kcentra. Other four-factor PCCs not available in the U.S. 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, 10-15 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: 1-2.5 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 3.0-4.5) (Patriquin, 2011).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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:

Infants:

0-6 months: 2 mcg/day

7-12 months: 2.5 mcg/day

Children:

1-3 years: 30 mcg/day

4-8 years: 55 mcg/day

9-13 years: 60 mcg/day

14-18 years: 75 mcg/day

Hemorrhagic disease of the newborn:

Prophylaxis: IM: 0.5-1 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.

Reconstitution

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).

Extemporaneously Prepared

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).

Administration

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; O’Connor, 1986); may administer undiluted or diluted in a beverage (eg, orange juice) (Vanier 2006).

Storage

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.

Drug Interactions

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

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, hypertension, hypotension

Central nervous system: Dizziness

Dermatologic: Diaphoresis, erythematous rash, pruritus

Gastrointestinal: Dysgeusia

Hypersensitivity: Anaphylactoid reaction (non-immunologic anaphylaxis), hypersensitivity reaction

Local: Fibrosis at injection site, injection site reaction

Respiratory: Cyanosis, dyspnea

ALERT: U.S. Boxed Warning

Hypersensitivity/anaphylactoid reactions (injection):

Severe reactions, including fatalities, have occurred during and immediately after intravenous (IV) injection of phytonadione, even when precautions have been taken to dilute the phytonadione and to avoid rapid infusion. Severe reactions, including fatalities, also have been reported following intramuscular (IM) administration. Typically, these severe reactions have resembled hypersensitivity or anaphylaxis, including shock and cardiac or respiratory arrest. Some patients have exhibited these severe reactions on receiving phytonadione for the first time. Therefore, restrict the IV and IM routes to those situations where the subcutaneous route is not feasible and the serious risk involved is considered justified.

Warnings/Precautions

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.

Disease-related concerns:

• 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.

Special populations:

• 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.

Other warnings/precautions:

• 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.

Monitoring Parameters

PT, INR; monitor for hypersensitivity reactions if administering IV.

Pregnancy Risk Factor

C

Pregnancy Considerations

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).

Patient Education

• 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 or irritation, change in taste, or flushing. Have patient report immediately to prescriber tachycardia, arrhythmia, severe 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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