Phytonadione

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:

Mephyton: 5 mg [scored]

Generic: 100 mcg, 5 mg

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

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 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

Anticoagulant-induced prothrombin deficiency: Treatment of anticoagulant-induced prothrombin deficiency caused by coumarin or indandione derivatives

Vitamin K deficiency bleeding (formerly known as hemorrhagic disease) of the newborn: Prophylaxis and therapy of vitamin K deficiency bleeding (formerly known as hemorrhagic disease) of the newborn (injection only)

Hypoprothrombinemia: Hypoprothrombinemia secondary to factors limiting absorption or synthesis of vitamin K (eg, obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, regional enteritis), and other drug-induced hypoprothrombinemia where it is definitely shown that the result is due to interference with vitamin K metabolism (eg, salicylates, antibacterial therapy)

Use: Off Label

Hypoprothrombinemia due to long-acting anticoagulant rodenticides (LAARs)c

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)yes

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].

Contraindications

Hypersensitivity to phytonadione or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: 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; DeZee 2006; Raj 1999). The IV route may be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (ACCP [Guyatt 2012]; Patriquin 2011). IM route should be avoided due to the risk of hematoma formation.

Anticoagulant-induced prothrombin deficiency (caused by coumarin or indanedione derivatives):

Usual dosage range:

Oral: Initial: 2.5 to 10 mg (rarely up to 25 to 50 mg) as a single dose. May repeat in 12 to 48 hours if needed.

SubQ, IV: Initial: 2.5 to 10 mg (rarely up to 25 to 50 mg) as a single dose. Measure INR after 6 to 8 hours and repeat dose if needed.

Dosing based on INR and bleeding:

If INR above therapeutic range to <4.5 (no evidence of bleeding): Lower or hold next warfarin dose and monitor frequently; when INR approaches desired range, resume warfarin 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 warfarin doses, monitor INR more frequently, and resume with an appropriately adjusted warfarin 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).

Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis:

Oral: Initial: 2.5 to 25 mg (rarely up to 50 mg)

SubQ, IV: Initial: 2.5 to 25 mg (rarely up to 50 mg). Measure INR after 6 to 8 hours and repeat dose if needed.

Acute liver failure coagulopathy: SubQ, IV: 5 to 10 mg (at least one dose) (AASLD [Lee 2011]; Pereira 2005)

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]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Route of administration varies with indication; careful evaluation of route of administration is important. The oral route is preferred in the treatment of nonbleeding patients with warfarin-associated coagulopathy; SubQ administration has fallen out of favor for this indication due to erratic and unpredictable absorption (Crowther 2002; DeZee 2006; Raj 1999). The IV route may be used in select nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (Bolton-Maggs 2002; CHEST [Monagle 2012]). The IV and SubQ routes may be used in the treatment of vitamin K deficiency bleeding (Kliegman 2016). The IM route should be avoided due to the risk of hematoma formation except in the prevention/treatment of vitamin K deficiency bleeding (Kliegman 2016). Dosing presented in mcg and mg; verify dosing units.

Vitamin K deficiency, prevention, and supplementation (Disease-specific): Limited data available:

Biliary atresia (Shneider 2012): Note: Dose and route are determined by INR value: Infants 1 to 6 months:

INR >1.2 to 1.5: 2.5 mg once daily orally

INR >1.5 to 1.8: Initial: 2 to 5 mg IM once followed by 2.5 mg once daily orally

INR >1.8: Initial: 2 to 5 mg IM once followed by 5 mg once daily orally

Cholestasis: Infants, Children, and Adolescents: Oral: 2.4 to 15 mg/day (Sathe 2010)

Cystic fibrosis: Infants, Children, and Adolescents: Oral: 0.3 to 0.5 mg/day (Borowitz 2002; Sathe 2010)

Liver disease: Infants, Children, and Adolescents: Oral: 2.5 to 5 mg/day (Nightingale 2009; Sathe 2010)

Reversal of Vitamin K antagonists (eg, warfarin): Limited data available: Infants, Children, and Adolescents:

Weight-based dosing (preferred): Chest recommendations: IV: 0.03 mg/kg/dose is recommended for excessively prolonged INR (usually INR >8; no evidence of bleeding) due to vitamin K-antagonist (eg, warfarin): if significant bleeding, consider use of fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa (Bolton-Maggs 2002; Monagle 2012)

Alternate dosing: Fixed dosing: Note: Smaller pediatric patients should receive doses on the low end of dosing range; excessive dosages may cause warfarin-resistance (Bolton-Maggs 2002; Michelson 1998)

No bleeding, rapid reversal needed, patient will require further oral anticoagulant therapy: SubQ, IV: 0.5 to 2 mg

No bleeding, rapid reversal needed, patient will not require further oral anticoagulant therapy: SubQ, IV: 2 to 5 mg

Significant bleeding, not life-threatening: SubQ, IV: 0.5 to 2 mg

Significant bleeding, life-threatening: SubQ, IV: 5 mg

Parenteral nutrition, maintenance requirement: Limited data available (Vanek 2012): IV: Note: Patients receiving warfarin may not require TPN supplementation of phytonadione.

Infants: 10 mcg/kg/day

Children and Adolescents: 200 mcg/day

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: 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. The IV route may be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (ACCP [Guyatt 2012]; Patriquin 2011).

SubQ: SubQ route has fallen out of favor due to erratic and unpredictable absorption (Crowther 2002; DeZee 2006; Raj 1999).

IM: IM route should be avoided due to the risk of hematoma formation.

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).

Dietary Considerations

Dietary adequate intake (IOM 2001; Vanek 2012):

1 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

>18 years: Males: 120 mcg/day; Females: 90 mcg/day

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 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: Chest pain, flushing, hypotension, tachycardia, weak pulse

Central nervous system: Dizziness

Dermatologic: Diaphoresis, eczematous rash, erythema, erythematous rash, pruritic plaques of the skin, urticaria

Gastrointestinal: Dysgeusia

Hepatic: Hyperbilirubinemia

Hypersensitivity: Anaphylactoid reaction, anaphylaxis, hypersensitivity reaction

Local: Injection site reaction (including pain, swelling, tenderness)

Respiratory: Cyanosis, dyspnea

Miscellaneous: Lesion (scleroderma-like)

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: Cutaneous reactions have occurred after parenteral administration, including delayed-type hypersensitivity reactions, eczematous reactions, scleroderma-like patches, and urticaria; onset may occur within 1 day to a year. If skin reactions occur, discontinue therapy and treat appropriately.
• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Fatal hypersensitivity reactions, including anaphylaxis, have occurred with parenteral use; onset may occur during or immediately after intravenous (IV) or intramuscular (IM) administration. Reactions have occurred despite dilution to avoid rapid IV infusion and with the first dose. Avoid IV and IM administration unless subcutaneous administration is not feasible and the serious risk is justified. 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).

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 warfarin-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. Therefore, the SubQ route has fallen out of favor due to erratic and unpredictable absorption (Crowther 2002; DeZee 2006; Raj 1999). The IV route may be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy (ACCP [Guyatt 2012]; Patriquin 2011). IM route should be avoided due to the risk of hematoma formation (except, for example, in the neonatal and pediatric populations for prevention/treatment of vitamin K deficiency bleeding). 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

Pregnancy Considerations

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). Use of preservative free solutions are preferred when the injection is needed during pregnancy.

Patient Education

What is this drug used for?

• It is used to replace low vitamin K, to undo the effects of certain blood thinners like warfarin, and to treat or prevent bleeding. It is often given to newborn babies.

Frequently reported side effects of this drug

• Injection site pain
• Edema
• Irritation
• Change in taste

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Flushing
• Skin reaction
• Chest pain
• Fast heartbeat
• Loss of strength and energy
• Abnormal heartbeat
• Dizziness
• Passing out
• Shortness of breath
• Sweating a lot
• Blue/gray skin discoloration
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.