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Phytonadione (Vitamin K1)


Phytonadione (Vitamin K1)

Article Author:
Curtis Ingold
Article Editor:
Shane Sergent
Updated:
6/21/2020 9:33:06 PM
For CME on this topic:
Phytonadione (Vitamin K1) CME
PubMed Link:
Phytonadione (Vitamin K1)

Indications

Phytonadione (vitamin K1) is FDA approved for anticoagulant-induced hypoprothrombinemia deficiency caused by coumarin or indanedione derivatives, hypoprothrombinemia due to antibacterial therapy, hypoprothrombinemia secondary to factors limiting absorption or synthesis of vitamin K, and other drug-induced hypoprothrombinemia due to interactions with vitamin K metabolism. Phytonadione is also FDA approved for prophylaxis and treatment of vitamin K-deficiency bleeding in neonates. 

Phytonadione is used off-label for intracranial hemorrhage associated with vitamin K antagonist anticoagulants.

Mechanism of Action

Vitamin K1 is a fat-soluble vitamin that is present in leafy green vegetables.[1] It is essential for normal coagulation.  It functions as a cofactor required for the activity of vitamin K-dependent (VKD) proteins, which include factors II (prothrombin), VII, IX, and X in addition to protein C and protein S.[2] In vitamin K deficiency, phytonadione therapy replenishes stores. Vitamin K is absorbed in the intestinal tract similarly to the way that most dietary lipids are absorbed by uptake into micelles composed of bile salts. They are absorbed into intestinal enterocytes into the lymphatic system and reach venous circulation by way of the thoracic duct. Estimates are that over 60% of absorbed vitamin K will be excreted from the body.[3] Phytonadione is metabolized in the liver and then excreted in the bile and urine.[4]

Administration

Phytonadione is available for oral, intravenous (IV), subcutaneous (SQ), and intramuscular (IM) administration. IM is not a recommendation due to the risk of developing a hematoma.  Supplemental Vitamin K can last up to two weeks and may impact therapeutic anticoagulation when given.  

Injectable phytonadione is available as a glass ampule. Caution is necessary to avoid the insertion of glass particles into the human body regardless of the route of administration by using a filter before administration. Some products may contain benzyl alcohol. Unpreserved phytonadione is recommended in nursing mothers to prevent benzyl alcohol exposure in breastmilk.[5]

Dose Form Strengths: 100 mcg; 5mg

Pregnancy Rating: C

Lactation Risk: Safe

Renal dosing not defined

Hepatic dosing may be required

Normal dosing in adults:

  • Oral, SQ, and IV: 1 to 10 mg, may repeat in 12 hours.
  • Total Parental Nutrition (TPN) or Peripheral Parental Nutrition (PPN): 150 mcg daily.[6]

Prophylaxis and treatment of vitamin K-deficiency bleeding in newborns:

  • SQ or IM: 0.5 to 1 mg single dose within one hour of birth.

Dosing for intracranial hemorrhage associated with vitamin K antagonist anticoagulants:

  • IV 10 mg as soon as possible; the rate of IV infusion should not exceed 1 mg/minute. 

In a single-center retrospective cohort study by Luc et al., they assessed the effectiveness of phytonadione to reverse warfarin in patients with obesity defined as a body mass index (BMI) ≥ 30 kg/m^2. The definition of warfarin reversal of warfarin is correcting an international normalized ratio (INR) to ≤ 2.0 within 72 hours after phytonadione administration. There was not a significant difference in the route of administration or dose, between the patients with obesity and the patients without obesity. The researchers found that warfarin reversal is not affected in patients with obesity.[7]

A Canadian article published by Dr. Afanasjeva in 2017, evaluated the safety and efficacy of IV phytonadione orally to reduce cost and in the situation that the tablet formulation of oral phytonadione is unavailable. They reiterated the importance of using a filtered needle to avoid glass particles administered to patients. Also, they found that the unpleasant taste of oral phytonadione was reportedly less when mixed with orange juice. Afanasjeva concluded that giving IV phytonadione can offer an inexpensive alternative to phytonadione tablets, especially when the tablet formulation is in shortage.[8]

A randomized, controlled trial by Cowther et al. in 2002, investigated the use of phytonadione administration in patients with an INR of 4.5 to 10 and on warfarin therapy. It was a multicenter, randomized, open-label, controlled study that evaluated the use of phytonadione in asymptomatic patients with an INR between 4.5 and 10. Patients were randomly assigned either oral or subcutaneous phytonadione with a dose of 1 mg. The study enrolled fifty-one patients, with 25 in the subcutaneous phytonadione group and 26 in the oral phytonadione group. One day after either oral or subcutaneous phytonadione, there were six patients (24%) who received subcutaneous phytonadione with an INR of 1.8 to 3.2 compared to 15 patients (58%) who received oral phytonadione; P = 0.015. Only two patients (8%) who had received subcutaneous phytonadione was found to have an INR that was higher than the day prior. However, there were five deaths in the oral phytonadione compared to none in the subcutaneous phytonadione group. One died of unknown causes, three died of cancer, and one died of progressive lung disease. Cowther et al. concluded that subcutaneous phytonadione does not produce rapid, reliable reductions in INR and that oral phytonadione is effective for warfarin-induced coagulopathy.[9]

Adverse Effects

Most adverse effects from phytonadione occur with IV, SQ, and IM administration[10][11]:

  • Anaphylactoid reactions
  • Dyspnea
  • Chest tightness
  • Injection site reaction

In a retrospective cohort study by Shields et al. published in 2001, they evaluated the efficacy and safety of IV phytonadione. Patients were included who received IV phytonadione between September 1, 1994, and March 31, 1996, and were taking warfarin for two weeks or longer. Patients were excluded if they were currently bleeding or received concomitant factor replacement therapy. Out of the 105 patients assessed, 29 patients received a second dose. The researchers found adverse reactions in only two patients. Both patients experienced dyspnea and chest tightness that resolved by stopping the infusion.[10]

Phytonadione (vitamin K1) has a black box warning due to severe anaphylaxis when given IV that may cause shock, respiratory arrest, and cardiac arrest.[8]

Contraindications

Phytonadione is contraindicated in phytonadione hypersensitivity, hereditary hypoprothrombinemia, heparin over-anticoagulation.

Monitoring

  • Monitor for hypersensitivity reactions, especially when administered IV
  • Monitor INR to assess for effectiveness and for the need to administer another dose
  • Xenical and mineral oil both reduce the oral absorption of fat-soluble vitamins A, D, E, and K.[12][5]

Toxicity

Doses up to 50 mg have been used. The majority of toxicity occurs when given by IV.

Enhancing Healthcare Team Outcomes

Phytonadione is often prescribed by emergency department physicians, primary care providers, internists, obstetrician-gynecologists, gastroenterologists, neonatologists, physician assistants, nurse practitioners, neurologists, and neurosurgeons for the treatment of vitamin K deficiency. A knowledgeable provider can utilize phytonadione to reduce a patient's bleeding and mortality. Phytonadione requires a prescription to obtain. Pharmacists can assist with proper dosing and administration recommendations, as well as counseling regarding maintaining a steady intake level when patients are starting on warfarin. Nursing can improve patient outcomes by monitoring for adverse effects. A dietician can assist in modifying a patient's eating habits in patients that have vitamin K deficiency due to inadequate dietary intake. Thus, phytonadione can be useful to reduce bleeding and mortality with an interprofessional collaborative approach.


References

[1] Vitamin K 2012;     [PubMed PMID: 31643538]
[2] Berkner KL, The vitamin K-dependent carboxylase. The Journal of nutrition. 2000 Aug;     [PubMed PMID: 10917896]
[3] Shearer MJ,Newman P, Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. Journal of lipid research. 2014 Mar;     [PubMed PMID: 24489112]
[4] Shearer MJ,Fu X,Booth SL, Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Advances in nutrition (Bethesda, Md.). 2012 Mar 1;     [PubMed PMID: 22516726]
[5] Mineral Oil 2006;     [PubMed PMID: 30000945]
[6] Vanek VW,Borum P,Buchman A,Fessler TA,Howard L,Jeejeebhoy K,Kochevar M,Shenkin A,Valentine CJ, A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2012 Aug;     [PubMed PMID: 22730042]
[7] Luc SA,Whitworth MM,King SE, Effects of Obesity on Warfarin Reversal With Vitamin K. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2019 Jan-Dec;     [PubMed PMID: 30808216]
[8] Afanasjeva J, Administration of Injectable Vitamin K Orally. Hospital pharmacy. 2017 Oct;     [PubMed PMID: 29276303]
[9] Crowther MA,Douketis JD,Schnurr T,Steidl L,Mera V,Ultori C,Venco A,Ageno W, Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Annals of internal medicine. 2002 Aug 20;     [PubMed PMID: 12186515]
[10] Shields RC,McBane RD,Kuiper JD,Li H,Heit JA, Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy. Mayo Clinic proceedings. 2001 Mar;     [PubMed PMID: 11243272]
[11] Ageno W,Gallus AS,Wittkowsky A,Crowther M,Hylek EM,Palareti G, Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;     [PubMed PMID: 22315269]
[12] Montan PD,Sourlas A,Olivero J,Silverio D,Guzman E,Kosmas CE, Pharmacologic therapy of obesity: mechanisms of action and cardiometabolic effects. Annals of translational medicine. 2019 Aug;     [PubMed PMID: 31555707]