Vitamin K (Phytonadione) promotes the synthesis of clotting factors (II, VII, IX, X) by the liver.

It is used in the treatment of the following conditions:

• Anticoagulant-induced prothrombin deficiency:

  • It is used in the treatment of anticoagulant-induced prothrombin deficiency due to coumarin or indandione derivatives

• Vitamin K deficiency bleeding (formerly known as a hemorrhagic disease) of the newborn:

  • It is used in prophylaxis and treatment of vitamin K deficiency bleeding (formerly known as a hemorrhagic disease) of the newborn (injection only)

• Hypoprothrombinemia:

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

• Off-Label Usage of Vitamin K in Adults:

  • It is used in hypoprothrombinemia due to long-acting anticoagulant rodenticides
  • It is also used in Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin)

Vitamin K Dose in Adults

• The oral route is preferred to the SubQ route in the treatment of nonbleeding patients with warfarin-associated coagulopathy
• The intravenous route can be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy.
• The intramuscular route is avoided due to the risk of hematoma formation.

Dosage in the treatment of Anticoagulant-induced prothrombin deficiency (caused by coumarin or indanedione derivatives):

• Usual dosage range:

  • Oral:

    • The initial dose is 2.5 to 10 mg (rarely up to 25 to 50 mg) as a single dose.
    • May be repeated in 12 to 48 hours if needed.

  • SubQ, Intravenous:

    • The initial dose is 2.5 to 10 mg (rarely up to 25 to 50 mg) as a single dose.
    • Monitor INR after 6 to 8 hours and repeat the dose if needed.

• Dosing based on INR and bleeding:

  • If INR is above the therapeutic range to <4.5 (no evidence of bleeding):

    • Lower or withhold the next warfarin dose and monitor frequently
    • If INR approaches desired range, restart warfarin dosing with a lower dose

  • If INR 4.5 to 10 (no evidence of bleeding):

    • The 2012 ACCP guidelines recommend against routine phytonadione (aka, vitamin K) administration in this scenario.
    • In past, 2008 ACCP guidelines recommended if no risk factors for bleeding exist, to omit the next 1 or 2 warfarin doses & monitor INR more frequently, and restart with an appropriately adjusted warfarin dose when INR in the desired range
    • vitamin K can be orally given 1 to 2.5 mg if other risk factors for bleeding exist.
    • Others  recommend consideration of vitamin K 1 mg orally or 0.5 mg Intravenous

  • If INR >10 (no evidence of bleeding):

    • The 2012 ACCP guidelines advise the administration of oral vitamin K (dose not specified) in this scenario.
    • In the past, 2008 ACCP guidelines recommended withholding warfarin & administer vitamin K orally 2.5 to 5 mg.
    • Expect INR to lessen within 24 to 48 hours,
    • Monitor INR more frequently and give additional vitamin K at an appropriate dose if required.
    • Restart warfarin at an appropriately adjusted dose when INR comes in the desired range.
    • Others recommend consideration of vitamin K 2 to 2.5 mg orally or 0.5 to 1 mg Intravenous.

  • If minor bleeding at any INR elevation:

    • Withhold warfarin
    • Vitamin K can be given orally in 2.5 to 5 mg
    • Repeat INR more frequently
    • The dose can be repeated after 24 hours if the INR correction incomplete
    • Restart warfarin at an appropriately adjusted dose when INR is in the desired range

  • If major bleeding at any INR elevation:

    • The 2012 ACCP guidelines recommended the administration of four-factor prothrombin complex concentrate (PCC) and Intravenous vitamin K 5 to 10 mg in this setting.
    • In the past, the 2008 ACCP guidelines advised holding warfarin, administering vitamin K 10 mg by slow Intravenous infusion, and supplementing with PCC depending on the urgency of the scenario
    • Intravenous vitamin K can be repeated every 12 hours.
    • Use of high doses of vitamin K (eg, 10 to 15 mg) can cause warfarin resistance for more than 1 week.
    • During this period of resistance, heparin or low-molecular-weight heparin (LMWH) is given until INR responds.

Dosage in the treatment of Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis:

• Initially, 2.5 to 25 mg orally is given (rarely up to 50 mg)

• SubQ or Intravenous:

  • The initial dose is 2.5 to 25 mg (rarely up to 50 mg).
  • Evaluate INR after 6 to 8 hours and repeat the dose if needed.

• Acute liver failure coagulopathy:

  • Intravenous, sub Q: 5 to 10 mg (at least one dose is given)

Dosage in the treatment of routine Preprocedural/ surgical INR normalization in patients receiving warfarin:

• 1 to 2.5 mg orally once given on the day before surgery
• Monitor INR on the day of the procedure/surgery.
• Others recommend the use of vitamin K 1 mg orally for mild INR elevations (ie, INR 3.0 to 4.5)

Off-label dosage in the treatment of Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin):

• Initially 10 mg Intravenous once is given as soon as possible and concomitantly with 4-factor prothrombin complex concentrate (PCC) for INR more than 1.4
• Subsequent phytonadione administration is guided by repeated INR values.
• If subsequent INR ≥1.4 within the first 24 - 48 hours after the starting dose, give a repeat dose of phytonadione 10 mg Intravenous.

Vitamin K Dose in Children

• Route of administration differs with indication.
• The oral route is used to treat non-bleeding patients with warfarin-associated coagulopathy.
• The intravenous route is used in select nonbleeding patients and should be used in patients with major bleeding due to warfarin-associated coagulopathy.
• The Intravenous and SubQ routes can be used in the treatment of vitamin K deficiency bleeding.
• The intramuscular route is not used due to the risk of hematoma formation except in the prevention or treatment of vitamin K deficiency bleeding.

Dosage in the prevention, and supplementation of Vitamin K deficiency (Disease-specific):

• Biliary atresia (Dose and route depend on INR value):
• Infants 1 to 6 months:

  • INR >1.2 to 1.5:

    • 2.5 mg once daily orally is given

  • INR >1.5 to 1.8:

    • The initial dose is 2 to 5 mg intramuscular once followed by 2.5 mg once a day orally

  • INR >1.8: Initial:

    • 2 to 5 mg intramuscular once, followed by 5 mg once daily orally

• Cholestasis:

  • 4 to 15 mg/day orally is given

• Cystic fibrosis:

  • 3 to 0.5 mg/day orally is given

• Liver disease:

  • 5 to 5 mg/day orally is given

Dosage in the treatment of Reversal of Vitamin K antagonists (eg, warfarin):

• Infants, Children, and Adolescents:

  • Weight-based dosing (preferred):

    • Chest recommendations:

      • 03 mg/kg/dose I/V is advised for excessively prolonged INR (usually INR >8 and no evidence of bleeding) due to vitamin K-antagonist (eg, warfarin)
      • If significant bleeding, use fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa

  • Alternate dosing: Fixed dosing:

• Smaller pediatric patients should get doses on the low end of the dosing range
• excessive dosages can cause warfarin-resistance

  • When rapid reversal of anticoagulation is needed in patients who are not bleeding (in patients who do will require further oral anticoagulant therapy):

    • 0.5 to 2 mg SubQ or Intravenously

  • When rapid reversal of anticoagulation is needed in patients who are not bleeding (in patients who do not require further oral anticoagulant therapy):

    • 2 to 5 mg SubQ or Intravenously

  • Significant bleeding but not life-threatening:

    • 0.5 to 2 mg subQ or intravenously

  • Significant life-threatening bleeding:

    • 5 mg subQ or intravenously

Dosage in the treatment of Parenteral nutrition as a maintenance requirement:

Patients using warfarin may not require TPN supplementation of phytonadione.

• Infants:

  • 10 mcg/kg/day intravenous is given.

• Children and Adolescents:

  • 200 mcg/day intravenous is given.

Vitamin K Pregnancy Risk Factor: C

• In very small amounts, Phytonadione crosses the placenta.
• Vitamin K requirements are the same for pregnant and unpregnant women.
• Antidotes that are prescribed for mothers should be considered in light of the prognosis and health of the mother.
• Pregnant women should only receive antidotes if they have been given a clear indication. They should not be withheld due to fears of teratogenicity.
• Preservative-free solutions are used for injections that are required during pregnancy.

Vitamin K uses during breastfeeding:

• Breast milk contains phytonadione.
• Breast milk contains small amounts of dietary Vitamin K.
• The dietary requirements for vitamin K in breastfeeding women and those who are not breastfeeding women are identical.
• According to the manufacturer of the product, when deciding whether to continue or stop breastfeeding during therapy, it is important to consider the risks to infant exposure, the benefits to the infant, and the benefits to the mother.
• Preservative-free solutions are preferred for injections that are required in nursing women.

Vitamin K Dose in Renal Disease:

• There are no dosage adjustments given in the manufacturer’s labeling.

Vitamin K Dose in Liver Disease:

• There are no dosage adjustments given in the manufacturer’s labeling. 

Side effects of Vitamin K:

• 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)

Contraindications to Vitamin K Include:

• Allergy to phytonadione, or any component of the formulation

Warnings and precautions

• Dermatologic toxicities:
  • Parenteral administration has been associated with cutaneous reactions such as delayed-type hypersensitivity reactions and eczematous responses, scleroderma patches and urticaria.
  • The onset can take anywhere from a day to one year.
  • Stop using therapy if you experience skin reactions.
• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]:
  • Parenteral use has been associated with fatal hypersensitivity reactions including anaphylaxis.
  • It can occur immediately following intravenous or intramuscular injections.
  • Reactions were observed even after IV infusions that were slow despite the fact that the dose was diluted.
  • If IV or IM administration is impossible, avoid them.
  • Anaphylactoid reactions are common when patients receive large intravenous doses of polyethoxylated casting oil quickly.
• Anticoagulant-induced hypoprothrombinemia:
  • Give a dose to patients who are receiving a therapeutic vitamin K antagonist, (eg warfarin), which will rapidly lower their INR to a safe level.
  • High doses of phytonadione can cause warfarin resistance lasting at most one week.
• Hypoprothrombinemia caused by liver disease
  • If the first dose of medication does not reverse coagulopathy then it is unlikely that higher doses will have any effect.
  • Ingestion of long-acting anticoagulant rodenticides (LAAR).
  • Patients with LAAR-induced coagulation require higher doses and longer treatment times (up to months) than patients with warfarin-induced coagulation.

Vitamin K (phytonadione): Drug Interaction

Monitor: 

• PT, INR
• Monitor for hypersensitivity reactions if giving Intravenously.

How to administer Vitamin K?

Intravenous:

• Infuse slowly
• The rate of infusion should not be more than 1 mg/minute.
• Alternatively, dilute dose in a minimum of 50 mL of compatible solution and give using an infusion pump over at least 20 minutes.
• The injectable route should be used if the oral route is not feasible or there is a greater urgency to reverse anticoagulation.
• The intravenous route can be used in selected nonbleeding patients and should be used in patients with major bleeding due to warfarin associated coagulopathy

Intramuscular:

• The intramuscular route should be avoided due to the risk of hematoma formation.

Oral:

• The parenteral formulation can also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed
• It may be administered undiluted or diluted in a beverage (eg, orange juice)

Mechanism of action of Vitamin K:

• It stimulates the liver to synthesize clotting factors (II-VII, VII and IX, X).
• Menadiol (Vitamin K3) is a water-soluble form of vitamin K
• Menadione is more effective than Phytonadione, but it has a shorter and faster effect.
• Menadiol sodium phosphate is half the potent than menadione.

The onset of action: (Increased coagulation factors):

• Oral: 6 -10 hours
• IV: 1 t-2 hour

Peak effect: (INR values return to normal):

• Oral: 24 - 48 hours;
• IV: 12 t-14 hours

Absorption:

• Oral: It is absorbed from intestines in the presence of bile.
• SubQ administration has variable absorption
• Intramuscular vitamin K is readily absorbed

Metabolism: Rapid hepatic metabolism

Excretion: Via Urine and feces 

International Brands of Vitamin K:

• Bonadiona
• Haemokion
• Hema-K
• Kanakion
• Kanavit
• Katimin-1
• Kenadion
• Konakion
• Konakion
• Konakion 10 mg
• Konakion MM
• Konakion MM Paediatric
• Konakion MM Pediatric
• Mepro K
• Neokay
• Phytomen
• Prohem
• Univitan K1
• Vitacon
• Vitak
• Vitamin K
• Vitamin K1
• Vitamine K!1 Roche
• Vitka Infant
• AquaMEPHYTO;
• Konakion
• Mephyton

Vitamin K brands in Pakistan:

• K-Lot (Inj. 2mg/ml) - GT Pharma
• K-Vit (Tab. 10 mg) - Irza
• Phyto-K (Inj. 10 mg) - Elite Pharma
• Phytomenadione (Inj. 10 mg) - Haji Medicine
• Vitamin K (Inj. 10 mg) - Drug's Inn
• Vitamin K (Inj. 10 mg) - Lawrence
• Vitamin K (Inj. 10 mg, Tab. 10 mg) - Venus
• Vitamin-K1 (Inj. 2mg/ml) - English Pharma