VITAMIN K1

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Oral absorption requires the presence of adequate bile salts. Bile salts must be given with the tablets when the endogenous supply of bile to the gastrointestinal tract is deficient.
-Phytonadione injection has been administered orally and is typically used when lower oral doses (e.g., 1 mg) are needed and no oral product is available. Injectable phytonadione solution (2 mg/mL) has been found to be stable for 30 days when stored under refrigeration in amber glass bottles or white polyethylene plastic bottles and when stored at room temperature in amber glass bottles. Phytonadione injection was packaged in 0.75 mL aliquots in amber glass dropper bottles with a glass dropper and rubber bulb and also in white polyethylene plastic squeeze dropper bottles with a dropper tip and detachable cap. Less than 10% loss in phytonadione occurred over 30 days in samples stored at room temperature exposed to light (8 hours/day) in amber glass bottles and in the refrigerator protected from light in both containers; however, more than 10% loss of phytonadione was observed in about 40 hours in the samples stored in plastic bottles at room temperature.
-Storage: Protect from light; phytonadione is fairly rapidly degraded by light.
Extemporaneous Compounding-Oral
Extemporaneous Preparation of 1 mg/mL Oral Suspension
-Triturate six 5-mg tablets into a fine powder.
-Add 5 mL of purified water, USP and 5 mL of 1% methylcellulose to the powder and mix into a uniform paste.
-Transfer mixture to a graduate and add sufficient amount of sorbitol 70% to make a total volume of 30 mL.
-Storage: Store under refrigeration for up to 3 days.
-Shake well before administration.



Injectable Administration
-Phytonadione can be administered intramuscularly (IM), subcutaneously, or intravenously (IV) by slow IV infusion. In general, IM and IV routes should be avoided; however, the IV route is the preferred route for rapid reversal of warfarin. IV and IM administration are associated with an increased risk of anaphylactoid reactions. Anaphylactoid reactions have occurred during the first infusion and in patients receiving IV phytonadione that has been diluted and injected by slow IV infusion. Similar reactions have been reported with IM administration. Therefore, restrict IV and IM administration to those situations where another route is not feasible and the increased risk involved is considered justified. Subcutaneous administration is the preferred parenteral route. However, subcutaneous administration often results in delayed and erratic absorption.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration.
-Storage: Protect from light at all times.
Intravenous Administration
Dilution
-Dilute the phytonadione injection with preservative-free 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection only; other diluents should not be used.
-Storage: Use diluted injections immediately and protect from light at all times. Discard any unused portions of undiluted or diluted injection.

Intermittent IV infusion
-Infuse slowly at a rate not exceeding 1 mg/minute.


Intramuscular Administration
-If IM injection is unavoidable, inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children and adolescents only]).

Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.

Adverse reactions have not been reported for individuals ingesting higher amounts of dietary vitamin K orally; tolerable upper intake levels have not been established.

During intravenous administration of phytonadione, serious hypersensitivity reactions or anaphylaxis can occur. Typically, these reactions occur upon first-time administration of phytonadione. Severe hypersensitivity/anaphylactoid reactions including anaphylactic shock, cardiac arrest and/or respiratory arrest, and death have occurred during and immediately after intravenous injection of phytonadione. Other effects associated with these reactions include transient flushing, "peculiar" sensations of taste (dysgeusia), dizziness, rapid and weak pulse, profuse sweating (hyperhidrosis), hypotension, weakness, sinus tachycardia, chest pain (unspecified), dyspnea, and cyanosis.

An injection site reaction consisting of pain, swelling, and tenderness at the site may occur. Skin hypersensitivity reactions, including rash and vesicular rash, have been reported with phytonadione injections. Cutaneous reactions, including eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions, have also been associated with parenteral phytonadione. Time of onset of such reactions has ranged from 1 day to a year after administration. Infrequently, usually after multiple phytonadione injections, erythematous, indurated plaques and pruritus have occurred; rarely, these have progressed to scleroderma-like lesions that have persisted for long periods. In other cases, these lesions have resembled erythema perstans. If skin or serious hypersensitivity reactions occur, discontinue phytonadione and institute medical management.

Hemolysis, jaundice, and hyperbilirubinemia have been rarely observed in newborns after administration of phytonadione. These reactions may be related to the dose of phytonadione administered; therefore, the recommended dose should not be exceeded.

The benefit of parenteral vitamin K administration to infants outweighs the previously reported possible risk of childhood cancer. The Vitamin K Ad Hoc Task Force of the American Academy of Pediatrics (AAP) reviewed the related data and concluded that there is no association between the intramuscular (IM) administration of vitamin K and childhood leukemia or other cancers. Oral vitamin K has been shown to have similar efficacy compared to parenteral therapy in the prevention of early neonatal vitamin K deficiency bleeding; however, there is evidence that oral vitamin K is less effective for the prevention of late bleeding than intramuscular therapy, particularly in exclusively breast-fed infants who receive a single oral dose. The optimal oral vitamin K regimen to maximize efficacy has yet to be determined.

Phytonadione is contraindicated in patients with hypersensitivity to phytonadione or inactive ingredients of the product.

There may be a decreased response to phytonadione in patients with hepatic disease. Failure to respond to vitamin K may indicate a condition that is inherently unresponsive to vitamin K. Repeated large doses are not warranted if the initial response is unsatisfactory. Patients with biliary tract disease or obstructive jaundice require concurrent administration of bile salts to ensure oral absorption of vitamin K. In a randomized controlled study of 40 infants younger than 6 months of age with conjugated hyperbilirubinemia, the absorption of oral vitamin K was impaired and erratic compared to IV administration.

Patients receiving phytonadione for anticoagulant-induced hypoprothrombinemia are at risk for developing a hypercoagulable state. Although phytonadione is not a clotting agent, overzealous therapy with phytonadione may restore the previous hypercoagulable state resulting in thromboembolic disease. Dosages of vitamin K1 should be kept as low as possible, and the prothrombin time or INR checked at regular intervals.

Temporary resistance to anticoagulant therapy may result following treatment with phytonadione, especially if large doses are used. If relatively large doses of phytonadione have been used, it may be necessary when re-instituting anticoagulant therapy to use somewhat higher doses or to use an anticoagulant that acts by a different mechanism (i.e., heparin). Additionally, vitamin K should NOT be given intramuscularly to patients on anticoagulant therapy because of the risk of intramuscular hemorrhage.

Fatal anaphylactoid reactions have occurred during and immediately after the intravenous administration (IV) and intramuscular administration (IM) of phytonadione; therefore, IV and IM routes of administration should be restricted to those situations where other routes are not feasible and the risk of serious hypersensitivity reactions or anaphylaxis is considered justified. Severe reactions, including shock and cardiac and/or respiratory arrest, have occurred primarily with IV administration, even when precautions have been taken to dilute phytonadione and to avoid rapid infusion. Similar reactions have occurred with IM administration. Some patients have experienced severe reactions when receiving phytonadione for the first time. Cutaneous reactions, including eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions, may also occur with parenteral phytonadione administration. Time of onset of such reactions has ranged from 1 day to a year after administration. If skin or serious hypersensitivity reactions occur, discontinue phytonadione and institute medical management.

Some parenteral phytonadione preparations contain benzyl alcohol as a preservative. Patients with a known benzyl alcohol hypersensitivity should not receive parenteral phytonadione. Use preservative-free phytonadione formulations in neonates, if available. A 'gasping syndrome' characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and low birth weight and premature neonates may be more likely to develop toxicity. Normal therapeutic phytonadione doses would deliver benzyl alcohol at amounts lower than those reported with 'gasping syndrome'; however, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered. If further dilution of phytonadione is necessary, solutions for dilution should be preservative-free. In addition, certain parenteral phytonadione preparations contain polysorbate 80 and should be avoided in patients with a known polysorbate 80 hypersensitivity. Some literature suggests that low birth weight premature neonates exposed to polysorbate 80 at high doses or for prolonged periods of time may experience hepatotoxicity, hypotension, renal failure, ascites, and thrombocytopenia.

Description: Phytonadione is a synthetic compound that is chemically indistinguishable from naturally occurring vitamin K1 (phylloquinone). Vitamin K received its name in 1935 when it was called 'Koagulationsvitamin', which means 'clotting vitamin.' Vitamin K refers to a group of compounds that have a common methylated naphthoquinone ring and vary in the aliphatic side chain at the 3 position. Because the naphthoquinone ring is the functional group, all K vitamins have a similar mechanism of action. However, there are substantial differences in absorption, bioavailability, transport, and tissue distribution due to the different lipophilicities of the side chains and the different foods in which K vitamins are found. Vitamin K is found in both plant and animal sources. Phylloquinone, the most common form of vitamin K, is found in green vegetables (e.g., broccoli, brussel sprouts, collard greens, lettuce, and spinach) and plant oils (e.g., soybean and canola oils).

Parenteral phytonadione, vitamin K1, is used for the prophylaxis and treatment of vitamin K deficiency bleeding (VKDB) in neonates and infants. Phytonadione is reported to have a more rapid and more prolonged effect than menadione (vitamin K3). Phytonadione is preferred over other forms of vitamin K (i.e., phenindione or menadiol) in infants because of a significant reduction in hemolytic anemia and hyperbilirubinemia. For prophylaxis of VKDB, IM administration of vitamin K is preferred over oral administration due to superior efficacy. Vitamin K is also used for the treatment or prevention of hypoprothrombinemia attributable to vitamin K deficiency or oral anticoagulant therapy. In these settings, orally administered phytonadione is preferred over other routes because subcutaneous administration often results in delayed and erratic absorption, and fatal anaphylactoid reactions have occurred during intravenous administration; however, anaphylactic reactions also have been reported with other parenteral routes of administration. Injectable phytonadione, vitamin K1, is FDA-approved for use in pediatric patients as young as neonates.

For nutritional supplementation:
-for nutritional supplementation in healthy persons based on recommended adequate intake (AI):
Oral dosage:
Neonates: 2 mcg/day PO. The AI is based on an average intake of milk of 0.78 L/day and an average phylloquinone concentration of 2.5 mg/L in human milk.
Infants 1 to 6 months: 2 mcg/day PO. The AI is based on an average intake of milk of 0.78 L/day and an average phylloquinone concentration of 2.5 mg/L in human milk.
Infants 7 to 11 months: 2.5 mcg/day PO. The vitamin K intake for this age category is higher than the AI based solely on human milk because other foods become a more important part of the infants diet.
Children 1 to 3 years: 30 mcg/day PO.
Children 4 to 8 years: 55 mcg/day PO.
Children and Adolescents 9 to 13 years: 60 mcg/day PO.
Adolescents 14 to 17 years: 75 mcg/day PO.
-for nutritional supplementation in persons with cystic fibrosis:
NOTE: There is no clear consensus on the optimal dosing regimen for vitamin K supplementation for patients with cystic fibrosis. As vitamin K is metabolized within 24 hours, it is likely that a daily dose will be required. Recommendations vary widely, ranging from 0.3 to 10 mg/day.
Oral dosage:
Neonates: 300 mcg/kg/dose PO once daily or 0.5 to 2 mg PO once daily. Although the Cystic Fibrosis Foundation recommends 0.3 to 0.5 mg/day PO in all patients, lower doses have been shown to achieve suboptimal vitamin K status and may not be adequate to prevent deficiency. Additionally, data have shown no adverse effects from vitamin K supplementation at any dose.
Infants: 300 mcg/kg/dose PO once daily or 0.5 to 2 mg PO once daily. Although the Cystic Fibrosis Foundation recommends 0.3 to 0.5 mg/day PO in all patients, lower doses have been shown to achieve suboptimal vitamin K status and may not be adequate to prevent deficiency. Additionally, data have shown no adverse effects from vitamin K supplementation at any dose.
Children and Adolescents: 1 to 10 mg PO once daily. Although the Cystic Fibrosis Foundation recommends 0.3 to 0.5 mg/day PO in all patients, lower doses have been shown to achieve suboptimal vitamin K status and may not be adequate to prevent deficiency. A supplemental dose of at least 1 mg/day PO has been shown to be necessary to achieve vitamin K status similar to healthy persons. Additionally, data have shown no adverse effects from vitamin K supplementation at any dose.
-for nutritional supplementation in persons with cholestatic liver disease or chronic liver disease:
Oral dosage:
Infants, Children, and Adolescents: 2.5 to 5 mg PO 2 to 7 days/week. However, higher doses of up to 10 mg PO once daily are often needed.
-for nutritional supplementation to prevent vitamin K deficiency in persons receiving parenteral nutrition (PN):
Intravenous dosage:
Neonates weighing less than 2.5 kg: 80 mcg/kg IV vitamin K (as 2 mL/kg of Pediatric MVI), added daily to the parenteral nutrition.
Neonates weighing 2.5 kg or more: 200 mcg IV vitamin K (as 5 mL of Pediatric MVI), added daily to the parenteral nutrition.
Infants and Children 1 to 11 years weighing 40 kg or less: 200 mcg IV vitamin K (as 5 mL of Pediatric MVI), added daily to the parenteral nutrition.
Children 1 to 11 years weighing more than 40 kg: 150 mcg IV vitamin K (as 10 mL of Adult MVI), added daily to the parenteral nutrition. Alternatively, if using the 12-vitamin formulation that does not contain vitamin K, 0.5 to 1 mg IV once daily or 5 to 10 mg IV once weekly as part of parenteral nutrition.
Children and Adolescents 12 to 17 years: 150 mcg IV vitamin K (as 10 mL of Adult MVI), added daily to the parenteral nutrition. Alternatively, if using the 12-vitamin formulation that does not contain vitamin K, 0.5 to 1 mg IV once daily or 5 to 10 mg IV once weekly as part of parenteral nutrition.
Intramuscular or Subcutaneous dosage:
Children and Adolescents 12 to 17 years: 0.5 to 1 mg IM/subcutaneously once daily or 5 to 10 mg IM/subcutaneously once weekly if using the 12-vitamin formulation that does not contain vitamin K.

For treatment of hemorrhagic disease of the newborn (HDN):
Intramuscular, Intravenous*, or Subcutaneous dosage:
Neonates: 1 mg IM/subcutaneously is the FDA-approved dosage. Higher doses may be necessary if the mother has been taking anticonvulsants or oral anticoagulants. Whole blood or component therapy may be indicated if bleeding is excessive; however, blood components do not correct the underlying disorder, and phytonadione therapy should be given concurrently. Doses of 1 to 3 mg IM/IV/subcutaneously have been administered in the setting of late Vitamin K deficiency bleeding (VKDB) in infants. In some cases, vitamin K 1 mg was given for up to 3 days. However, most other cases have been successfully treated with 1 dose of vitamin K and studies have shown that a single dose of vitamin K in the setting of VKDB may be adequate to correct coagulation abnormalities. Although the FDA-approved labeling recommends IM or subcutaneously administration, in most reported cases of VDKB, vitamin K was given IV. It is recommended that vitamin K be given IV, and not IM, until coagulation parameters normalize to minimize the risk of hematoma at the injection site.
Infants 1 to 5 months*: Doses of 1 to 3 mg IM/IV/subcutaneously have been administered in the setting of late Vitamin K deficiency bleeding (VKDB) in infants. Whole blood or component therapy may be indicated if bleeding is excessive; however, blood components do not correct the underlying disorder, and phytonadione therapy should be given concurrently. In some cases, vitamin K 1 mg was given for up to 3 days. However, most other cases have been successfully treated with 1 dose of vitamin K and studies have shown that a single dose of vitamin K in the setting of VKDB may be adequate to correct coagulation abnormalities. In most reported cases, vitamin K was given IV. It is recommended that vitamin K be given IV, and not IM, until coagulation parameters normalize to minimize the risk of hematoma at the injection site.

For hemorrhagic disease of the newborn (HDN) prophylaxis:
NOTE: The use of prophylactic vitamin K1 administration is standard practice in the US and most Western countries.
Intramuscular dosage:
Premature Neonates*: 0.2 to 0.5 mg IM as a single dose immediately after birth has been recommended. A single dose of 0.3 to 0.5 mg/kg IM for premature neonates weighing less than 1,000 g at birth and 1 mg IM for those weighing more than 1,000 g at birth is recommended by the American Academy of Pediatrics (AAP). The Canadian Pediatric Society recommends 0.5 mg IM as a single dose for premature neonates with birthweight of 1,500 g or less and 1 mg IM as a single dose for those with birthweight more than 1,500 g. Vitamin K plasma concentrations have been shown to be higher in premature neonates, particularly those less than 32 weeks gestational age. Studies in premature neonates given a wide range of prophylactic vitamin K doses from 0.2 mg/kg to a full 1-mg dose have shown median vitamin K concentrations in the first week of life up to 1,000 times higher than the normal adult range of 0.15 to 1.55 ng/mL. A randomized, controlled study in 98 premature neonates (less than 32 weeks gestation; range: 22.4 to 31.9 weeks; birthweight range: 454 to 1,950 g) found a significantly lower vitamin K1 serum concentration in neonates who received 0.2 mg IM compared to those who received 0.5 mg IM at 5 days postnatal age (median 59.3 ng/mL vs. 111.8 ng/mL; p = 0.45); however, there was no significant difference in undercarboxylated prothrombin (PIVKA-II) concentrations, a sensitive functional marker of deficiency in vitamin K, at 5 or 25 days postnatal age, indicating that the 0.2 mg dose maintained adequate vitamin K status. Vitamin K epoxide concentrations were significantly higher in infants who received 0.5 mg compared to those who received 0.2 mg, indicating possible overload of the immature liver. In another study, plasma vitamin K concentrations were not statistically significantly different on day 2 or day 10 of life in 7 premature neonates (mean gestational age 27.3 weeks; mean birthweight 1.08 kg) given 0.5 mg vitamin K compared to 20 premature neonates (mean gestational age 30 weeks; mean birthweight 1.48 kg) given 1 mg vitamin K. However, the plasma vitamin K concentrations were still very high in the premature neonates who received a lower prophylactic dose of 0.5 mg, suggesting that lower doses of vitamin K are necessary in this group.
Term Neonates: 1 mg IM as a single dose given immediately after birth is recommended by the American Academy of Pediatrics (AAP) and the FDA-approved labeling. Reserve the IV route for emergency use only. Larger or repeat doses may be required in infants whose mothers are taking anticonvulsants or oral anticoagulants.
Oral dosage*:
NOTE: Oral administration of vitamin K for prophylaxis of vitamin K deficiency bleeding (VKDB) is common in other countries; however, IM administration of vitamin K is standard practice in the US due to its superior efficacy for preventing late VKDB.
Healthy Term Neonates: 2 mg PO soon after birth, at 1 to 2 weeks of age, and at 4 weeks of age in breast-fed infants is recommended by the American Academy of Pediatrics (AAP) if IM vitamin K cannot be given ; however, the AAP recommends additional research to determine the optimal oral dosing regimen to ensure prevention of both early and late bleeding due to deficiency in vitamin K. A single oral dose should not be used because the oral bioavailability is variable and does not result in adequate body stores of vitamin K. Although oral vitamin K has been shown to have similar efficacy compared to parenteral therapy in the prevention of early bleeding due to deficiency in vitamin K, there is evidence that oral vitamin K is less effective for the prevention of late bleeding than intramuscular therapy, particularly in exclusively breast-fed infants who received a single oral dose. Repeated oral phytonadione doses given either weekly (1 mg) or daily (25 mcg) have been suggested to be as effective as intramuscular prophylaxis. Higher oral doses may be necessary in infants with bile disorders, such as biliary atresia and cholestasis, as higher rates of late vitamin K deficiency bleeding have been noted in these patients. Larger or repeat doses may also be required in infants whose mothers are taking anticonvulsants or oral anticoagulants.
Mothers of Breast-feeding Infants: Maternal supplements of 5 mg PO daily of phylloquinone through the first 12 weeks of life increase plasma vitamin K concentrations (in breast milk and infant plasma) in exclusively breast-fed infants who receive one IM dose of vitamin K at birth. In exclusively breast-fed infants, a deficiency in vitamin K may be a concern because the intestinal flora of breast-fed infants produces less vitamin K and the content of vitamin K in human milk is lower than that of formula.

For the treatment of vitamin K antagonist-induced prothrombin deficiency (i.e., vitamin K antagonist reversal*):
NOTE: Vitamin K should NOT be given intramuscularly to pediatric patients on anticoagulants because of the risk of intramuscular hemorrhage.
Intravenous dosage:
Infants, Children, and Adolescents: Data are limited in pediatric patients. 30 mcg/kg/dose IV is recommended by guidelines for excessively prolonged INR (typically more than 8) with no bleeding. In the presence of significant bleeding, immediate reversal using fresh frozen plasma (FFP), prothrombin complex concentrates, or recombinant factor VIIa may be necessary.

For the treatment of familial hypocholesterolemia* (eg., abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, CRD):
Oral dosage:
Infants, Children, and Adolescents: 15 mg PO once weekly has been associated with normal coagulation function and no hemorrhages. INR should be monitored during therapy.

For the treatment of vitamin K deficiency* or hypoprothrombinemia* due to biliary fistulas, chronic liver disease, obstructive jaundice, malabsorption syndromes, or administration of antibiotics, salicylates, or other drugs:
Oral dosage:
Infants, Children, and Adolescents: 2.5 to 5 mg PO 2 to 7 days/week. However, higher doses of up to 10 mg PO once daily are often needed.
Intramuscular, Intravenous, or Subcutaneous dosage:
Infants, Children, and Adolescents: 5 to 10 mg IM/IV/subcutaneously, repeated as necessary, depending on patient response and the severity of the deficiency.

Maximum Dosage Limits:
Upper tolerable intake levels in healthy, non-vitamin deficient individuals of all ages are not determinable due to a lack of data.
-Neonates
Dependent on indication, but upper limits of single doses are 2 mg/day PO and 1 mg/day IV/IM/subcutaneously.
-Infants
Dependent on indication, but upper limits of single doses are 10 mg/day PO/IV/IM/subcutaneously.
-Children
Dependent on indication, but upper limits of single doses are 10 mg/day PO/IV/IM/subcutaneously.
-Adolescents
Dependent on indication, but upper limits of single doses are 10 mg/day PO/IV/IM/subcutaneously.

Patients with Hepatic Impairment Dosing
No dosage adjustment necessary. However if no response is seen, the underlying condition (e.g., coagulopathy) may not be related to vitamin K deficiency, but a reduced ability of the liver to produce vitamin K dependent proteins.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Phytonadione has identical activity to the natural K vitamins. Vitamin K functions as a co-factor for gamma-glutamylcarboxylase, which is involved in the post-translational carboxylation of glutamate residues into gamma-carboxyglutamate (Gla). Gamma-carboxyglutamate residues are found in specific proteins (Gla proteins) including the vitamin K-dependent clotting (factors II, VII, IX, and X) and regulatory proteins (proteins C and S), proteins of bone metabolism (osteocalcin), and vascular proteins (matrix Gla protein [MGP], growth-arrest-specific gene 6 protein [Gas6]). The oxidation of vitamin K hydroquinone (KH2) into vitamin K 2,3, epoxide (KO) provides the energy to drive the carboxylation reaction to form Gla, which takes place late in the biosynthesis of specific proteins. Vitamin K must be reduced by vitamin K epoxide reductase from the quinone oxidation state to the hydroquinone form (KH2), which is the active cofactor for the vitamin-K dependent carboxylase. In addition, vitamin K epoxide reductase reduces KO formed during the carboxylation reaction back to KH2. Due to the limited amount of vitamin K intake and the 1:1 relationship between the conversion of KH2 into KO and the formation of Gla residues, vitamin K must be recycled. Vitamin K epoxide reductase works at low concentrations of vitamin K epoxide and vitamin K quinone and is important for the recycling of vitamin K. A second enzyme, DT-diapharase, reduces the quinone form of vitamin K but not the epoxide form; however, this enzyme requires high concentrations of vitamin K and does not appear to contribute to the recycling of vitamin K. This enzyme may play an important role when phytonadione is used to overcome warfarin-induced hypoprothrombinemia. During vitamin K deficiency, the carboxylation reaction cannot proceed, so Gla proteins are released in an undercarboxylated form. These descarboxy proteins or proteins induced by vitamin K absence (PIVKAs) have been shown to be inactive. Gla residues form calcium-binding groups in proteins, so the major difference between normal and descarboxy proteins is the binding of calcium and the adsorption of these proteins onto insoluble calcium salts.
Vitamin K-dependent proteins in blood coagulation: The role of vitamin K in blood coagulation is considered the classic activity of vitamin K. Gla residues in the coagulation factors (factors II, VII, IX, and X) and proteins C and S function to facilitate the binding of these proteins to the negatively charged phospholipids on the surface of platelets. The Gla domains of these proteins are necessary for proper function of the coagulation proteins. The binding of calcium ions to the coagulation factors via Gla residues causes the factors to undergo structural changes leading to internalization of the Gla-calcium complex and exposure of the phospholipid-binding domain. Warfarin inhibits vitamin K epoxide reductase thus preventing the carboxylation reaction and results in Gla blood coagulation proteins to be released in an undercarboxylated form, and thus inactive form.
Vitamin K-dependent proteins in the bone: Although the exact function of Gla proteins in the bone (matrix Gla protein (MGP), osteocalcin, and protein S) has not been determined, all the known bone Gla proteins are produced by osteoblasts. Osteocalcin is only produced by osteoblasts and makes up about 20% of noncollagenous protein in bone. In mice, osteocalcin has been shown to be a negative regulator of bone growth; however, after ovariectomy, the decrease in bone mass is more pronounced in mice deficient in osteocalcin. Both epidemiologic and clinical studies have reported a decrease in hip fractures and increased bone mineral density in subjects receiving supplemental vitamin K. MGP appears to be critical for bone mineralization and growth; spontaneous and fatal calcification of arteries and cartilage has been observed in mice with MGP deficiency. In humans with Keutel syndrome, a DNA mutation leading to nonfunctional MGP has been discovered.
Vitamin K-dependent proteins in the vasculature: In arterial vessels, Gla proteins include protein S, MGP, and Gas6. Studies in MGP-deficient mice have shown that MGP is a strong inhibitor of soft-tissue calcification, including cartilage and vessel wall. The function of Gas6 has only been studied in vitro and may affect other tissues as well (e.g., spinal motor neurons, neurons of the basal root ganglia, and Schwann cells among others). Gas6 was shown to prevent the death of fibroblasts and smooth muscle cells from serum starvation and may act as a growth promoter.

Pharmacokinetics: Phytonadione is administered orally, intramuscularly, intravenously, and subcutaneously. Triglyceride-rich lipoproteins, in addition to LDL and HDL, are carriers of vitamin K; apolipoprotein E is also important for transport of vitamin K. Phytonadione concentrates in the liver temporarily. Skeletal muscle contains little vitamin K, but significant concentrations are found in the heart and other tissues. In infants, the liver contains about one-fifth the amount of vitamin K1 as adults. Turnover of vitamin K in the liver is rapid and hepatic reserves are rapidly depleted in periods of low intake of vitamin K. In adults, circulating vitamin K concentrations after overnight fasting range from 200 to 800 pg/mL, but decrease rapidly with prolonged low intake. Although it is considered a fat-soluble vitamin, the ability of the body to store vitamin K is much less than for other fat-soluble vitamins. It has been suggested that overall vitamin K status is not adequately assessed using plasma concentrations, and measuring Gla content of Gla-proteins may be more worthwhile. Circulating osteocalcin is more sensitive to poor vitamin K status than other Gla-proteins. Little is known about the metabolic fate of vitamin K. Almost no free, unmetabolized vitamin K appears in the bile or urine. High fecal concentrations are attributable to synthesis of the vitamin by intestinal bacteria.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Oral Route
Oral phytonadione is absorbed from the gastrointestinal tract only if bile salts are present. In general, effects are observed with 6 to 10 hours of tablet administration. Improvement in INR may take 1 to 8 hours. Vitamin K is fat-soluble; dietary fat enhances absorption.

Intravenous Route
After parenteral administration of phytonadione, increased concentrations of blood-coagulation factors are evident within 1 to 2 hours, and hemorrhage is typically controlled within 3 to 6 hours. A normal prothrombin concentration may often be achieved in 12 to 14 hours.

Intramuscular Route
Phytonadione is readily absorbed after intramuscular administration.