General Administration Information Route-Specific Administration Oral Administration Injectable Administration Intermittent IV
infusion Intramuscular Administration Subcutaneous Administration 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 to prevent vitamin K deficiency and/or hypoprothrombinemia: For treatment of hemorrhagic disease of the newborn
(HDN): For hemorrhagic disease of
the newborn (HDN) prophylaxis: For the treatment of hemorrhage* or bleeding prophylaxis* in
patients with coumarin toxicity* (i.e., warfarin-induced hypoprothrombinemia): For the treatment of familial hypocholesterolemia* (eg., abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, CRD): Maximum Dosage Limits: Patients with Hepatic Impairment Dosing Patients with Renal Impairment Dosing *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. 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 Intravenous Route Intramuscular
Route DISCLAIMER: This drug information content is provided for informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always consult their physician with any questions regarding a medical condition and to obtain medical advice and treatment. Drug information is sourced from GSDD (Gold Standard Drug Database ) provided by Elsevier. |