AHFS Class:

• Vitamin K Activity 88:24

Generic Name(s):

• Phytonadione

Phytonadione is a fat-soluble naphthoquinone derivative that is identical to naturally occurring vitamin K₁.

Phytonadione is used in the prophylaxis and/or treatment of coagulation disorders due to faulty formation of factors II, VII, IX, and X caused by vitamin K deficiency or interference with vitamin K activity.34,113,134 Phytonadione is more effective than, and is preferred to, other vitamin K preparations in the presence of impending or actual hemorrhage. However, because phytonadione may require 3 hours or longer to stop active bleeding, administration of clotting factors (e.g., prothrombin complex concentrate [human]), fresh whole blood, or plasma may be necessary for more rapid control of severe bleeding.

Hypoprothrombinemia Caused by Vitamin K-Antagonist Anticoagulants

Phytonadione is the drug of choice for the treatment of moderate or severe hemorrhage caused by vitamin K-antagonist (coumarin [e.g., warfarin] or indandione derivative) oral anticoagulants. Withholding one or more doses of the vitamin K-antagonist anticoagulant may be sufficient to correct excessively prolonged prothrombin time/international normalized ratio (PT/INR) in asymptomatic (nonbleeding) patients or those with minor hemorrhage, although low doses of phytonadione will hasten the return of the INR to the therapeutic range.150,158,159 If excessive phytonadione is used, the resulting near-normal INRs may restore the conditions that originally required administration of anticoagulant drugs, and large doses of coumarin or indandione anticoagulants may be required to reinstitute anticoagulant therapy. If anticoagulation is needed following overcorrection with phytonadione, heparin may be used.

Hypoprothrombinemia Caused by Drugs Other than Vitamin K-Antagonist Anticoagulants

Phytonadione may also be valuable in restoring normal clotting time in patients with hypoprothrombinemia induced by drugs such as salicylates or broad-spectrum antibiotic therapy, when it is definitely caused by interference with vitamin K activity. If possible, discontinuance or reduction of the dosage of drugs interfering with the coagulation mechanism should be used as an alternative to phytonadione therapy.

Vitamin K-Deficiency Bleeding in Neonates

Phytonadione is used for the prophylaxis and treatment of bleeding due to vitamin K deficiency in neonates (formerly known as hemorrhagic disease of the newborn).34,113,135,136,137 The American Academy of Pediatrics (AAP) recommends that IM phytonadione be administered routinely to infants at birth to prevent bleeding due to vitamin K deficiency.34,135,136,137

Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis

Phytonadione is used in the treatment of hypoprothrombinemia secondary to conditions limiting absorption or synthesis of Vitamin K (e.g., obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, regional enteritis).113,134

Phytonadione is not effective in the treatment of hereditary hypoprothrombinemia. The drug is also ineffective in reversing hypoprothrombinemia caused by severe liver disease, and high doses may prolong the INR and aggravate the disease.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.112 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).112 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).121

Because of the lack of adequate data, the NAS was unable to establish accurate EARs and RDAs for vitamin K.121 The NAS has established an AI for vitamin K for adults, adolescents, and children 1 year of age or older based on reported vitamin K dietary intake in apparently healthy population groups (Third National Health and Nutrition Examination Survey [NHANES III]).121 Dietary intakes reportedly are slightly lower in women than men.121 An AI has been established for infants through 6 months of age based on the observed mean vitamin K intake of infants fed principally human milk.121 An AI for infants 7-12 months of age has been set based on the AI for younger infants.121 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)

The principal goal of maintaining an adequate intake of vitamin K in the US and Canada is to prevent vitamin K deficiency, and thus prevent vitamin K-responsive hypothrombinemia.121 Although dietary sources of vitamin K are usually adequate (except during the first 5-8 days of the neonatal period), deficiency can occur in infants who are breast-fed and in patients receiving prolonged parenteral nutrition, as well as in the presence of malabsorption syndromes. (See Uses: Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis.) Diagnosis of vitamin K deficiency may be based on tests for vitamin K-dependent clotting factors (e.g., prothrombin time, which is sensitive to the levels of factors II, VII, and X) or on a therapeutic trial of phytonadione. Adequate intake of vitamin K usually can be accomplished through consumption of foodstuffs.121 Spinach, collards, broccoli, iceberg lettuce, and plant oils are the major contributors of vitamin K in the diet of US adults and children.121

For specific information on currently recommended AIs of vitamin K for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration.

Administration

Phytonadione may be administered orally or parenterally (IV, IM, or subcutaneously). 113,134,160 The parenteral preparation also has been administered orally † in neonates.34,35,37,102,103,104,105,136,159 The route of administration of phytonadione depends on the severity of the prothrombin deficiency and the risks associated with administration by each route. The manufacturers state that because of the possibility of severe adverse reactions (see Cautions: Adverse Effects), IV or IM administration is indicated only when other routes of administration are not feasible and the serious risk is justified.113,160 However, the effects of phytonadione have been reported to be delayed and/or unpredictable following subcutaneous injection,144,145,146,147,148 and subcutaneous administration may be less effective for reversal of excessive anticoagulation than IV or oral administration.144,145,147,148,159 The American College of Chest Physicians (ACCP)150 and other clinicians158,161 recommend IV administration of phytonadione in emergency situations for major bleeding due to vitamin K-antagonist anticoagulants because of its more rapid onset; these clinicians recommend that subcutaneous administration be avoided.150,151,157,158,161

Oral administration of phytonadione usually reduces international normalized ratio (INR) levels in 24-48 hours and generally is recommended over parenteral administration in selected asymptomatic (nonbleeding) patients with hypoprothrombinemia due to vitamin K-antagonist anticoagulants.148,151,157,158,161,162,163 In patients with decreased bile secretion, bile salts (e.g., ox bile extract 300 mg or dehydrocholic acid 500 mg) should be given with each oral dose of phytonadione to ensure absorption. Parenteral administration is indicated in patients who are unable to retain or absorb the drug from the GI tract.

When phytonadione injection is administered IV, it should be injected at a rate not exceeding 1 mg/minute .113 The drug may be diluted for infusion with 0.9% sodium chloride, 5% dextrose, or 5% dextrose in 0.9% sodium chloride injection; other diluents that may contain benzyl alcohol should not be used. 113,160 (See Cautions: Pediatric Precautions.) The drug should be administered immediately after dilution, and any unused portion of the dilution and the unused contents of the ampul or vial should be discarded.113,160 The infusion container must be protected from light at all times.113,160 (See Chemistry and Stability: Stability.)

Dosage

Dose, frequency of administration, and duration of treatment with phytonadione depend on the severity of the prothrombin deficiency and the response of the patient; the lowest effective dose of phytonadione should be used.113,134,160

Hypoprothrombinemia Caused by Vitamin K-Antagonist Anticoagulants

For the treatment of hypoprothrombinemia caused by vitamin K-antagonist (coumarin- or indandione-derivative) anticoagulants, the usual initial parenteral dose of phytonadione recommended by the manufacturers is 2.5-10 mg administered by IV, IM, or subcutaneous injection; initial doses of up to 25 mg or, rarely, 50 mg may be required.113,160 However, ACCP and some clinicians state that subcutaneous injection of phytonadione should be avoided or reserved as a last resort because of unpredictable and/or delayed absorption.144,150,158,159,161 (See Dosage and Administration: Administration.)

For patients with major bleeding associated with vitamin K-antagonist anticoagulants (e.g. warfarin), ACCP and some clinicians suggest rapid reversal of anticoagulation with clotting factor preparations (e.g., prothrombin complex concentrate [human]) in conjunction with administration of phytonadione (e.g., 5-10 mg) by slow IV injection.150,157,159,161

When given orally as tablets, the usual initial dosage of phytonadione recommended by the manufacturer for hypoprothrombinemia caused by vitamin K-antagonist anticoagulants is 2.5-10 mg or up to 25 mg; the manufacturers state that 50 mg rarely may be required.134 Varying oral doses of phytonadione have been suggested for reversal of excessive hypoprothrombinemia caused by vitamin K-antagonist anticoagulants.148,150,152,157,158,161,162 Some clinicians suggest administration of oral phytonadione (e.g., 2.5-5 mg) for patients with INRs exceeding 10 and no evidence of bleeding or only minor bleeding or for INRs of 4.5-10 in the presence of other risk factors for bleeding.148,150,157,158,161,162 In asymptomatic (nonbleeding) patients with INRs of 4.5-10 who are not at high risk for bleeding, withholding vitamin K-antagonist anticoagulant therapy until the INR has decreased to a level nearer the therapeutic range may be sufficient, although some clinicians suggest administering low-dose oral phytonadione (e.g., 1-2.5 mg) in addition to withholding warfarin in such patients;158,159,161 ACCP suggests against routine use of phytonadione in these cases.149,150

Phytonadione should be administered in the lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and INR is not decreased below the effective anticoagulant level.134 The manufacturer states that the dose of oral phytonadione may be repeated 12-48 hours after the first oral dose if the initial response is not satisfactory.134 Failure to respond to phytonadione may indicate a disorder that is not vitamin K-dependent, and repeated large doses of the drug are not warranted.

Vitamin K-Deficiency Bleeding in Neonates

For prophylaxis of vitamin K-deficiency bleeding in neonates (formerly known as hemorrhagic disease of the newborn), the manufacturers and the American Academy of Pediatrics (AAP) recommend that phytonadione in a single IM dose of 0.5-1 mg be administered to the neonate within 1 hour of delivery.34,113,135,136,160 The AAP states that additional research should be performed on the efficacy, safety, and bioavailability of oral formulations and on optimal dosing regimens to prevent late vitamin K-deficiency bleeding.135

For the treatment of vitamin K-deficiency bleeding in neonates (hemorrhagic disease of the newborn), the usual dose of phytonadione recommended by the manufacturers is 1 mg administered subcutaneously or IM.113,160 Larger doses may be considered for neonates whose mothers have received vitamin K-antagonist anticoagulant therapy during pregnancy.113,160

Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis

For the treatment of non-anticoagulation-induced hypoprothrombinemia (e.g., resulting from malabsorption syndromes, therapy with broad-spectrum antibiotics or salicylates), single oral or parenteral doses of 2.5-25 mg may be administered to adults; the dose and route of administration depend on the severity of the deficiency and the response to the drug.113,134,160 Up to 50 mg as a single dose rarely may be required.113,134,160

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of vitamin K currently recommended by the National Academy of Sciences (NAS) for healthy infants through 6 months of age is 2 mcg daily and for those 7-12 months of age is 2.5 mcg daily.121 The substantial increase in the AI from infancy to early childhood presumably is due to the method used to set the AI for older infants and the increased proportion of the diet containing vitamin K-rich vegetables as the diet becomes more diversified.121 The AI of vitamin K currently recommended by NAS for healthy children 1-3, 4-8, 9-13, or 14-18 years of age is 30, 55, 60, or 75 mcg daily, respectively.121 The AI for healthy men of all ages (19-70 years of age and those older than 70 years of age) is 120 mcg of vitamin K daily, and the AI for healthy women of all ages (19-70 years of age and those older than 70 years of age) is 90 mcg daily.121

Limited data suggest that the vitamin K status in pregnant women does not differ from that in nonpregnant women.121 Therefore, the NAS states that the AI of vitamin K does not need to be increased during pregnancy (i.e., pregnant women can receive the usual AI appropriate for their age).121 Available evidence indicates that the vitamin K status of lactating women is comparable to that of nonlactating women.121 Vitamin K is not distributed in clinically important amounts into milk, and the AI for lactating women does not differ from that for nonlactating women.121

Adverse Effects

Severe hypersensitivity reactions have occurred rarely during or immediately following IV or IM administration of phytonadione; fatalities have been reported.113,142,149,156,160 These severe reactions, which may occur in patients receiving phytonadione for the first time or on subsequent administrations despite dilution of the injection and slow infusion, resemble anaphylactic/anaphylactoid reactions.113,142,149,156,160 Manifestations have included shock, circulatory collapse, cardiorespiratory arrest, brief hypotension, flushing, diaphoresis, chest pain, a sense of chest tightness, tachycardia/cardiac irregularities, rapid and weak pulse, cyanosis, weakness, dyspnea, tremors, dulled consciousness, bronchospasm, alteration of taste (dysgeusia), and dizziness.113,142,149,156,160 It is not known whether these adverse reactions are caused by the drug or the injection vehicle. The manufacturers state that IV or IM administration of the drug should be restricted to situations in which subcutaneous administration is not feasible and the serious risk of IV or IM administration is justified.113,160 However, subcutaneous injection of phytonadione has been associated with unpredictable and/or delayed absorption, and many clinicians recommend that the drug not be administered by this route in emergent situations.144,145,146,147,148,150,158,159,161 (See Dosage and Administration: Administration.)

Eczematous reactions (e.g., erythematous, indurated, pruritic plaques), urticaria, and delayed hypersensitivity reactions have occurred infrequently following parenteral administration of phytonadione, usually after repeated injection.113,138,139,140,141,149,160 Such reactions generally have occurred within 1 day to a year following parenteral administration of the drug.113 Rarely, these reactions have progressed to scleroderma-like lesions that have persisted for long periods of time.113,138,160 In other cases, these lesions have resembled erythema perstans.113,160 The manufacturer recommends that phytonadione injection be discontinued and medical management be instituted following such cutaneous reactions.113

Pain, swelling, and tenderness at the injection site occur rarely after parenteral administration of phytonadione.113,160

Precautions and Contraindications

Phytonadione is contraindicated in individuals who are hypersensitive to the drug or any ingredients in the formulations.

Pediatric Precautions

Hyperbilirubinemia, jaundice, and severe hemolytic anemia have been reported rarely in neonates, particularly premature neonates, following large doses (10-20 mg) of phytonadione. However, the incidence of these adverse effects is much less with phytonadione than with other vitamin K preparations.

Some preparations of phytonadione injection may contain benzyl alcohol as a preservative.160 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.113,114,115,116,117,118,119,120,160,163 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.114,115,116,117,118,119,120 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,113,114,116 the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.114,163

Geriatric Precautions

Clinical studies of oral phytonadione did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently from younger patients.134 However, other reported clinical experience has not identified differences in response between geriatric and younger patients.134 In general, dosage selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in the elderly.134

Pregnancy and Fertility

Pregnancy

Reproduction studies have not been conducted in animals, and it is not known if phytonadione has teratogenic effects.

Fertility

Reproduction studies have not been conducted in animals, and it is not known if phytonadione affects fertility in humans.

Because vitamin K₁ is a pharmacologic antagonist to coumarin and indandione derivatives, patients being treated with these anticoagulants should not receive phytonadione except for the treatment of excessive hypoprothrombinemia. Phytonadione does not antagonize the anticoagulant effects of heparin,113,134,160 low molecular weight heparins, fondaparinux, or direct-acting oral anticoagulants.157

Orlistat may result in decreased GI absorption of fat-soluble vitamins such as phytonadione (vitamin K₁).122 At least 2 hours should elapse between (before or after) any orlistat dose and phytonadione administration; administering fat-soluble vitamins at bedtime may be a convenient time.122,124,128,130 Although the manufacturer of orlistat recommends that a vitamin supplement containing fat-soluble vitamins (A, D, E, and K) be used during orlistat therapy,122,128 such vitamin concentrations in clinical studies with the drug remained within the normal range for most patients despite decreases, and vitamin supplementation was only occasionally needed.123,124,125,126,127,129

Pharmacology

Phytonadione has the same activity as naturally occurring vitamin K₁, which is required for the synthesis of blood coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor or plasma thromboplastin component), and X (Stuart-Prower factor) in the liver. Studies indicate vitamin K is involved in carboxylation of the preformed, inactive precursors of these coagulation factors. The resulting γ-carboxyglutamyl residues are required for the calcium-dependent phospholipid binding exhibited by active vitamin K-dependent clotting factors. In adequate doses, phytonadione reverses the inhibitory effect of coumarin and indandione derivatives on the synthesis of these factors. A rare genetic mutation of the vitamin K receptor site which is associated with resistance to coumarin and indandione derivative anticoagulants and increased sensitivity to small amounts of exogenous vitamin K has occurred in some patients.

Pharmacokinetics

Absorption

Phytonadione is absorbed from the GI tract only in the presence of bile salts. Radioisotope studies show that absorption occurs via intestinal lymph. There is some evidence that absorption of phytonadione across the GI mucosa is a saturable, energy-dependent process that occurs in the proximal small intestine.100,101,102 Following oral administration of phytonadione, blood coagulation factors increase in 6-10 hours. The increase generally occurs within 1-2 hours following parenteral administration. In a randomized controlled trial in patients with excessive anticoagulation due to warfarin, the international normalized ratio (INR) response was more rapid with IV than with oral phytonadione at 6 and 12 hours following the dose, but mean INR values were similar at 24 hours.152 Bleeding is usually controlled within 3-6 hours, and a normal INR may often be obtained 12-14 hours after parenteral administration. Following oral administration of a single 2-mg dose of the drug in neonates with a gestational age of 31-38 weeks, serum phytonadione concentrations increased from a baseline of 17 ng/mL to 213 and 275 ng/mL at 6 and 12 hours, respectively, after administration and were 65 ng/mL at 5 days.103

Distribution

Although the drug may be concentrated in the liver for a short time after absorption, only small amounts of phytonadione are stored in body tissues.

Phytonadione appears to cross the placenta to a limited extent.34,102,107 Following IV administration of a 1-mg dose of phytonadione to pregnant women 11-47 minutes prior to delivery, cord plasma concentrations of the drug were undetectable to 0.14 ng/mL while concurrent maternal plasma concentrations were 45-93 ng/mL.107 Phytonadione is distributed into milk.34,35,108,109,110,111 Although vitamin K₁ is present in human breast milk in relatively low concentrations34,35,108,109,110,111 (about 2 ng/mL),108 oral administration of phytonadione to lactating women may increase the concentration of the vitamin in breast milk.102,108 Oral administration of a single 20-mg dose of phytonadione in one lactating woman increased milk concentrations of the vitamin from undetectable to about 140, 50, and 5 ng/mL 12, 36, and 48 hours, respectively, after administration.108 Phytonadione concentrations are higher in cow's milk than in human breast milk.34,35,108,109,110,111

Elimination

Little is known about the excretion of vitamin K. High fecal concentrations of vitamin K probably result from bacterial synthesis in the intestine.

Chemistry and Stability

Chemistry

Phytonadione is a fat-soluble naphthoquinone derivative which is identical to naturally occurring vitamin K₁. Vitamin K₁ is present in many foods including leafy green vegetables, meat, cow's milk, vegetable oils, egg yolks, and tomatoes; it differs from other naturally occurring types of vitamin K in the degree of saturation and length of its 20-carbon polyisoprenoid side chain. Commercially available phytonadione is prepared synthetically. Natural vitamin K₁ occurs as the all- trans -isomer, whereas phytonadione occurs as a mixture of the cis - and trans -isomers, with the cis -isomer not exceeding 20%. Phytonadione occurs as a clear, yellow to amber, very viscous liquid and is insoluble in water and slightly soluble in alcohol.

Phytonadione injection is a sterile, aqueous dispersion of phytonadione and contains suitable solubilizing and/or dispersing agents. Phytonadione injections have a pH of 5-7.

Stability

Phytonadione is stable to heat and moisture and may be autoclaved. The drug is photosensitive and must be protected from light at all times. Phytonadione injection should be stored at 20-25°C (may be exposed to 15-30°C) in the original carton until used.113,160 Infusion solutions should be protected from light by wrapping the container with aluminum foil or other opaque material. Phytonadione tablets should be stored at 25°C in well-closed, light-resistant containers, but may be exposed to temperatures ranging from 15-30°C.

Phytonadione injection has been reported to be incompatible with many drugs, but the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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