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Phytonadione

Class: Vitamin K Activity
VA Class: VT702
CAS Number: 84-80-0

Medically reviewed by Drugs.com. Last updated on March 9, 2020.

Warning

    Hypersensitivity Reactions with IV or IM Administration
  • Severe and fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after IV or IM administration of phytonadione injection.113 142 149 156

  • Such severe reactions have occurred after initial and subsequent administrations despite employing measures to prevent hypersensitivity reactions, including dilution of the injection and administration by slow infusion.113 142 149 156 160

  • These severe reactions have included shock and cardiac and/or respiratory arrest and have occurred after initial and subsequent administrations.113 142 149 160

  • Manufacturers recommend restriction of IV and IM administration to those situations where sub-Q administration is not feasible and the serious risk associated with IV or IM administration is considered justified.113 160 (See Administration under Dosage and Administration.)

.

Introduction

A fat-soluble naphthoquinone derivative; identical to naturally occurring vitamin K1.113 134 160 c

Uses for Phytonadione

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

More effective than and preferred to other vitamin K preparations in the presence of impending or actual hemorrhage.c

Hypoprothrombinemia Caused by Vitamin K-Antagonist Anticoagulants

Drug of choice for the treatment of moderate or severe hemorrhage caused by overdosage of vitamin K-antagonist anticoagulants (coumarin [e.g., warfarin] or indandione derivatives).c

Withholding vitamin K-antagonist anticoagulant alone may be sufficient to correct excessively prolonged PT/INR in asymptomatic (nonbleeding) patients with INRs of 4.5–10 who are not at high risk for bleeding.158 161

Hypoprothrombinemia Caused by Drugs Other than Vitamin K-Antagonist Anticoagulants

Treatment of hypoprothrombinemia secondary to drugs other than vitamin K-antagonist anticoagulants (e.g., salicylates, broad-spectrum anti-infectives) when it is definitely caused by interference with vitamin K activity.113 134 160 c

Discontinuance or dosage reduction of drug interfering with coagulation attempted first, if possible, as alternative to phytonadione.c

Vitamin K-Deficiency Bleeding in Neonates

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 f

AAP recommends routine IM administration to infants at birth to prevent vitamin K deficiency-related bleeding.34 135 136 137 f

Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis

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);113 134 160 c bile salts must be administered concomitantly to facilitate absorption of oral phytonadione.134

Ineffective in the treatment of hereditary hypoprothrombinemia.c

Dietary Requirements

Prevention of vitamin K deficiency and vitamin K-responsive hypothrombinemia.121 c

Diagnosis of vitamin K deficiency may be based on tests for vitamin K-dependent clotting factors (e.g., PT, which is sensitive to the levels of factors II, VII, and X) or on a therapeutic trial of phytonadione.c

Adequate intake of vitamin K usually can be accomplished through consumption of foodstuffs (except in first 5–8 days of neonatal period).121 c However, vitamin K deficiency may occur in breast-fed infants or patients receiving prolonged parenteral nutrition or with malabsorption syndromes.c

Spinach, collards, broccoli, iceberg lettuce, and plant oils are the major contributors of vitamin K in the diet of US adults and children.121 c

National Academies (formerly National Academy of Sciences; NAS) unable to establish accurate Recommended Dietary Allowances (RDAs) or Dietary Reference Intakes (DRIs) for vitamin K due to lack of adequate data.121

Adequate Intake (AI) for adults, adolescents, and children ≥1 year of age is based on reported vitamin K dietary intake in apparently healthy population groups (Third National Health and Nutrition Examination Survey [NHANES III]).121

Dietary intakes slightly lower in women than men.121

AI established for infants ≤6 months of age based on observed mean vitamin K intake of infants fed principally human milk.121

AI for infants 7–12 months of age set based on the AI for younger infants.121

Phytonadione Dosage and Administration

General

  • Monitor INR regularly as dictated by clinical condition.113

Administration

Administer orally or parenterally.113 134 160

Route of administration depends on the severity of the prothrombin deficiency and the risks associated with administration by each route.c

Because of the possibility of severe hypersensitivity reactions, IV or IM administration is indicated only when the serious risk involved is considered justified and other routes of administration are not feasible.113 160 (See Boxed Warning.)

Oral Administration

Avoid oral route when the clinical disorder would prevent proper absorption.134

Patients with decreased bile secretion: Give bile salts (e.g., ox bile extract 300 mg or dehydrocholic acid 500 mg) with each oral dose of phytonadione to ensure absorption.134 c

The parenteral preparation also has been administered orally to neonates.34 35 37 102 103 104 105 136

IV, IM, or Sub-Q Administration

Manufacturers state that sub-Q administration preferred because of hypersensitivity risk with IV or IM administration.113 160 (See Boxed Warning.) However, delayed and/or unpredictable effects reported following sub-Q injection of phytonadione.145 146 147 148 150 The American College of Chest Physicians (ACCP) and other clinicians recommend IV administration of phytonadione for anticoagulant-related bleeding in emergency situations because of its more rapid onset of effect; these clinicians recommend avoidance of sub-Q administration.150 158 161

Parenteral administration also is indicated in patients unable to retain or absorb the drug from the GI tract.c

Dilution

Dilute phytonadione injection with 0.9% sodium chloride, 5% dextrose, or 5% dextrose in 0.9% sodium chloride injection before IV infusion; do not use other diluents that may contain benzyl alcohol.c

Administer IV immediately after dilution, and discard any unused portion of the dilution and the unused contents of the ampul or vial.113 160 Protect the infusion bottle from light at all times.c (See Storage under Stability.)

Rate of Administration

Inject IV very slowly, at a rate ≤1 mg/minute.113 (See Boxed Warning.)

Dosage

Dose, frequency of administration, and duration of treatment depend on the severity of the prothrombin deficiency and the response of the patient; use lowest effective dose.113 134 160 c

Coagulant effect is not immediate after parenteral administration; measurable improvement in INR generally occurs after a minimum of 1–2 hours.113 160

Whole blood or clotting factor (e.g., prothrombin complex concentrate) therapy may also be necessary for severe bleeding.113 160

Use minimum effective dosage when treating anticoagulant-induced hypoprothrombinemia to avoid subsequent anticoagulant refractoriness; monitor INR regularly according to clinical conditions.113

Pediatric Patients

Vitamin K-Deficiency Bleeding in Neonates
Prophylaxis
IM

Manufacturers and AAP recommend a single IM dose of 0.5–1 mg within 1 hour of delivery.34 113 135 136 160 f

Treatment
IM or Sub-Q

1 mg.113 160 Consider higher doses if the mother has been receiving vitamin K-antagonist anticoagulants.113

Failure of a prompt response (reduction of INR in 2–4 hours) following phytonadione administration may indicate another diagnosis or coagulation disorder.113 160

Dietary and Replacement Requirements
Healthy Infants ≤6 Months of Age
Oral

2 mcg daily.121

Healthy Infants 7–12 Months of Age
Oral

2.5 mcg daily.121

Healthy Children 1–3 Years of Age
Oral

30 mcg daily.121

Healthy Children 4–8 Years of Age
Oral

55 mcg daily.121

Healthy Children 9–13 Years of Age
Oral

60 mcg daily.121

Healthy Children 14–18 Years of Age
Oral

75 mcg daily.121

Adults

Hypoprothrombinemia Caused by Vitamin K-Antagonist Anticoagulants
Oral

Usual initial dosage: 2.5–10 mg.134 Initial doses up to 25 mg have been used; rarely, may require 50 mg.134

Subsequent frequency of administration and dosage should be determined by INR response and/or clinical condition.134

Administer lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and INR is not decreased below the effective anticoagulant level.134 c

Repeat dose in 12–48 hours if INR not satisfactorily reduced.134

IV, IM, or Sub-Q

Usual initial dosage: 2.5–10 mg.113 160 Manufacturer states that up to 25–50 mg may be administered as a single dose.113 160

Failure to respond may indicate that condition being treated is inherently unresponsive to phytonadione.113

Administer lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and INR is not decreased below the effective anticoagulant level.113 c

Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis
Oral

Usual initial dosage: 2.5–25 mg, depending on deficiency, severity, and response.134 Rarely, larger doses (e.g., up to 50 mg as a single dose) may be required.134

Determine subsequent dosage and frequency of administration by INR response and/or clinical condition in addition to reduction or discontinuance of interfering drug(s) (if drug therapy causing hypoprothrombinemia).134

IV, IM, or Sub-Q

Usual initial dosage: 2.5–25 mg, depending on deficiency severity and response.113 160 Rarely, larger doses (e.g., up to 50 mg as a single dose) may be required.113 160

Determine subsequent dosage and frequency of administration by INR response and/or clinical condition in addition to reduction or discontinuance of interfering drug(s) (if drug therapy causing hypoprothrombinemia).113 160

Dietary and Replacement Requirements
Healthy Men ≥ 19 Years of Age
Oral

120 mcg daily.121

Healthy Women ≥19 Years of Age
Oral

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, 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

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.160

Hepatic Impairment

Repeated large doses not indicated in liver disease if the response to initial therapy with phytonadione is unsatisfactory.113 160 Lack of response may indicate the condition is inherently unresponsive to phytonadione.113 160

Cautions for Phytonadione

Contraindications

  • Known hypersensitivity to phytonadione or any ingredient in the formulation.113 134 160

Warnings/Precautions

Warnings

IV or IM Administration

Fatal and severe hypersensitivity reactions, including anaphylaxis, reported after IV or IM administration.113 160 (See Boxed Warning.)

Manufacturers recommend restriction of IV and IM administration to those situations where sub-Q administration is not feasible and the risk of anaphylaxis associated with IV or IM administration is considered justified.113 160

Effects on Non-Vitamin K-Antagonist Anticoagulants

Does not counteract the anticoagulant effect of heparin,113 134 160 low molecular weight heparins, fondaparinux, or direct-acting oral anticoagulants.157

Anticoagulant Refractoriness

When used to treat excessive anticoagulant-induced hypoprothrombinemia and continued anticoagulant therapy is indicated, clotting hazards that existed prior to anticoagulant therapy should be considered.113 Phytonadione is not a clotting agent, but excessive dosage may restore conditions originally underlying the thromboembolic phenomena.113

Sensitivity Reactions

Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, including anaphylaxis, after IV or IM administration.113 142 149 156 (See Boxed Warning.)

Cutaneous Reactions

Infrequently, usually after repeated injection, eczematous reactions (e.g., erythematous, indurated, pruritic plaques), urticaria, and delayed hypersensitivity reactions reported; rarely, progression to persistent scleroderma-like lesions.113 138 139 140 141 149 160 Also, may resemble erythema perstans.113 160

Discontinue phytonadione for skin reactions and institute medical management.113

General Precautions

Light Sensitivity

Rapidly degraded by light; protect phytonadione injection from light at all times.113 160 Store in closed original carton until use.113 160 (See Stability.)

Specific Populations

Pregnancy

No clear association with phytonadione and adverse developmental events.113 134 160 g Vitamin K deficiency during pregnancy associated with maternal and fetal risks.113 134 160 No reproduction studies conducted in animals.113 134 160

Lactation

Distributes into milk, but amount is too low to protect against bleeding due to vitamin K deficiency in neonates.c g Caution if used in nursing women,113 134 160 but maternal use considered compatible with breast-feeding; use preservative-free phytonadione if available.113 g

Pediatric Use

Oral administration: Safety and efficacy of oral phytonadione not established.134

Severe hemolytic anemia, hyperbilirubinemia, and jaundice reported rarely in neonates, particularly premature neonates, following large doses (10–20 mg).134 163 c However, the incidence of these adverse effects is much less with phytonadione than with other vitamin K preparations.c

Some preparations of phytonadione injection may contain benzyl alcohol as a preservative.160 Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.113 114 115 116 117 118 119 120 160 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

Whenever possible use of drugs or diluents preserved with benzyl alcohol should be avoided in neonates;113 114 116 160 however, AAP states that the small amount of the preservative in commercially available injection should not proscribe its use when indicated in neonates.114 163

Geriatric Use

Response in patients ≥65 years of age does not appear to differ from that in younger adults; however, select dosage with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.134

Common Adverse Effects

Parenteral Administration: Pain, swelling, and tenderness at the injection site, transient “flushing sensations,” “peculiar” sensations of taste (dysgeusia).113 160

Interactions for Phytonadione

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, oral (coumarins and indandiones)

Vitamin K1 is a pharmacologic antagonistc

Avoid concomitant use; only use concomitant phytonadione for treatment of excessive hypoprothrombinemiac

Consider alternative to prothrombin-depressing anticoagulant (e.g., heparin) if necessary113 160

Orlistat

Possible decreased GI absorption of fat-soluble vitamins, including phytonadione (vitamin K1)122

Separate oral administration of orlistat and phytonadione by ≥2 hours 122 124 128 130

Phytonadione Pharmacokinetics

Absorption

Absorbed from GI tract only in the presence of bile salts.c

Onset

Oral administration: blood coagulation factors increase in 6–10 hours.134 c

Parenteral administration: blood coagulation factors increase within 1–2 hours.113 c

Some data indicate more rapid INR response with IV than with oral administration at 6 and 12 hours following dose; similar INR values at 24 hours.152

Parenteral administration: bleeding usually controlled within 3–6 hours, and a normal INR often obtained within 12–14 hours.113 c

Distribution

Extent

May be concentrated in the liver for a short time after absorption; only small amounts are stored in body tissues.c

Appears to cross the placenta to a limited extent.c

Distributes into milk.34 35 102 107 108 109 110 111 g

Elimination

Route of excretion of vitamin K is not known.c High fecal concentrations of vitamin K probably result from bacterial synthesis in the intestine.c

Stability

Storage

Oral

Tablets

Tight, light resistant, original container at 25°C (may be exposed to 15–30°C).134

Always protect from light.134

Parenteral

Injection

Protect from light.113 160 Store in carton at 20–25°C; may be exposed to 15–30°C.113

Protect infusion solutions from light by wrapping the container with aluminum foil or other opaque material.c

Use immediately after dilution; discard unused portion of ampul and dilution.c

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Amino acids 4.25%, dextrose 25%

Dextran 6% in dextrose 5%

Dextran 6% in sodium chloride 0.9%

Dextrose 2½, 5, or 10% in water

Dextrose–Ringer’s injection combinations

Dextrose–Ringer’s injection, lactated, combinations

Dextrose–saline combinations

Fat emulsion 10%, IV

Fructose 10% in sodium chloride 0.9%

Fructose 10% in water

Invert sugar 5 and 10% in sodium chloride 0.9%

Invert sugar 5 and 10% in water

Ionosol products

Ringer’s injection

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate 1/6 M

Incompatible

Amino acids 2%, dextrose 12.5%

Dextran 12%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Amikacin sulfate

Chloramphenicol sodium succinate

Cimetidine HCl

Sodium bicarbonate

Incompatible

Ranitidine HCl

Y-site CompatibilityHID

Compatible

Ampicillin sodium

Epinephrine HCl

Famotidine

Heparin sodium

Hydrocortisone sodium succinate

Potassium chloride

Vitamin B complex with C

Incompatible

Dobutamine HCl

Actions

  • 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.c

  • Involved in carboxylation of the preformed, inactive precursors of these coagulation factors, resulting γ-carboxyglutamyl residues are required for the calcium-dependent phospholipid binding exhibited by active vitamin K-dependent clotting factors.c

  • Reverses the inhibitory effect of coumarin and indandione derivatives on the synthesis of these factors.c

Advice to Patients

  • Importance of advising patients to immediately report signs and symptoms of hypersensitivity reactions after receiving phytonadione injection.113 160

  • Importance of advising patient and caregivers of the risk of gasping syndrome in neonates and infants associated with the use of products (including phytonadione) that contain benzyl alcohol.113

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.c

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.c

  • Importance of informing patients of other important precautionary information.c (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Phytonadione

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

5 mg*

Mephyton (scored)

Merck

Parenteral

Injection

2 mg/mL*

Phytonadione Injection

10 mg/mL*

Phytonadione Injection

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 9, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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