Introduction

A fat-soluble naphthoquinone derivative; identical to naturally occurring vitamin K₁.

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.

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

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).

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.

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.

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

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).

AAP recommends routine IM administration to infants at birth to prevent vitamin K deficiency-related bleeding.

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); bile salts must be administered concomitantly to facilitate absorption of oral phytonadione.

Ineffective in the treatment of hereditary hypoprothrombinemia.

Dietary Requirements

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

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.

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

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

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.

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]).

Dietary intakes slightly lower in women than men.

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

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

Phytonadione Dosage and Administration

General

• Monitor INR regularly as dictated by clinical condition.

Administration

Administer orally or parenterally.

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

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. (See Boxed Warning.)

Oral Administration

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

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.

The parenteral preparation also has been administered orally^{† [off-label]} to neonates.

IV, IM, or Sub-Q Administration

Manufacturers state that sub-Q administration preferred because of hypersensitivity risk with IV or IM administration. (See Boxed Warning.) However, delayed and/or unpredictable effects reported following sub-Q injection of phytonadione. 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.

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

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.

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

Rate of Administration

Inject IV very slowly, at a rate ≤1 mg/minute. (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.

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

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

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

Pediatric Patients

Vitamin K-Deficiency Bleeding in Neonates

Prophylaxis

Manufacturers and AAP recommend a single IM dose of 0.5–1 mg within 1 hour of delivery.

Treatment

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

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

Dietary and Replacement Requirements

Healthy Infants ≤6 Months of Age

2 mcg daily.

Healthy Infants 7–12 Months of Age

2.5 mcg daily.

Healthy Children 1–3 Years of Age

30 mcg daily.

Healthy Children 4–8 Years of Age

55 mcg daily.

Healthy Children 9–13 Years of Age

60 mcg daily.

Healthy Children 14–18 Years of Age

75 mcg daily.

Adults

Hypoprothrombinemia Caused by Vitamin K-Antagonist Anticoagulants

Oral

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

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

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

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

IV, IM, or Sub-Q

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

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

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

Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis

Oral

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

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).

IV, IM, or Sub-Q

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

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).

Dietary and Replacement Requirements

Healthy Men ≥ 19 Years of Age

120 mcg daily.

Healthy Women ≥19 Years of Age

90 mcg daily.

Limited data suggest that the vitamin K status in pregnant women does not differ from that in nonpregnant women. 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).

Available evidence indicates that the vitamin K status of lactating women is comparable to that of nonlactating women. 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.

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.

Hepatic Impairment

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

Contraindications

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

Warnings/Precautions

Warnings

IV or IM Administration

Fatal and severe hypersensitivity reactions, including anaphylaxis, reported after IV or IM administration. (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.

Effects on Non-Vitamin K-Antagonist Anticoagulants

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

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. Phytonadione is not a clotting agent, but excessive dosage may restore conditions originally underlying the thromboembolic phenomena.

Sensitivity Reactions

Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, including anaphylaxis, after IV or IM administration. (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. Also, may resemble erythema perstans.

Discontinue phytonadione for skin reactions and institute medical management.

General Precautions

Light Sensitivity

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

Severe hemolytic anemia, hyperbilirubinemia, and jaundice reported rarely in neonates, particularly premature neonates, following large doses (10–20 mg). 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. Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100–400 mg/kg daily) of benzyl alcohol in these neonates.

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

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.

Common Adverse Effects

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

General

• Monitor INR regularly as dictated by clinical condition.

Administration

Administer orally or parenterally.

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

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. (See Boxed Warning.)

Oral Administration

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

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.

The parenteral preparation also has been administered orally^{† [off-label]} to neonates.

IV, IM, or Sub-Q Administration

Manufacturers state that sub-Q administration preferred because of hypersensitivity risk with IV or IM administration. (See Boxed Warning.) However, delayed and/or unpredictable effects reported following sub-Q injection of phytonadione. 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.

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

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.

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

Rate of Administration

Inject IV very slowly, at a rate ≤1 mg/minute. (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.

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

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

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

Pediatric Patients

Vitamin K-Deficiency Bleeding in Neonates

Prophylaxis

Manufacturers and AAP recommend a single IM dose of 0.5–1 mg within 1 hour of delivery.

Treatment

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

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

Dietary and Replacement Requirements

Healthy Infants ≤6 Months of Age

2 mcg daily.

Healthy Infants 7–12 Months of Age

2.5 mcg daily.

Healthy Children 1–3 Years of Age

30 mcg daily.

Healthy Children 4–8 Years of Age

55 mcg daily.

Healthy Children 9–13 Years of Age

60 mcg daily.

Healthy Children 14–18 Years of Age

75 mcg daily.

Adults

Hypoprothrombinemia Caused by Vitamin K-Antagonist Anticoagulants

Oral

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

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

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

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

IV, IM, or Sub-Q

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

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

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

Hypoprothrombinemia Due to Conditions Limiting Vitamin K Absorption or Synthesis

Oral

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

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).

IV, IM, or Sub-Q

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

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).

Dietary and Replacement Requirements

Healthy Men ≥ 19 Years of Age

120 mcg daily.

Healthy Women ≥19 Years of Age

90 mcg daily.

Limited data suggest that the vitamin K status in pregnant women does not differ from that in nonpregnant women. 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).

Available evidence indicates that the vitamin K status of lactating women is comparable to that of nonlactating women. 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.

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.

Hepatic Impairment

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

Specific Drugs