Phytonadione

Pronunciation

Class: Vitamin K Activity
VA Class: VT702
CAS Number: 84-80-0
Brands: AquaMEPHYTON, Mephyton

Warning(s)

  • IV and IM Administration
  • Severe hypersensitivity reactions, including fatal anaphlaxis, have occurred during and immediately after IV or IM injection of phytonadione injection.b

  • Such severe reactions have occurred despite employing measures to prevent hypersensitivity reactions, including dilution of the injection and administration by slow infusion.b

  • These severe reactions are consistent with hypersensitivity or anaphylaxis, including shock and cardiac and/or respiratory arrest and have occurred after initial administration.b

  • Restrict 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.b

.

Introduction

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

Uses for Phytonadione

Prophylaxis and 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.a

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

Anticoagulant-induced Hypoprothrombinemia

Drug of choice for the treatment of moderate or severe hemorrhage caused by overdosage of coumarin or indandione derivatives.a c

Withdrawal of oral anticoagulant alone usually corrects excessively prolonged prothrombin time or minor hemorrhage.c

Not effective against anticoagulant action of heparins, argatroban, bivalirudin, fondaparinux, or lepirudin.c

Hemorrhagic Disease of the Newborn

Prophylaxis and treatment of hemorrhagic disease of the newborn.b c f 34 135 136 137

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AAP recommends routine IM administration to infants at birth to prevent hemorrhagic disease of the newborn.34 135 136 137 f

Treatment of vitamin K deficiency in infants who are breast-fed or receiving prolonged hyperalimentation.c

Drug-induced Hypoprothrombinemia

Treatment of hypoprothrombinemia secondary to drug therapy (e.g., salicylates, broad-spectrum anti-infectives, quinine, quinidine, sulfonamides) when it is definitely caused by interference with vitamin K activity.a b c

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

Other Causes of Hypoprothrombinemia

Treatment of hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas; bile salts must be administered concomitantly with oral therapy.a

Ineffective in the treatment of hereditary hypoprothrombinemia.c

Vitamin K Deficiency

Treatment of vitamin K deficiency (e.g., in patients receiving prolonged hyperalimentation, as well as in the presence of malabsorption syndromes such as sprue, celiac disease, ulcerative colitis, regional enteritis, cystic fibrosis, prolonged diarrhea, obstructive jaundice, internal biliary fistula, dysentery, after extensive bowel resection).c

Dietary Requirements

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

Adequate intake of vitamin K usually can be accomplished through consumption of foodstuffs.121 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

  • Restrict IV or IM administration to situations when sub-Q is not possible.a

  • Monitor prothrombin time regularly as dictated by clinical condition.b

  • If possible, discontinue or reduce dosage of drugs interfering with the coagulation mechanism as an alternative or adjunct to phytonadione therapy.c

  • 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.c

Administration

Administer orally or parenterally.a b

Parental therapy: Sub-Q preferred because of hypersensitivity risk with IV or IM administration.a (See Boxed Warning.)

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

Oral Administration

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

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.b c

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

IV, IM, or Sub-Q Administration

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.b (See Boxed Warning.)

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

Sub-Q or IM administration may be contraindicated in hypoprothrombinemia because of the possibility of inducing hemorrhage or hematoma at the site of injection.c

Dilution

Dilute for infusion with preservative-free 5% dextrose, 0.9% sodium chloride, or 5% dextrose in 0.9% sodium chloride injection; other diluents should not be used.c

Administer IV immediately after dilution, and any unused portion of the dilution and the unused contents of the ampul should be discarded.c The infusion container must be protected from light at all times.c (See Storage under Stability.)

Rate of Administration

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

Pediatric Patients

Hemorrhagic Disease of the Newborn
Prophylaxis
IM

AAP recommends a single IM dose of 0.5–1 mg within 1 hour of delivery.34 113 135 136 c f

Oral

Alternatively, 1–2 mg orally (can use injection formulation) immediately after delivery.135 136 137 Several oral doses, administered over a period of up to 3 months, may be required (e.g., at 1–2 weeks and 4 weeks of age in breast-fed infants, repeatedly if diarrhea occurs in breast-fed infants).135 136 137 f

Treatment

Empiric administration should not replace proper laboratory evaluation of the coagulation mechanism.b

A prompt response (shortening of the prothrombin time in 2–4 hours) following phytonadione usually is diagnostic of hemorrhagic disease of the newborn, and failure to respond indicates another diagnosis or coagulation disorder.b

IM or Sub-Q

1 mg sub-Q or IM.b Higher doses may be necessary if the mother has been receiving oral anticoagulants.b

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

Anticoagulant-induced Hypoprothrombinemia
Oral

Usual initial dosage: 2.5–10 mg.a Initial doses up to 25 mg have been used.a

Subsequent frequency and dosage should be determined by prothrombin time response and/or clinical condition.a

Dose may be repeated in 12–48 hours.a

Rarely, larger doses (e.g., 50 mg) may be required; however, administer lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and prothrombin time is not decreased below the effective anticoagulant level.a c

IV, IM, or Sub-Q

Usual initial dosage: 2.5–10 mg.b Initial doses up to 25 mg have been used.b

Subsequent frequency and dosage should be determined by prothrombin time response and/or clinical condition.b

Dose may be repeated in 6–8 hours.b

Rarely, larger doses (e.g., 50 mg) may be required; however, administer lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and prothrombin time is not decreased below the effective anticoagulant level.b c

Hypoprothrombinemia from Other Causes
Oral

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

Determine subsequent frequency and dosage by prothrombin time response and/or clinical condition in addition to reduction or discontinuance of drug (if drug therapy causing hypoprothrombinemia).a

IV, IM, or Sub-Q

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

Determine subsequent frequency and dosage by prothrombin time response and/or clinical condition in addition to reduction or discontinuance of interfering drug (if drug therapy causing hypoprothrombinemia).a

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.a

Cautions for Phytonadione

Contraindications

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

Warnings/Precautions

Warnings

IV or IM Administration

Restrict 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.b (See Boxed Warning.)

Delayed Coagulant Effect

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

Whole blood or component therapy may also be necessary for severe bleeding.b

Heparins and Other Non-coumarin/Indandione Coagulants

Does not counteract the anticoagulant effect of heparins, argatroban, bivalirudin, fondaparinux, or lepirudin.b

Anticoagulant-induced Hypoprothrombinemia

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

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

Hepatic Disease

Repeated large doses are not indicated in liver disease if the response to initial therapy with the vitamin is unsatisfactory.b

Lack of response may indicate the condition is inherently unresponsive to phytonadione.b

Sensitivity Reactions

Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, including anaphylaxis, after IV or IM administration.b (See Boxed Warning.)

Pruritic Plaques

Infrequently, usually after repeated injection, erythematous, indurated, pruritic plaques reported; rarely, progression to persistent sclerodermalike lesions.b Also, may resemble erythema perstans.b

General Precautions

Light-Sensitivity

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

Specific Populations

Pregnancy

Category C.a g

Lactation

Distributes into milk, but amount is too low to protect against hermorrhagic disease of newborn.c g Caution if used in nursing women,a b but maternal use considered compatible with breast-feeding.g

Pediatric Use

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

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

Phytonadione injection contains 9 mg/mL of benzyl alcohol as a preservative.113 Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.113 114 115 116 117 118 119 120 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;114 116 however, AAP states that the small amount of the preservative in commercially available injection should not proscribe its use when indicated in neonates114 and the manufacturers state that there is no evidence that the amount of benzyl alcohol contained in the injections is associated with toxicity when the drug is used as recommended.113

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.a

Common Adverse Effects

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

Fatal anaphylactic reaction reported after IV and IM administration.b (See Boxed Warning.)

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 alternate to prothrombin-depressing anticoagulant (e.g., heparins) if neccesaryb

Orlistat

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

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

Phytonadione Pharmacokinetics

Absorption

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

Onset

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

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

Parenteral administration: bleeding usually controlled within 3–6 hours, and a normal prothrombin time often obtained within 12–14 hours.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).a

Always protect from light.a

Parenteral

Injection

Protect from light.b Store in carton to protect from light until used.b

Infusion solutions should be protected 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 receiving coumarin or indandione anticoagulants

    to avoid vitamin K supplementation or foods high in vitamin K (e.g., spinach, collards, broccoli, iceberg lettuce, plant oils).

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

  • 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. (See Cautions.)

Preparations

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

* 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*

AquaMEPHYTON (with polyoxyethylated fatty acid derivative, dextrose, and benzyl alcohol 0.9%)

Merck

Phytonadione Injection

Hospira, IMS

10 mg/mL*

AquaMEPHYTON (with polyoxyethylated fatty acid derivative, dextrose, and benzyl alcohol 0.9%)

Merck

Phytonadione Injection

Hospira

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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35. American Academy of Pediatrics Committee on Nutrition. Vitamin K supplementation for infants receiving milk substitute infant formulas and for those with fat malabsorption. Pediatrics. 1971; 48:483-7. [PubMed 5109893]

37. Vest M. Vitamin K in medical practice—pediatrics. Vitam Horm. 1966; 24:649-63. [PubMed 5340884]

100. Shearer MJ, Barkhan P, Webster GR. Absorption and excretion of an oral dose of titrated vitamin K1 in man. Br J Haematol. 1970; 18:297-308. [PubMed 5491582]

101. Hollander D. Intestinal absorption of vitamins A, E, D, and K. J Lab Clin Med. 1981; 97:449-62. [PubMed 7205056]

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103. Sann L, Leclercq M, Bourgeois J et al. Pharmacokinetics of vitamin K1 in newborn infants. Pediatr Res. 1983; 17:155A.

104. Dunn PM. Vitamin K1 for all newborn babies. Lancet. 1982; 2:770. [IDIS 158995] [PubMed 6125839]

105. Shoskes M. “Solubilized” vitamin K1 (phytonadione) in neonatal hypoprothrombinemia. J Pediatr. 1961; 58:27-31.

106. Hemorrhage in the newborn infant. In: Behrman RE, Vaughn RC III, eds. Nelson textbook of pediatrics. 12th ed. Philadelphia: WB Saunders Company; 1983:389-90.

107. Shearer MJ, Rahim S, Barkhan P et al. Plasma vitamin K1 in mothers and their newborn babies. Lancet. 1982; 2:460-3. [IDIS 155850] [PubMed 6125638]

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121. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2002:162-98. (Prepublication copy uncorrected proofs.)

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a. Merck. Mephyton (phytonadione) vitamin K1 tablets prescribing information. Whitehouse Station, NJ; 2002 Feb.

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g. Briggs GG, Freeman RK, Yaffe SJ. Phytonadione. In: Drugs in pregnancy and lactation. 6th ed. Baltimore: Lippincott Williams & Wilkins; 1128-1131.

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