Phytonadione

Name: Phytonadione

What happens if I miss a dose?

Call your doctor for instructions if you miss a dose of phytonadione.

Introduction

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

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.)

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

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.)

Phytonadione Dosage and Administration

Whenever possible, Phytonadione should be given by the subcutaneous route (see Box WARNING). When intravenous or intramuscular administration is considered unavoidable, the drug should be injected very slowly, not exceeding 1 mg per minute.

Protect from light at all times.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Directions for Dilution

Phytonadione may be diluted with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and Sodium Chloride Injection. Benzyl alcohol as a preservative has been associated with toxicity in newborns. Therefore, all of the above diluents should be preservative-free. (See WARNINGS) Other diluents should not be used. When dilutions are indicated, administration should be started immediately after mixture with the diluent, and unused portions of the dilution should be discarded, as well as unused contents of the vial.

Prophylaxis of Hemorrhagic Disease of the Newborn

The American Academy of Pediatrics recommends that vitamin K1 be given to the newborn. A single intramuscular dose of Phytonadione 0.5 to 1 mg within one hour of birth is recommended.

Treatment of Hemorrhagic Disease of the Newborn

Empiric administration of vitamin K1 should not replace proper laboratory evaluation of the coagulation mechanism. A prompt response (shortening of the prothrombin time in 2 to 4 hours) following administration of vitamin K1 is usually diagnostic of hemorrhagic disease of the newborn, and failure to respond indicates another diagnosis or coagulation disorder.

Phytonadione 1 mg should be given either subcutaneously or intramuscularly. Higher doses may be necessary if the mother has been receiving oral anticoagulants.

Whole blood or component therapy may be indicated if bleeding is excessive. This therapy, however, does not correct the underlying disorder and Phytonadione should be given concurrently.

Anticoagulant-Induced Prothrombin Deficiency in Adults

To correct excessively prolonged prothrombin time caused by oral anticoagulant thearpy - 2.5 to 10 mg or up to 25 mg initially is recommended. In rare instances 50 mg may be required. Frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition (see WARNINGS). If in 6 to 8 hours after parenteral administration the prothrombin time has not been shortened satisfactorily, the dose should be repeated.

Phytonadione Summary of Dosage Guidelines (See insert text for details)

In the event of shock or excessive blood loss, the use of whole blood or component therapy is indicated.

Hypoprothrombinemia Due to Other Causes in Adults

A dosage of 2.5 to 25 mg or more (rarely up to 50 mg) is recommended, the amount and route of administration depending upon the severity of the condition and response obtained.

If possible, discontinuation or reduction of the dosage of drugs interfering with coagulation mechanisms (such as salicylates, antibiotics) is suggested as an alternative to administering concurrent Phytonadione. The severity of the coagulation disorder should determine whether the immediate administration of Phytonadione is required in addition to discontinuation or reduction of interfering drugs.

Sample package label

Phytonadione 
Phytonadione injection, emulsion
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:52584-043(NDC:76329-1240)
Route of Administration PARENTERAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Phytonadione (Phytonadione) Phytonadione 1 mg  in 0.5 mL
Packaging
# Item Code Package Description
1 NDC:52584-043-05 1 CARTON in 1 BAG
1 1 SYRINGE in 1 CARTON
1 0.5 mL in 1 SYRINGE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA083722 02/13/2013
Labeler - General Injectables & Vaccines, Inc (108250663)
Revised: 01/2017   General Injectables & Vaccines, Inc

Dosing Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

For Healthcare Professionals

Applies to phytonadione: compounding powder, injectable solution, oral tablet

Local

Rare (less than 0.1%): Injection site reactions (inflammation, atrophy, necrosis)
Very rare (less than 0.01%): Venous irritation or phlebitis (IV route)
Frequency not reported: Pain, swelling, and tenderness at the injection site[Ref]

Cardiovascular

Rare (less than 0.1%): Rapid and weak pulse, brief hypotension, cyanosis
Very rare (less than 0.01%): Facial flushing[Ref]

Hypersensitivity

Very rare (less than 0.01%): Anaphylactoid reactions (IV route)
Frequency not reported: Allergic sensitivity, anaphylaxis[Ref]

Fatalities and other severe reactions have occurred during or immediately after the parenteral administration of phytonadione. The majority of these reactions have occurred with intravenous administration. These reactions resemble hypersensitivity or anaphylaxis and include shock and cardiac or respiratory arrest. Feelings of uneasiness, flushing, diaphoresis, chest pain, tachycardia, cyanosis, weakness, and dyspnea may precede the cardiopulmonary event. These severe reactions are more likely with, but are not limited to, rapid infusions of undiluted drug.[Ref]

Gastrointestinal

Gastrointestinal side effects have rarely included 'peculiar' sensations of taste.

Respiratory

Rare (less than 0.1%): Dyspnea[Ref]

Other

Frequency not reported: Death (IV and IM routes)[Ref]

Dermatologic

Uncommon (0.1% to 1%): Erythematous, indurated, pruritic plaques
Rare (less than 0.1%): Profuse sweating, scleroderma-like lesions,
Very rare (less than 0.01%): Sweating
Frequency not reported: Erythema perstans-like lesions[Ref]

Nervous system

Rare (less than 0.1%): Dizziness
Very rare (less than 0.01%): Unusual taste[Ref]

Hepatic

Hyperbilirubinemia occurred primarily with doses above those recommended.[Ref]

Rare (less than 0.1%): Hyperbilirubinemia in newborns
Frequency not reported: Jaundice in newborns[Ref]

Hematologic

Frequency not reported: Hemolysis in newborns[Ref]

General

The most common adverse events were dermatologic and injection site reactions.[Ref]

Some side effects of phytonadione may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Usual Pediatric Dose for Hypoprothrombinemia - Not Associated with Anticoagulant Therapy

1 mg, subcutaneously or IM

Comments:
-Empiric vitamin K should not replace proper lab evaluation of the coagulation mechanism.
-A prompt response (prothrombin time shortened in 2 to 4 hours) is usually diagnostic of hemorrhagic disease of the newborn;
-Failure to respond indicates another diagnosis or coagulation disorder.
-Whole blood or component therapy may be needed for excessive bleeding, however vitamin K should still be given to correct the underlying disorder.

Use: Hemorrhagic disease of the newborn.

Precautions

US BOXED WARNINGS:
-Severe reactions, including death, have occurred during and immediately after IV injections of phytonadione, even when precautions have been taken to dilute the product and avoid rapid infusion.
-Severe reactions, including death, have been reported after IM administration, and with first exposure to the medication.
-Severe reactions typically resemble hypersensitivity or anaphylaxis, including shock and cardiac and/or respiratory arrest.
-The majority of these events occurred after IV administration.
Recommendation:
-Restrict IV use to times when another route is not feasible and the serious risk is considered justified.

Safety and efficacy of the TABLET formulation has not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

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