PHYTONADIONE

PHYTONADIONE- phytonadione injection, emulsion
General Injectables & Vaccines, Inc

1 INDICATIONS AND USAGE

1.1 Treatment of Hypoprothrombinemia Due to Vitamin K Deficiency or Interference

Phytonadione Injectable Emulsion, USP is indicated for the treatment of the following coagulation disorders which are due to faulty formation of factors II, VII, IX and X when caused by vitamin K deficiency or interference with vitamin K activity;

• anticoagulant-induced hypoprothrombinemia caused by coumarin or indanedione derivatives;
• hypoprothrombinemia due to antibacterial therapy;
• hypoprothrombinemia secondary to factors 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, and regional enteritis;
• other drug-induced hypoprothrombinemia where it is definitely shown that the result is due to interference with vitamin K metabolism, e.g., salicylates.

1.2 Prophylaxis and Treatment of Vitamin K-Deficiency Bleeding in Neonates

Phytonadione Injectable Emulsion, USP is indicated for prophylaxis and treatment of vitamin K-deficiency bleeding in neonates.

DOSAGE AND ADMINISTRATION

2.1 Dosing Considerations

Whenever possible, administer Phytonadione Injectable Emulsion, USP by the subcutaneous route [see Boxed Warning] . When intravenous administration is unavoidable, inject the drug very slowly, not exceeding 1 mg per minute [see Warnings and Precautions (5.1)] .

Monitor international normalized ratio (INR) regularly and as clinical conditions indicate. Use the lowest dose of Phytonadione Injectable Emulsion, USP.

The coagulant effects of Phytonadione Injectable Emulsion, USP are not immediate; improvement of INR may take 1-8 hours. Interim use of whole blood or component therapy may also be necessary if bleeding is severe.

Whenever possible, administer benzyl alcohol-free formulations in pediatric patients [see Warnings and Precautions (5.2), Use in Specific Populations (8.4)].

When Phytonadione Injectable Emulsion, USP is used to correct excessive anticoagulant-induced hypoprothrombinemia, anticoagulant therapy still being indicated, the patient is again faced with the clotting hazards existing prior to starting the anticoagulant therapy. Phytonadione Injectable Emulsion, USP is not a clotting agent, but overzealous therapy with Phytonadione Injectable Emulsion, USP may restore conditions which originally permitted thromboembolic phenomena. Dosage should be kept as low as possible, and INR should be checked regularly as clinical conditions indicate.

2.2 Recommended Dosage for Coagulation Disorders from Vitamin K Deficiency or Interference

The recommended dosage of Phytonadione Injectable Emulsion, USP is based on whether the hypoprothrombinemia is anticoagulant-induced (e.g., due to coumarin or indanedione derivatives) or non-anticoagulant-induced (e.g., due to antibiotics; salicylates or other drugs; factors limiting absorption or synthesis) as follows:

• Anticoagulant-induced Hypoprothrombinemia: Phytonadione Injectable Emulsion, USP 2.5 mg to 10 mg or more subcutaneously, intramuscularly, or intravenously. Up to 25 mg to 50 mg may be administered as a single dose.

Repeated large doses of Phytonadione Injectable Emulsion, USP are not warranted in liver disease if the initial response is unsatisfactory. Failure to respond to Phytonadione Injectable Emulsion, USP may indicate that the condition being treated is inherently unresponsive to Phytonadione Injectable Emulsion, USP.

• Hyppoprothrombinemia Due to Other Causes (Non-Anticoagulation-Induced Hypoprothrombinemia: Phytonadione Injectable Emulsion, USP 2.5 mg to 25 mg or more intravenously, intramuscularly, or subcutaneously. Up to 50 mg may be administered as a single dose.

Evaluate INR after 6-8 hours, and repeat dose if INR remains prolonged. Modify subsequent dosage (amount and frequency) based on the INR or clinical condition.

2.3 Recommended Dosage for Prophylaxis and Treatment of Vitamin K Deficiency Bleeding in Neonates

Prophylaxis of Vitamin K-Deficiency Bleeding in Neonates

The recommended dosage of Phytonadione Injectable Emulsion, USP is 0.5 mg to 1 mg within one hour of birth for a single dose.

Treatment of Vitamin K Deficiency Bleeding in Neonates

The recommended dosage of Phytonadione Injectable Emulsion, USP is 1 mg given either subcutaneously or intramuscularly.

Consider higher doses if the mother has been receiving oral anticoagulants.

A failure to respond (shortening of the INR in 2 to 4 hours) may indicate another diagnosis or coagulation disorder.

2.4 Directions for Dilution

Dilute Phytonadione Injectable Emulsion, USP with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and Sodium Chloride Injection. Avoid use of other dilutents that may contain benzyl alcohol, which can cause serious toxicity in newborns or low birth weight infants [see Warnings and Precautions (5.2)  and Use in Specific Populations (8.4)] .

When diluted, start administration of Phytonadione Injectable Emulsion, USP immediately after dilution.

Discard unused portions of diluted solution as well as unused contents of the vial.

Protect Phytonadione Injectable Emulsion, USP from light at all times.

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

DOSAGE FORMS AND STRENGTHS

Injection: 1 mg/0.5 mL single-dose vial and a SAF-T-Jet vial injector.

CONTRAINDICATIONS

Hypersensitivity to phytonadione or any other componet of this medication [see Warnings and Precautions (5.1)] .

WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Fatal and severe hypersensitivity reactions, including anaphylaxis, have occurred with intravenous or intramuscular administration of Phytonadione Injectable Emulsion, USP. Reactions have occurred despite dilution to avoid rapid intravenous infusion and upon first dose. These reactions have included shock, cardiorespiratory arrest, flushing, diaphoresis, chest pain, tachycardia, cyanosis, weakness, and dyspnea. Administer Phytonadione Injectable Emulsion, USP subcutaneously whenever feasible. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified [see Dosage and Administration (2.1)] .

5.2 Risk of Serious Adverse Reaction in Infants due to Benzyl Alcohol Preservative

Use benzyl alcohol-free formulations in neonates and infants, if available. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Phytonadione. The “gasping syndrome” is characterized by central system depression, metabolic acidosis, and gasping respirations.

When prescribing Phytonadione in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including Phytonadione and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.1, 8.2 and 8.4)] .

5.3 Cutaneous Reactions

Parenteral administration of vitamin K replacements (including Phytonadione Injectable Emulsion, USP) may cause cutaneous reactions. Reactions have included eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions. Time of onset ranged from 1 day to a year after parenteral administration. Discontinue Phytonadione Injectable Emulsion, USP for skin reactions and institute medical management.

ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Cutaneous Reactions [see Warnings and Precautions (5.3)]

6.3 Clinical Trials and Post-Marketing Experience

The following adverse reactions associated with the use of Phytonadione Injectable Emulsion, USP were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size. It is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.

Cardiac Disorders: Tachycardia, hypotension.

General disorders and administration site conditions: Generalized flushing; pain, swelling, and tenderness at injection site.

Hepatobiliary Disorders: Hyperbilirubinemia

Immune System Disorders: Fatal hypersensitivity reactions, anaphylactic reactions.

Neurologic: Dysgeusia, dizziness.

Pulmonary: Dyspnea.

Skin and Subcutaneous Tissue Disorders: Erythema, pruritic plaques, scleroderma-like lesions, erythema perstans.

Vascular: Cyanosis.