VITAMIN K1

Phytonadione is a vitamin K replacement, which is a clear, yellow to amber, viscous, odorless or nearly odorless liquid. It is insoluble in water, soluble in chloroform and slightly soluble in ethanol. It has a molecular weight of 450.70. Phytonadione is 2-methyl-3-phytyl-1, 4-naphthoquinone. Its empirical formula is C 31 H 46 O 2 and its molecular structure is: Vitamin K 1 Injection (Phytonadione Injectable Emulsion, USP) is a yellow, sterile, nonpyrogenic aqueous dispersion available for injection by the intravenous, intramuscular and subcutaneous routes. Vitamin K 1 Injection is available in 1 mg (1 mg/0.5 mL) and 10 mg (10 mg/mL) single-dose ampuls. Each milliliter contains phytonadione 2 mg or 10 mg, polyoxyethylated fatty acid derivative 70 mg, dextrose, hydrous 37.5 mg in water for injection; benzyl alcohol 9 mg added as preservative. May contain hydrochloric acid for pH adjustment. pH is 6.3 (5.0 to 7.0). Phytonadione is oxygen sensitive. structural formula phytonadione

Vitamin K 1 Injection is a vitamin K replacement 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 deficiency caused by coumarin or indanedione derivatives. ( 1.1 ) • Hypoprothrombinemia due to antibacterial therapy. ( 1.1 ) • 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. ( 1.1 ) • Other drug-induced hypoprothrombinemia where it is definitely shown that the result is due to interference with vitamin K metabolism, e.g., salicylates. ( 1.1 ) Vitamin K 1 Injection is indicated for prophylaxis and treatment of vitamin K-deficiency bleeding in neonates. ( 1.2 ) 1.1 Treatment of Hypoprothrombinemia Due to Vitamin K Deficiency or Interference Vitamin K 1 Injection 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 Vitamin K 1 Injection is indicated for prophylaxis and treatment of vitamin K-deficiency bleeding in neonates.

• Administer Vitamin K 1 Injection by the subcutaneous route, whenever possible. ( 2.1 ) • When intravenous administration is unavoidable, inject the drug very slowly, not exceeding 1 mg per minute. ( 2.1 ) 2.1 Dosing Considerations Whenever possible, administer Vitamin K 1 Injection 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 effective dose of Vitamin K 1 Injection. The coagulant effects of Vitamin K 1 Injection are not immediate; improvement of INR may take 1 to 8 hours. Interim use of whole blood or component therapy may also be necessary if bleeding is severe. Whenever possible, administer benzyl alcohol-free phytonadione formulations in pediatric patients [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ] . When Vitamin K 1 Injection 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. Vitamin K 1 Injection is not a clotting agent, but overzealous therapy with Vitamin K 1 Injection 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 Vitamin K 1 Injection 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: Vitamin K 1 Injection 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 Vitamin K 1 Injection are not warranted in liver disease if the initial response is unsatisfactory. Failure to respond to Vitamin K 1 Injection may indicate that the condition being treated is inherently unresponsive to Vitamin K 1 Injection. • Hypoprothrombinemia Due to Other Causes (Non-Anticoagulation-Induced Hypoprothrombinemia): Vitamin K 1 Injection 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 to 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 Vitamin K 1 Injection 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 Vitamin K 1 Injection 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 Vitamin K 1 Injection with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and Sodium Chloride Injection. Avoid use of other diluents that may contain benzyl alcohol, which can cause serious toxicity in newborns or low birth weight infants [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ]. When diluted, start administration of Vitamin K 1 Injection immediately after dilution. Discard unused portions of diluted solution as well as unused contents of the ampul. Protect Vitamin K 1 Injection 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.

Hypersensitivity to phytonadione or any other component of this medication [see Warnings and Precautions (5.1) ] . Hypersensitivity to any component of this medication. ( 4 )

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) ] Most common adverse reactions are cyanosis, diaphoresis, dizziness, dysgeusia, dyspnea, flushing, hypotension and tachycardia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1‑800‑438‑1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vitamin K 1 Injection. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 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.

Anticoagulants Vitamin K 1 Injection may induce temporary resistance to prothrombin-depressing anticoagulants, especially when larger doses of Vitamin K 1 Injection are used. Should this occur, higher doses of anticoagulant therapy may be needed when resuming anticoagulant therapy, or a change in therapy to a different class of anticoagulant may be necessary (i.e., heparin sodium). Vitamin K 1 Injection does not affect the anticoagulant action of heparin. Anticoagulants: May induce temporary resistance to prothrombin-depressing anticoagulants. ( 7 )