PHYTONADIONE

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: Phytonadione Injectable Emulsion, USP injection is a yellow, sterile, aqueous colloidal solution of vitamin K 1 , with a pH of 3.5 to 7.0, available for injection by the intravenous, intramuscular, and subcutaneous routes. Phytonadione Injectable Emulsion, USP is available in 1 mg (1 mg/0.5 mL) single-dose vials. Each 0.5 mL of Phytonadione Injectable Emulsion, USP contains the following inactive ingredients: 10 mg polysorbate 80, 10.4 mg propylene glycol, 0.17 mg sodium acetate anhydrous, and 0.00002 mL glacial acetic acid. Additional glacial acetic acid or sodium acetate anhydrous may have been added to adjust pH to meet USP limits of 3.5 to 7.0. structure

Phytonadione Injectable Emulsion 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 is it definitely shown that the result is due to interference with vitamin K metabolism, e.g., salicylates. ( 1.1 ) Phytonadione Injectable Emulsion 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 Phytonadione Injectable Emulsion 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 is indicated for prophylaxis and treatment of vitamin K-deficiency bleeding in neonates.

• Administer Phytonadione Injectable Emulsion 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 Phytonadione Injectable Emulsion by the subcutaneous route [see Boxed Warning ] . When intravenous administration is unavoidable, inject the drug very slowly, not exceeding 1 mg per minute [see WARNING AND PRECAUTIONS (5.1) ] . Monitor international normalized ratio (INR) regularly and as clinical conditions indicate. Use the lowest effective dose of Phytonadione Injectable Emulsion. The coagulant effects of Phytonadione Injectable Emulsion 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. When Phytonadione Injectable Emulsion 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 is not a clotting agent, but overzealous therapy with Phytonadione Injectable Emulsion 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 of Interference The recommended dosage of Phytonadione Injectable Emulsion 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 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 are not warranted in liver disease if the initial response is unsatisfactory. Failure to respond to Phytonadione Injectable Emulsion may indicate that the condition being treated is inherently unresponsive to Phytonadione Injectable Emulsion. • Hypoprothrombinemia Due to Other Causes (Non-Anticoagulation-Induced Hypoprothrombinemia): Phytonadione Injectable Emulsion 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 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 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 with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 5% Dextrose and Sodium Chloride Injection. When diluted, start administration of Phytonadione Injectable Emulsion immediately after dilution. Discard unused portions of diluted solution as well as unused contents of the vial. Protect Phytonadione Injectable Emulsion 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 WARNING 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 WARNING AND PRECAUTIONS (5.1) ] • Cutaneous Reactions [see WARNING 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 Amphastar Pharmaceuticals, Inc. at 1-800-423-4136, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials and Post-Marketing 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. The following adverse reactions have been identified during post-apporval use of Phytonadione Injectable Emulsion. 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 Phytonadione Injectable Emulsion may induce temporary resistance to prothrombin-depressing anticoagulants, especially when larger doses of Phytonadione Injectable Emulsion 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). Phytonadione Injectable Emulsion does not affect the anticoagulant action of heparin. Anticoagulants: May induce temporary resistance to prothrombin-depressing anticoagulants. ( 7 )