Phytonadione

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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 WARNINGS 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 to 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 or 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 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 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 prefilled syringe. 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 …

Whenever possible, phytonadione injectable emulsion, should be given by the subcutaneous route. (See Box Warning.) When intravenous 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 injectable emulsion 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 startedimmediately after mixture with the diluent, and unused portions of the dilution should be discarded, as well as unused contents of the ampule. Prophylaxis of Hemorrhagic Diseas e of the Newborn The American Academy of Pediatrics recommends that phytonadione be given to the newborn. A single intramuscular dose of phytonadione injectable emulsion 0.5 to 1 mg within one hour of birth is recommended. Treatment of Hemorrhagic Diseas e of the Newborn Empiric administration of phytonadione 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 phytonadione is usually diagnostic of hemorrhagic disease of the newborn, and failure to respond indicates another diagnosis or coagulation disorder. Phytonadione injectable emulsion 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 injectable emulsion should be given concurrently. Anticoagulant-Induced Prothrombin Deficiency in Adults To correct excessively prolonged prothrombin time caused by oral anticoagulant therapy—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 Injectable Emulsion, USP Summary of Dosage Guidelines (See circular 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 injectable emulsion. The severity of the coagulation disorder should determine whether the immediate administration of phytonadione injectable emulsion is required in addition to discontinuation or reduction of interfering drugs. Table

4 CONTRAINDICATIONS Hypersensitivity to phytonadione or any other component of this medication [see WARNINGS AND PRECAUTIONS ( 5.1 )] . Hypersensitivity to any component of this medication. ( 4 )

6 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 )] Most common adverse reactions are cyanosis, diaphoresis, dizziness, dysgeusia, dyspnea, flushing, hypotension and tachycardia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Orbicular Pharmaceutical Technologies Private Limited at 1-888-370-4186, 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-approval 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.

7 DRUG INTERACTIONS 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 )

8 USE IN SPECIFIC POPULATIONS • Pregnancy: If available, use the preservative-free formulation in pregnant women. ( 8.1 ) • Lactation: If available, use the preservative-free formulation in lactating women. ( 8.2 ) • Pediatric Use: The safety and effectiveness of phytonadione injectable emulsion in pediatric patients from 6 months to 17 years have not been established. ( 8.4 ) 8.1 Pregnancy Risk Summary Phytonadione injectable emulsion contains benzyl alcohol, which has been associated with gasping syndrome in neonates. The preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants . If phytonadione injectable emulsion is needed during pregnancy, consider using a benzyl alcohol-free formulation [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ] . Published studies with the use of phytonadione during pregnancy have not reported a clear association with phytonadione and adverse developmental outcomes [see Data ] . There are maternal and fetal risks associated with vitamin K deficiency during pregnancy [see Clinical Considerations ] . Animal reproduction studies have not been conducted with phytonadione. The estimated background risk for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnant women with vitamin K deficiency hypoprothrombinemia may be at an increased risk for bleeding diatheses during pregnancy and hemorrhagic events at delivery. Subclinical maternal vitamin K deficiency during pregnancy has been implicated in rare cases of fetal intracranial hemorrhage. Data Human Data Phytonadione has been measured in cord blood of infants whose mothers were treated with phytonadione during pregnancy in concentrations lower than seen in maternal plasma. Administration of vitamin K 1 to pregnant women shortly before delivery increased both maternal and cord blood concentrations. Published data do not report a clear association with phytonadione and adverse maternal or fetal outcomes when used during pregnancy. However, these studies cannot definitively establish the absence of any risk because of methodologic limitations including small sample size and lack of blinding. Animal Data In pregnant rats receiving vitamin K 1 orally, fetal plasma and liver concentrations increased following administration, supporting placental transfer. 8.2 Lactation Risk Summary Phytonadione injectable emulsion contains benzyl alcohol. If available, preservative-free phytonadione injectable emulsion is recommended when phytonadione injectable emulsion is needed during lactation [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ] . Phytonadione is present in breastmilk. There are no data on the effects of phytonadione injectable emulsion on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the clinical need for phytonadione injectable emulsion and any potential adverse effects on the breastfed child from phytonadione injectable emulsion or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of phytonadione injectable emulsion for prophylaxis and treatment of vitamin K deficiency have been established in neonates. Use of phytonadione injection for prophylaxis and treatment of vitamin K deficiency is based on published clinical studies. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/k …

12.1 Mechanism of Action Phytonadione injectable emulsion aqueous colloidal solution of vitamin K 1 for parenteral injection, possesses the same type and degree of activity as does naturally-occurring vitamin K, which is necessary for the production via the liver of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). Vitamin K is an essential cofactor for a microsomal enzyme that catalyzes the post- translational carboxylation of multiple, specific, peptide-bound glutamic acid residues in inactive hepatic precursors of factors II, VII, IX, and X. The resulting gamma-carboxy-glutamic acid residues convert the precursors into active coagulation factors that are subsequently secreted by liver cells into the blood. In normal animals and humans, phytonadione is virtually devoid of activity. However, in animals and humans deficient in vitamin K, the pharmacological action of vitamin K is related to its normal physiological function, that is, to promote the hepatic biosynthesis of vitamin K dependent clotting factors.

11 DESCRIPTION Phytonadione, USP is a vitamin K replacement, which is a clear, yellow to amber, very viscous liquid. It is soluble in dehydrated alcohol, in benzene, in chloroform, in ether and in vegetable oils; slightly soluble in alcohol and insoluble in water. It has a molecular weight of 450.70 g/mol. Phytonadione is 2-Methyl-3-(3,7,11,15-tetramethylhexadec-2-en-1-yl)naphthalene-1,4-dione. Its molecular formula is C 31 H 46 O 2 and its molecular structure is: Phytonadione Injectable Emulsion, USP is a sterile, clear yellow color 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 prefilled glass syringe. Each 0.5 mL of Phytonadione Injectable Emulsion, USP contains: Active: Phytonadione, USP (Vitamin K1)..................1 mg Inactive: Polysorbate 80 ..............................10 mg Propylene glycol ...........................10.4 mg Sodium acetate anhydrous..................0.17 mg Glacial acetic acid ............................0.00002 mL Water for injection..........................q.s. to 0.5 mL 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. 1

10 OVERDOSAGE Hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, may result from Phytonadione Injectable Emulsion overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING Phytonadione Injectable Emulsion USP, 1 mg/0.5 mL is available as clear yellow color, solution filled in prefilled glass syringe with SRC tip cap, assembled with grey plunger stopper and natural plunger rod. It is supplied in carton containing ten plastic trays, each having one single-dose prefilled glass syringes and one, SurGuard ® 3 safety hypodermic 27 G. x 1/2” needle with the following presentations: Unit of Sale Strength Each NDC 70121-1682-7 (Carton of 10) 1 mg/0.5 mL NDC 70121-1682-1 (0.5 mL prefilled syringe) Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect phytonadione injectable emulsion from light. Store container in closed original carton until contents have been used. Syringe Assembly Directions: See User Guide USE ASEPTIC TECHNIQUE Do not remove from carton or assemble until ready to use. CAUTION: The syringe may not be compatible with Luer-activated valve (LAV) connectors that have internal pin designs, such as LAVs with CLAVE design. 1. Remove the prefilled syringe cap by unscrewing it counter-clockwise (see Figure A) . Figure A 2. Open the needle package by using both thumbs to pull apart the packaging (see Figure B) . Remove the needle from the package. Figure B 3. Attach the needle with the needle cap to the syringe by turning clockwise until it cannot twist any further (see Figure C) . Do not remove the needle cap. Figure C Pull back the needle safety shield (see Figure D) . Figure D 4. Carefully remove needle cap from the needle by pulling straight off (see Figure E) and throw it away in a sharp disposal container. Make sure the needle does not touch anything before the injection. Figure E 5. Hold the syringe at eye level with the needle pointing upwards. Check to see air bubble. Remove it by tapping the side of the syringe with your finger until it rise towards the tip (see Figure F) . Then, slowly push the plunger up until a small amount of liquid drips from the needle (see Figure G) . Figure F Figure G 6. After injection, position shield in preparation for device activation: Using a one-handed technique, push the tab forward with your finger or thumb so that the shield is less than 90 degrees from the needle (see Figure H) . NOTE: Keep your finger or thumb behind the tab at all times. Figure H 7. Activate shield: Position the shield approximately 45 degrees to flat surface. Press down with a GENTLE, QUICK, MOTION until a distinct AUDIBLE CLICK is heard (see Figure I) . Note: Audible click may not be heard on small needle sizes: visual confirmation is required. Figure I 8. VISUALLY CONFIRM that needle is fully engaged under lock (see Figure J) . Figure J 9. Following activation of the needle shield, immediately discard the unit into an approved sharps container. CAUTION: LIQUID IN GLASS. HANDLE WITH CARE. INSPECT SYRINGE FOR DAMAGE PRIOR TO ASSEMBLY. 01 02 03 04 05 06 07 08 09 10