Phytonadione

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 Cipla Ltd at 1-866-604-3268 , 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.

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 )

11 DESCRIPTION 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 is a clear yellow, sterile, aqueous colloidal solution of vitamin K 1 , with a pH of 4.5 to 7.0, available for injection by the intravenous, intramuscular, and subcutaneous routes. Phytonadione injectable emulsion, USP is available in 1 mg (2 mg/mL) and 10 mg (10 mg/mL) single-dose vials. Each milliliter of phytonadione injectable emulsion, USP contains the following inactive ingredients: 70 mg polyoxyl 35 castor oil, 37.5 mg dextrose monohydrate, 9 mg benzyl alcohol (preservative), and water for injection. Phytonadione injectable emulsion, USP contains glacial acetic acid for pH adjustment to 6.3 (4.5 – 7.0). structure

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 1-8 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 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 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 6-8 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. 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 ) and Use in Specific Populations ( 8.4 )] . 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.

10 OVERDOSAGE Hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, may result from phytonadione injectable emulsion overdose.

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 )

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics The action of the aqueous dispersion, when administered intravenously, is generally detectable within an hour or two and hemorrhage is usually controlled within 3 to 6 hours. A normal INR may often be obtained in 12 to 14 hours. 12.3 Pharmacokinetics Absorption : Phytonadione is readily absorbed following intramuscular administration. Distribution : After absorption, phytonadione is initially concentrated in the liver, but the concentration declines rapidly. Very little vitamin K accumulates in tissues. Elimination : Little is known about the metabolic fate of vitamin K. Almost no free unmetabolized vitamin K appears in bile or urine.

20240712

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3 DOSAGE FORMS AND STRENGTHS Injection: 2 mg/mL and 10 mg/mL single-dose vials. Injection: 2 mg/mL and 10 mg/mL single-dose vials. ( 3 )

Phytonadione Phytonadione PHYTONADIONE PHYTONADIONE POLYOXYL 35 CASTOR OIL DEXTROSE MONOHYDRATE BENZYL ALCOHOL WATER ACETIC ACID Phytonadione Phytonadione PHYTONADIONE PHYTONADIONE POLYOXYL 35 CASTOR OIL DEXTROSE MONOHYDRATE BENZYL ALCOHOL WATER ACETIC ACID

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of carcinogenicity, genotoxicity or impairment of fertility have not been conducted with phytonadione.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of carcinogenicity, genotoxicity or impairment of fertility have not been conducted with phytonadione.

ANDA214596

Phytonadione

Phytonadione

69097-708

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,INTRAVENOUS,SUBCUTANEOUS

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 69097-709-30 RX Only Phytonadione Injectable Emulsion, USP 1 mg/0.5 mL Neonatal Concentration 0.5 mL Single-Dose Vial Contains no more than 500 mcg/L of aluminum. Protect from Light. Cipla NDC 69097-708-31 RX Only Phytonadione Injectable Emulsion, USP10 mg/ mL 1 mL Single-Dose Vial Contains no more than 500 mcg/L of aluminum. Protect from Light. Cipla NDC 69097-709-96 RX Only Phytonadione Injectable Emulsion, USP 1 mg/0.5 mL Neonatal Concentration For INTRAMUSCULAR, SUBCUTANEOUS or INTRAVENOUS (with caution). Protect from light. Keep vials in carton until time of use. 10 X 0.5 mL vials per carton Single-Dose Vials Cipla NDC 69097-708-96 RX Only Phytonadione Injectable Emulsion, USP 10 mg/ mL For INTRAMUSCULAR, SUBCUTANEOUS or INTRAVENOUS (with caution). Protect from light. Keep vials in carton until time of use. 10 X 1 mL vials per carton Single-Dose Vials Cipla containerlabel1mgper0pt5ml contaner-label-10mg carton-label-1mg carton-labels-10mg

17 PATIENT COUNSELING INFORMATION Inform the patient of the following important risks of phytonadione injectable emulsion: Serious Hypersensitivity Reactions Advise the patient and caregivers to immediately report signs of hypersensitivity after receiving phytonadione injectable emulsion [see Warnings and Precautions ( 5.1 )] . Risk of Gasping Syndrome Due to Benzyl Alcohol Advise the patient and caregivers of the risk of gasping syndrome associated with the use of products that contain benzyl alcohol (including phytonadione injectable emulsion) in neonates, infants, and pregnant women [see Warnings and Precautions ( 5.2 )] . Cutaneous Reactions Advise the patient and caregivers to report the occurrence of new rashes after receiving phytonadione injectable emulsion. These reactions may be delayed for up to a year after treatment [see Warnings and Precautions ( 5.3 )] . Manufactured by: Cipla Ltd., India At M/s Immacule Lifesciences Pvt. Ltd. India Manufactured for: Cipla USA, Inc. 10 Independence Boulevard, Suite 300, Warren, NJ 07059 Revised: 3 /2022

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 2-4% and 15-20%, 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/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing phytonadione injectable emulsion in infants consider the combined daily metabolic load of benzyl alcohol from all sources including phytonadione injectable emulsion (phytonadione injectable emulsion contains 9 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions ( 5.2 )] . Whenever possible, use preservative-free phytonadione formulations in neonates. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. Premature and low-birth weight infants may be more likely to develop toxicity.

16 HOW SUPPLIED/STORAGE AND HANDLING Phytonadione injectable emulsion, USP is a clear yellow, sterile, aqueous colloidal solution and is supplied in a package of 10 as follows: NDC No. Container Amount of Phytonadione injectable emulsion In Container Volume Concentration 69097-709-96 10 single-dose vials per carton 1 mg 0.5 mL 2 mg/mL 69097-708-96 10 single-dose vials per carton 10 mg 1 mL 10 mg/mL Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Protect phytonadione injectable emulsion from light. Store container in closed original carton until contents have been used.

WARNING-HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after intravenous and intramuscular injection of phytonadione injectable emulsion. Reactions have occurred despite dilution to avoid rapid intravenous infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified [see Warnings and Precautions ( 5.1 )] . WARNING-HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE See full prescribing information for complete boxed warning. Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of phytonadione injectable emulsion. Reactions have occurred despite dilution to avoid rapid infusion and upon first and subsequent doses. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified. ( 5.1 )