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.

Injection: 1 mg/0.5 mL and 10 mg/mL single-dose ampuls. Injection: 1 mg/0.5 mL and 10 mg/mL single-dose ampuls. ( 3 )

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

• Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative: Use benzyl alcohol-free phytonadione formulations in neonates and infants, if available. ( 5.2 )
• Cutaneous Reactions: May occur with parenteral use. Discontinue drug and manage medically. ( 5.3 )

5.1 Hypersensitivity Reactions Fatal and severe hypersensitivity reactions, including anaphylaxis, have occurred with intravenous or intramuscular administration of Vitamin K 1 Injection. 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 Vitamin K 1 Injection 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 phytonadione 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 Vitamin K 1 Injection. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Vitamin K 1 Injection in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including Vitamin K 1 Injection (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 Use in Specific Populations (8.1 , 8.2 and 8.4) ] .

5.3 Cutaneous Reactions Parenteral administration of vitamin K replacements (including Vitamin K 1 Injection) 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 Vitamin K 1 Injection for skin reactions and institute medical management.

5.4 Aluminum Toxicity WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

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 )

• Pregnancy: If available, use a preservative-free phytonadione formulation in pregnant women. ( 8.1 )
• Lactation: If available, use a preservative-free phytonadione formulation in lactating women. ( 8.2 )
• Pediatric Use: The safety and effectiveness of Vitamin K 1 Injection in pediatric patients from 6 months to 17 years have not been established. ( 8.4 )

8.1 Pregnancy Risk Summary Vitamin K 1 Injection 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 Vitamin K 1 Injection is needed during pregnancy, consider using a benzyl alcohol-free phytonadione 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 Vitamin K 1 Injection contains benzyl alcohol. If available, a preservative-free phytonadione formulation is recommended when Vitamin K 1 Injection 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 Vitamin K 1 Injection on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the clinical need for Vitamin K 1 Injection and any potential adverse effects on the breastfed child from Vitamin K 1 Injection or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of Vitamin K 1 Injection 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 Vitamin K 1 Injection in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Vitamin K 1 Injection (Vitamin K 1 Injection 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.

Vitamin K 1 Injection aqueous dispersion 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.