mulsion, usp is indicated for prophylaxis and treatment of vitamin k-deficiency bleeding in neonates. phytonadione injectable emulsion, usp 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 cause 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, usp is indicated for prophylaxis and treatment of vitamin k-deficiency bleeding in neonates. (1.2)

ated with benzyl alcohol-preserved drugs, including phytonadione. the "gasping syndrome" is characterized by central system depression, metabolic acidosis, and gasping respirations. when prescribing phytonadione in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including phytonadione 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 phytonadione injectable emulsion, usp) 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 phytonadione injectable emulsion, usp for skin reactions and institute medical management. risk of serious adverse reactions in infants due to benzyl alcohol preservative: use benzyl alcohol-free formulations in neonates and infants, if available. (5.1) cutaneous reactions: may occur with parenteral use. discontinue drug and manage medically. (5.3)

the patient is again faced with the clotting hazards existing prior to starting the anticoagulant therapy. phytonadione injectable emulsion, usp is not a clotting agent, but overzealous therapy with phytonadione injectable emulsion, usp 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, usp 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, usp 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, usp are not warranted in liver disease if the initial response is unsatisfactory. failure to respond to phytonadione injectable emulsion, usp may indicate that the condition being treated is inherently unresponsive to phytonadione injectable emulsion, usp. hyppoprothrombinemia due to other causes (non-anticoagulation-induced hypoprothrombinemia : phytonadione injectable emulsion, usp 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, usp 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, usp 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, usp with 0.9% sodium chloride injection, 5% dextrose injection, or 5% dextrose and sodium chloride injection. avoid use of other dilutents 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, usp immediately after dilution. discard unused portions of diluted solution as well as unused contents of the vial. protect phytonadione injectable emulsion, usp from light at all times. parenteral drug products should be inspected visually for particulate matter and discoloration prior to adminstration, whenever solution and container permit. administer phytonadione injectable emulsion, usp 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)

subcutaneous tissue disorders: erythema, pruritic plaques, scleroderma-like lesions, erythema perstans. vascular: cyanosis. 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.

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 k1 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 k1 orally, fetal plasma and liver concentrations increased following administration, supporting placental transfer. 8.2 lactation risk summary if available, preservative-free phytonadione is recommended when phytonadione is needed during lactation [see warnings and precautions (5.2), use in specific populations (8.4)]. phytonadione is present in breastmilk. there are not data on the effects of phytonadione injectable emulsion, usp 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, usp and any potential adverse effects on the breasfed child from phytonadione injectable emulsion, usp or from the underlying maternal condition. 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 aabnormalities, 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 in infants consider the combined daily metabolic load of benzyl alcohol from all sources including phytonadione 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. 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, usp in pediatric patients from 6 months from 17 years have not been established. (8.4)

s 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.