on of factors ii, vii, ix and x when caused by vitamin k deficiency or interference with vitamin k activity: • anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives. (1) • hypoprothrombinemia secondary to antibacterial therapy. (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) • other drug-induced hypoprothrombinemia where it is definitively shown that the result is due to interference with vitamin k metabolism, e.g., salicylates. (1)

atient is again faced with the clotting hazards existing prior to starting the anticoagulant therapy. phytonadione tablets are not a clotting agent, but overzealous therapy with vitamin k1 may restore conditions which originally permitted thromboembolic phenomena. dosage should be kept as low as possible, and prothrombin time should be checked regularly as clinical conditions indicate. 2.2 recommended dosage anticoagulant-induced prothrombin deficiency in adults the recommended dose to correct excessively prolonged prothrombin times caused by oral anticoagulant therapy is, 2.5 mg to 10 mg or up to 25 mg initially. in some instances 50 mg may be required. frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition. if, in 12 to 48 hours after oral administration, the prothrombin time has not been shortened satisfactorily, repeat the dose. repeated large doses of phytonadione tablets are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. failure to respond to phytonadione may indicate a congenital coagulation defect or that the condition being treated is unresponsive to vitamin k. hypoprothrombinemia due to other causes in adults 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 tablets. the severity of the coagulation disorder should determine whether the immediate administration of phytonadione tablets are required in addition to discontinuation or reduction of interfering drugs. the recommended dose is 2.5 mg to 25 mg or more (sometimes up to 50 mg). evaluate inr after 6 to 8 hours, and repeat dose if inr remains prolonged. modify subsequent dosage (amount and frequency) based upon the inr or clinical condition.

e those recommended. most common adverse reactions are transient “flushing sensations”, “peculiar” sensations of taste and instances of dizziness, rapid and weak pulse, profuse sweating, brief hypotension, dyspnea, and cyanosis. (6) to report suspected adverse reactions, contact amneal pharmaceuticals at 1-877-835-5472 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

inical 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 phytonadione is present in breastmilk. there are no data on the effects of phytonadione 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 and any potential adverse effects on the breastfed child from phytonadione or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established with phytonadione. hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, have been reported with vitamin k. 8.5 geriatric use clinical studies of phytonadione did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ring 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.

macological 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 phytonadione tablets generally exert their effect within 6 to 10 hours. 12.3 pharmacokinetics absorption oral phytonadione is adequately absorbed from the gastrointestinal tract only if bile salts are present. 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.