PHYTONADIONE

Phytonadione is a vitamin K replacement, which is a clear, yellow to amber, very viscous, odorless or practically odourless liquid. It is soluble in dehydrated alcohol, benzene, chloroform and ether; slightly soluble in alcohol (96%) and insoluble in water. It has a molecular weight of 450.70 g/mol. Phytonadione is 1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-,[R-[R*,R*-(E)]]. Its molecular formula is C 31 H 46 O 2 and its structural formula is: Phytonadione tablets, USP for oral administration contain 5 mg of phytonadione, USP and are light yellow to yellow colored, round, scored tablets, debossed with “AA” and “05” on either side of scoring and plain on the other side. Inactive ingredients are acacia, anhydrous dibasic calcium phosphate, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, and talc. chemical structure

Phytonadione tablets are indicated for the treatment of adults with 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 secondary to antibacterial therapy. Hypoprothrombinemia secondary to factors limiting absorpsion or synthesis of vitamin K, e.g., obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancrease, 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. Phytonadione is a vitamin K replacement indicated for the treatment of adults with 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 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)

Anticoagulant-Induced Prothrombin Deficiency: 2.5 mg to 10 mg or up to 25 mg. (2.2) Hypoprothrombinemia Due to Other Causes: 2.5 mg to 25 mg or more. (2.2) Must be given with bile salts when endogenous supply of bile to gastrointestinal track is deficient. (2.1) 2.1 Dosing Considerations Avoid the oral route when the clinical disorder would prevent proper absorption. Bile salts must be given with the tablets when the endogenous supply of bile to the gastrointestinal tract is deficient. The coagulant effects of phytonadione tablets are not immediate; improvement of international normalized ratio (INR) may take 1 to 8 hours. Interim use of whole blood or component therapy may also be necessary if bleeding is severe. Phytonadione tablets will not counteract the anticoagulant action of heparin. When phytonadione tablets are 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 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.

Phytonadione tablets are contraindicated in patients with a history of a hypersensitivity reaction to phytonadione or inactive ingredients [see Description (11) ] . Hypersensitivity to any component of this medication. (4)

The following adverse reactions associated with the use of parenteral phytonadione were identified in clinical studies or post-marketing reports. Because some of 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. Severe hypersensitivity reactions, including anaphylactoid reactions and deaths, have been reported following parenteral administration. The majority of these reported events occurred following intravenous administration. Transient “flushing sensations” and “peculiar” sensations of taste have been observed with parenteral phytonadione, as well as instances of dizziness, rapid and weak pulse, profuse sweating, brief hypotension, dyspnea, and cyanosis. Hyperbilirubinemia has been observed in the newborn following administration of parenteral phytonadione. This has occurred primarily with doses above 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 .

Anticoagulants Phytonadione may induce temporary resistance to prothrombin-depressing anticoagulants, especially when larger doses of phytonadione 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 does not affect the anticoagulant action of heparin. Anticoagulants: May induce temporary resistance to prothrombin-depressing anticoagulants. (7)