OVERDOSAGE SECTION.

OVERDOSAGE. The intravenous and oral LD50s in the mouse are approximately 1.17 g/kg and greater than 24.18 g/kg, respectively.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel Phytonadione Tablets, USP5 mg20 Tablets. carton label.

PEDIATRIC USE SECTION.

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.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. 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 rare 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 rarely and primarily with doses above those recommended.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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies of carcinogenicity or impairment of fertility have not been performed with phytonadione. Phytonadione at concentrations up to 2,000 mcg/plate with or without metabolic activation, was negative in the Ames microbial mutagen test.

NURSING MOTHERS SECTION.

Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when phytonadione is administered to nursing woman.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Phytonadione possess 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). The prothrombin test is sensitive to the levels of three of these four factors II, VII, and X. Vitamin is an essential cofactor for 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-carboxyglutamic acid residues convert the precursors into active coagulation factors that are subsequently secreted by liver cells into the blood.Oral phytonadione is adequately absorbed from the gastrointestinal tract only if bile salts are present. After absorption, phytonadione is initially concentrated in the liver, but the concentration declines rapidly. Very little vitamin accumulates in tissues. Little is known about the metabolic fate of vitamin K. Almost no free unmetabolized vitamin appears in bile or urine.In normal animals and humans, phytonadione is virtually devoid of pharmacodynamic activity. However, in animals and humans deficient in vitamin K, the pharmacological action of vitamin is related to its normal physiological function; that is, to promote the hepatic biosynthesis of vitamin K-dependent clotting factors. Phytonadione tablets generally exert their effect within to 10 hours.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Hypersensitivity to any component of this medication.

DESCRIPTION SECTION.

DESCRIPTION. Phytonadione is vitamin which is clear, yellow to amber, viscous, and nearly odorless liquid. It is insoluble in water, soluble in chloroform and slightly soluble in ethanol. It has molecular weight of 450.70.Phytonadione is 2-methyl-3-phytyl-1, 4-naphthoquinone. Its empirical formula is C31H46O2 and its structural formula is:Phytonadione tablets, USP containing mg of phytonadione, USP, is light yellow to yellow colored, round tablets. Inactive IngredientsPhytonadione tablets USP, mg contains: acacia, anhydrous dibasic calcium phosphate, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch and talc.. structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Phytonadione Tablets Summary of Dosage Guidelines (See circular text for details)AdultsInitial DosageAnticoagulant-InducedProthrombin Deficiency(caused by coumarin or indanedione derivatives)2.5 mg to 10 mg or up to25 mg (rarely 50 mg)Hypoprothrombinemia dueto other causes(Antibiotics; Salicylates or other drugs;Factors limiting absorption or synthesis)2.5 mg to 25 mg or more(rarely up to 50 mg)Anticoagulant-Induced Prothrombin Deficiency in AdultsTo correct excessively prolonged prothrombin times caused by oral anticoagulant therapy 2.5 to 10 mg or up to 25 mg initially is recommended. In rare instances 50 mg may be required. Frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition (see WARNINGS). If, in 12 to 48 hours after oral administration, the prothrombin time has not been shortened satisfactorily, the dose should be repeated. Hypoprothrombinemia Due to Other Causes in AdultsIf 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 is required in addition to discontinuation or reduction of interfering drugs.A dosage of 2.5 to 25 mg or more (rarely up to 50 mg) is recommended, the amount and route of administration depending upon the severity of the condition and response obtained. The oral route should be avoided 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.

DRUG INTERACTIONS SECTION.

Drug Interactions. Temporary resistance to prothrombin-depressing anticoagulants may result, especially when larger doses of phytonadione are used. If relatively large doses have been employed, it may be necessary when reinstituting anticoagulant therapy to use somewhat larger doses of the prothrombin-depressing anticoagulant, or to use one which acts on different principle, such as heparin sodium.

GENERAL PRECAUTIONS SECTION.

General. Vitamin K1 is fairly rapidly degraded by light; therefore, always protect phytonadione from light. Store phytonadione in closed original carton until contents have been used (see also HOW SUPPLIED, Storage).

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Phytonadione tablets USP, mg are supplied as light yellow to yellow colored, round, scored tablets, debossed with AA and 05 on either side of scoring and plain on the other side.They are available as follows:Carton of 20 tablets (10 tablets per blister pack 2), NDC 0904-6882-10Storage:Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Always protect phytonadione tablets, USP from light. Store in tightly closed original container and carton until contents have been used (see PRECAUTIONS, General).Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Oral Solid Dosage UnitAhmedabad 382213, INDIADistributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Distributed By:MAJOR(R) PHARMACEUTICALSLivonia, MI 48152Refer to package label for Distributors NDC Number Rev. 10-2017-00.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Phytonadione tablets are indicated in the following coagulation disorders which are due to faulty formation of factors II, VII, IX and when caused by vitamin deficiency or interference with vitamin activity.Phytonadione tablets are indicated in:-- anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives;-- hypoprothrombinemia secondary to antibacterial therapy;-- hypoprothrombinemia secondary to administration of salicylates; -- hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas but only if bile salts are administered concurrently, since otherwise the oral vitamin will not be absorbed.

LABORATORY TESTS SECTION.

Laboratory Tests. Prothrombin time should be checked regularly as clinical conditions indicate.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Vitamin K1 is fairly rapidly degraded by light; therefore, always protect phytonadione from light. Store phytonadione in closed original carton until contents have been used (see also HOW SUPPLIED, Storage).. Drug Interactions. Temporary resistance to prothrombin-depressing anticoagulants may result, especially when larger doses of phytonadione are used. If relatively large doses have been employed, it may be necessary when reinstituting anticoagulant therapy to use somewhat larger doses of the prothrombin-depressing anticoagulant, or to use one which acts on different principle, such as heparin sodium.. Laboratory Tests. Prothrombin time should be checked regularly as clinical conditions indicate.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies of carcinogenicity or impairment of fertility have not been performed with phytonadione. Phytonadione at concentrations up to 2,000 mcg/plate with or without metabolic activation, was negative in the Ames microbial mutagen test.. Pregnancy. Pregnancy Category C: Animal reproduction studies have not been conducted with phytonadione. It is also not known whether phytonadione can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Phytonadione should be given to pregnant woman only if clearly needed.. 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. Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when phytonadione is administered to nursing woman. 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.

PREGNANCY SECTION.

Pregnancy. Pregnancy Category C: Animal reproduction studies have not been conducted with phytonadione. It is also not known whether phytonadione can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Phytonadione should be given to pregnant woman only if clearly needed.

WARNINGS SECTION.

WARNINGS. An immediate coagulant effect should not be expected after administration of phytonadione.Phytonadione will not counteract the anticoagulant action of heparin.When vitamin K1 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 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. Repeated large doses of vitamin are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. Failure to respond to vitamin may indicate congenital coagulation defect or that the condition being treated is unresponsive to vitamin K.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Phytonadione tablets USP, mg 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.. Tablets: mg (3).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Vitamin K1 is fairly rapidly degraded by light; therefore, advise patients to always protect phytonadione tablets from light. Store phytonadione tablets in closed original carton until contents have been used [see How Supplied/Storage and Handling (16)]. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Oral Solid Dosage Unit Ahmedabad 382213, INDIADistributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Distributed by:MAJOR(R) PHARMACEUTICALSLivonia, MI 48152 USARefer to package label for Distributors NDC NumberRev. 10-2021-01.

LABOR & DELIVERY SECTION.

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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Phytonadione tablets possess 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). The prothrombin test is sensitive to the levels of three of these four factors II, VII, and X. Vitamin is an essential cofactor for microsomal enzyme that catalyzes the posttranslational carboxylation of multiple, specific, peptide-bound glutamic acid residues in inactive hepatic precursors of factors II, VII, IX, and X. The resulting gamma-carboxyglutamic 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 pharmacodynamic activity. However, in animals and humans deficient in vitamin K, the pharmacological action of vitamin is related to its normal physiological function, that is, to promote the hepatic biosynthesis of vitamin K-dependent clotting factors.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Studies of carcinogenicity or impairment of fertility have not been performed with phytonadione. Phytonadione at concentrations up to 2,000 mcg/plate, with or without metabolic activation, was negative in the Ames microbial mutagen test.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Phytonadione tablets generally exert their effect within to 10 hours.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionOral 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 accumulates in tissues. Elimination Little is known about the metabolic fate of vitamin K. Almost no free unmetabolized vitamin appears in bile or urine.

SPL UNCLASSIFIED SECTION.

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 to 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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary Published studies with the use of phytonadione during pregnancy have not reported clear association with phytonadione and adverse developmental outcomes [see Data]. There are maternal and fetal risks associated with vitamin 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 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% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal riskPregnant women with vitamin deficiency hypoprothrombinemia may be at increased risk for bleeding diatheses during pregnancy and hemorrhagic events at delivery. Subclinical vitamin 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 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.