Tablets MEPHYTON® (PHYTONADIONE) Vitamin K1

MEPHYTON - phytonadione tablet 
Aton Pharma, Inc.

----------

Tablets
MEPHYTON®
(PHYTONADIONE)
Vitamin K1

DESCRIPTION

Phytonadione is a vitamin which is a clear, yellow to amber, viscous, and nearly odorless liquid. It is insoluble in water, soluble in chloroform and slightly soluble in ethanol. It has a molecular weight of 450.70.

Phytonadione is 2-methyl-3-phytyl-1, 4-naphthoquinone. Its empirical formula is C31H46O2 and its structural formula is:

Chemical Structure

MEPHYTON1 (Phytonadione) tablets containing 5 mg of phytonadione are yellow, compressed tablets, scored on one side. Inactive ingredients are acacia, calcium phosphate, colloidal silicon dioxide, lactose, magnesium stearate, starch, and talc.


1
Registered trademark of ATON PHARMA, INC.
COPYRIGHT © 2008 ATON PHARMA, INC.
All rights reserved

CLINICAL PHARMACOLOGY

MEPHYTON 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 K is an essential cofactor for a microsomal enzyme that catalyzes the posttranslational carboxylation of multiple, specific, peptidebound glutamic acid residues in inactive hepatic precursors of factors II, VII, IX, and X. The resulting gammacarboxyglutamic 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 K accumulates in tissues. Little is known about the metabolic fate of vitamin K. Almost no free unmetabolized vitamin K 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 K is related to its normal physiological function; that is, to promote the hepatic biosynthesis of vitamin K-dependent clotting factors.

MEPHYTON tablets generally exert their effect within 6 to 10 hours.

INDICATIONS AND USAGE

MEPHYTON is indicated in 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.

MEPHYTON 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 K will not be absorbed.

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

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 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.

Repeated large doses of vitamin K are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. Failure to respond to vitamin K may indicate a congenital coagulation defect or that the condition being treated is unresponsive to vitamin K.

PRECAUTIONS

General

Vitamin K1 is fairly rapidly degraded by light; therefore, always protect MEPHYTON from light. Store MEPHYTON 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 a 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 MEPHYTON. MEPHYTON at concentrations up to 2000 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 MEPHYTON. It is also not known whether MEPHYTON can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. MEPHYTON should be given to a pregnant woman only if clearly needed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established with MEPHYTON. 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 MEPHYTON is administered to a nursing woman.

Geriatric Use

Clinical studies of MEPHYTON 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.

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.

OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

MEPHYTON Summary of Dosage Guidelines (See circular text for details)
AdultsInitial Dosage
Anticoagulant-Induced Prothrombin Deficiency
(caused by coumarin or indanedione derivatives)
2.5 mg-10 mg or up to 25 mg
(rarely 50 mg)
Hypoprothrombinemia due to other causes
(Antibiotics; Salicylates or other drugs; Factors limiting absorption or synthesis)
2.5 mg-25 mg or more (rarely up to 50 mg)

Anticoagulant-Induced Prothrombin Deficiency in Adults

To 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 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 MEPHYTON. The severity of the coagulation disorder should determine whether the immediate administration of MEPHYTON 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.

HOW SUPPLIED

Tablets MEPHYTON, 5 mg vitamin K1, are yellow, round, scored, compressed tablets, coded ATON 405 on one side and MEPHYTON on the other. They are supplied as follows:

NDC 25010-405-15 bottles of 100.

Storage

Store in tightly closed original container at 25°C (77°F); excursions permitted to 15-30°C(59-86°F) [see USP Controlled Room Temperature]. Always protect MEPHYTON from light. Store in tightly closed original container and carton until contents have been used. (See PRECAUTIONS, General.)

Distributed by:
ATON PHARMA
Lawrenceville
NJ 08648
USA

Manufactured by:
Draxis Specialty Pharmaceuticals, Inc.
Kirkland, Quebec H9H 4J4

Issued January 2008

201290

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Carton

ATON
PHARMA

NDC 25010-405-15

100 TABLETS

MEPHYTON®
(PHYTONADIONE)

Each tablet contains:
5 mg Phytonadione

Rx only

Distributed by:
ATON PHARMA, INC.
Lawrenceville, NJ 08648, USA

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Carton

MEPHYTON 
phytonadione   tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)25010-405
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
phytonadione (phytonadione) phytonadione5 mg
Inactive Ingredients
Ingredient NameStrength
Acacia 
Calcium phosphate 
Silicon Dioxide 
Lactose 
Magnesium stearate 
Starch, Corn 
Talc 
Product Characteristics
ColorYELLOW (pale yellow) Score2 pieces
ShapeROUNDSize6mm
FlavorImprint Code Aton;405;Mephyton
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
125010-405-151 BOTTLE In 1 CARTONcontains a BOTTLE
1100 TABLET In 1 BOTTLEThis package is contained within the CARTON (25010-405-15)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA01010409/30/1955

Labeler - Aton Pharma, Inc. (795419675)
Establishment
NameAddressID/FEIOperations
Draxis Pharma, Inc. (Produits Pharmaceutiques Specialises Draxis Inc)243604761MANUFACTURE
Revised: 11/2009Aton Pharma, Inc.