Phylloquinone

KEEP WELL CLOSED & PROTECTED FROM LIGHT.

The drug is photosensitive and must be protected from light at all times. Infusion solutions should be protected from light by wrapping the container with aluminum foil or other opaque material. Phytonadione tablets should be stored in well-closed, light-resistant containers.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Vit k antagonizes inhibitory effect of /acenocoumarol, phenprocoumon, anisindione, diphenadione, & phenindione/ on hepatic synthesis of vit k-dependent clotting proteins... /vit k/

Requirements for vitamin K may be increased in patients receiving /broad-spectrum antibiotics, moxalactam, quinidine, quinine, high doses of salicylates, or antibacterial sulfonamides/.

Concurrent use /with dactinomycin/ may decrease the effects of vitamin K; evidence is inconclusive, observation of patients is recommended and a higher dose of vitamin K may be required. /Vitamin K/

Concurrent use /of coumarin- or indandione-derivative anticoagulants/ with vitamin K may decrease the effects of these anticoagulants as a result of increased hepatic synthesis of procoagulant factors. When reinstituting oral anticoagulant therapy after the administration of large doses of vitamin K, it may be necessary to temporarily increase the dose of the oral anticoagulant, or to use one such as heparin that acts on a different principle. /Vitamin K/

For more Interactions (Complete) data for PHYTONADIONE (18 total), please visit the HSDB record page.

Subcutaneous, Intramuscular, Intravenous injection. Oral phylloquinone is adequately absorbed from the gastrointestinal tract only if bile salts are present. After absorption, phylloquinone is initially concentrated in the liver, but the concentration declines rapidly. Very little vitamin K accumulates in tissues.

Doses up to 50 mg have been used. The majority of toxicity occurs when given by IV.

Vitamin K is an essential cofactor for the gamma-carboxylase enzymes which catalyze the posttranslational gamma-carboxylation of glutamic acid residues in inactive hepatic precursors of coagulation factors II (prothrombin), VII, IX and X. Gamma-carboxylation converts these inactive precursors into active coagulation factors which are secreted by hepatocytes into the blood. Supplementing with Phylloquinone results in a relief of vitamin K deficiency symptoms which include easy bruisability, epistaxis, gastrointestinal bleeding, menorrhagia and hematuria.

FAT-SOL VIT OCCURRING NATURALLY AS TRANS ISOMER. ... FIRST ISOLATED FROM ALFALFA; ALSO SHOWS WIDESPREAD DISTRIBUTION IN HIGHER GREEN PLANTS: DAM ET AL, HELV CHIM ACTA 22, 310 (1939).

Phylloquinone is widely distributed in higher plants and in some blue-green algae. It is present in many foods, especially leafy green vegetables and some vegetable oils.

/HUMAN EXPOSURE STUDIES/ To determine whether vitamin K administration affects urinary calcium excretion in postmenopausal women. Before- and after-trials with a 2-week treatment period. Healthy postmenopausal women (55 to 75 years old) were recruited from the convents in and around Maastricht. Controls (25 to 40 years old) were healthy premenopausal volunteers. Daily administration of 1 mg of vitamin K for 2 weeks. Serum immunoreactive osteocalcin: hydroxylapatite binding (HAB) capacity of serum immunoreactive osteocalcin; excretion of calcium, hydroxyproline, and creatinine in the urine during the last 2 h of a 16-h fasting period. In premenopausal women, no effect of vitamin K administration was seen. In the postmenopausal group, vitamin K induced increased serum immunoreactive osteocalcin concentration; normalization of the HAB capacity of serum immunoreactive osteocalcin (this marker was less than 50% that of the controls in the pretreatment samples); a decrease in urinary calcium excretion, notably in the "fast losers" of calcium; and a parallel decrease in urinary hydroxyproline excretion in the fast losers of calcium. The serum immunoreactive osteocalcin level may vary with vitamin K status. This variance should be taken into consideration if osteocalcin is used as a marker for osteoblast activity. Vitamin K is one factor that may play a role in the loss of bone mass in postmenopausal osteoporosis.

/EPIDEMIOLOGY STUDIES/ A retrospective review of anaphylaxis after i.v. phytonadione over a 58-month period at a large academic center was performed. During the period of the study a protocol for the administration of i.v. phytonadione was in place. A review of computerized records and survey of staff identified cases of anaphylaxis meeting predefined inclusion criteria. In addition, a literature review was performed for articles concerning anaphylaxis after i.v. phytonadione. Over the 58 months of the study, a total of 6,572 doses of i.v. phytonadione were administered. Two cases of anaphylaxis after i.v. phytonadione were identified. The incidence of anaphylaxis was 3 per 10,000 doses with 95% confidence intervals of 0.04 to 11 per 10,000 doses. The literature review identified 14 cases meeting inclusion criteria with no reviews of the literature or estimates of incidence. The incidence of anaphylaxis after i.v. phytonadione is overall comparable or slightly less than other drugs known to cause anaphylaxis.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Phytonadione

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The offspring of mice treated with phylloquinone by injection had cleft lip and exencephaly. Six pregnant Sprague-Dawley rats were dosed with 10 mg/kg body weight phylloquinone (Konakion) daily on days 9-20 of gestation, and the fetuses were delivered on day 21 and examined for external malformations and the presence of hemorrhages only. No adverse effects were noted when compared with a group of five untreated controls.

/GENOTOXICITY/ In fetal sheep that received a catheter in the femoral vein 10-15 days before term, phylloquinone significantly increased the frequency of sister chromatid exchange in peripheral blood lymphocytes sampled 24 hours later.

/GENOTOXICITY/ /Phytonadione/ ... at concentrations up to 2,000 mcg/plate with or without metabolic activation, was negative in the Ames microbial mutagen test.

/GENOTOXICITY/ /Phylloquinone/ ... enhanced the frequency of sister chromatid exchange in cultured human maternal lymphocytes at concentrations that are relevant in vivo, and a similar increase in sister chromatid exchange frequency was observed in cultured lymphocytes from human placental blood.

Evaluation: There is inadequate evidence in humans for the carcinogenicity of vitamin K. There is inadequate evidence in experimental animals for the carcinogenicity of vitamin K. Overall evaluation: Vitamin K is not classifiable as to its carcinogenicity to humans (Group 3). /Vitamin K/

The US Food and Drug Administration ... requires that all infant formula sold in the USA contain a minimum of 4 ug/100 kcal (0.2 mg/kg) of vitamin K; and that any vitamin K added shall be in the form of phylloquinone.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl phytonadione, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The major dietary source of vitamin K found in green plants, algae, and photosynthetic bacteria; Used as a vitamin (prothrombogenic) and veterinary antidote for dicoumarol poisoning; [Merck Index] Essential vitamin for the synthesis of coagulation factors II, VII, IX, and X in the liver; Used to reverse anticoagulation (prolonged prothrombin time) caused by coumarin and indanedione derivatives; [Olson, p. 633]

MEDICATION (VET)

MEDICATION

Use (kg; approx.) in Germany (2009): >25

For the treatment of haemorrhagic conditions in infants, antidote for coumarin anticoagulants in hypoprothrombinaemia.

Commercial preparations may contain up to 20% of the cis isomer.

Commercially available phylloquinone (vitamin K1) is prepared synthetically and may contain not only 2',3'-trans-phylloquinone (not less than 75%), but also 2',3'-cis-phylloquinone and trans-epoxyphylloquinone (not more than 4.0 percent). Phylloquinone occurs in nature only as the 2',3'-trans-7R,11R-stereoisomer.

Partial syntheses from menadione and phytol ... Synthesis using a pi-allylic nickel(I) complex ... .

Synthetically from 2-methyl-1,4-naphthoquinone and phytol.

The first syntheses and structural elucidation of phylloquinone were published in 1939 almost simultaneously by four groups. The starting materials were menadione or menadiol as the aromatic component and natural phytol or one of its derivatives. A breakthrough in commercial synthesis was achieved in the 1950s, when it was found that monoacylated menadiols (e.g. the monoacetate or the monobenzoate) could be used advantageously in the alkylation step and that natural phytol could be replaced by isophytol, which is easy to synthesize.

PHYTONADIONE, USP (VIT K1, AQUAMEPHYTON, KONAKION, MEPHYTON)... MARKETED IN 5-MG TABLETS, & IN AMPULS CONTAINING EMULSION OF 2 OR 10 MG/ML OF PHYTONADIONE DISPERSED IN SOLN OF BUFFERED POLYSORBATE & PROPYLENE GLYCOL (KONAKION) OR POLYETHYLATED FATTY ACID DERIV & DEXTROSE (AQUAMEPHYTON).

KONAKION IS ADMIN ONLY IM; AQUAMEPHYTON MAY BE GIVEN BY ANY PARENTERAL ROUTE.

COLLOIDAL SOLN IS MARKETED UNDER NAME AQUA-MEPHYTON.

Oral tablets; 5 mg, Mephyton (scored) Merck.

For more Formulations/Preparations (Complete) data for PHYTONADIONE (6 total), please visit the HSDB record page.

1,4-Naphthalenedione, 2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-yl]-: ACTIVE

PHYLLOQUINONE IS FOUND IN PLANTS; IT IS ONLY NATURAL VIT K AVAIL FOR THERAPEUTIC USE.

SYNTH YIELDS MIXT OF CIS & TRANS ISOMERS OF WHICH TRANS FORM PREDOMINATES. COMMERCIAL PREPN MAY CONTAIN UP TO 20% OF CIS ISOMER.

METABOLIC STUDIES: SHEARER ET AL, BRIT J HAEMATOL 18, 297 (1970); 22, 579 (1972). CIS ISOMER HAS LITTLE, IF ANY, VIT K ACTIVITY: MATSCHINER ET AL, J NUTR 102, 625 (1972).

DRUGS WITH VIT K ACTIVITY MAY BE CHEMICALLY ASSAYED & DO NOT REQUIRE BIOASSAY. ...DETERMINATION OF VIT K CONTENT OF FOODS, ASSAY BASED UPON ABILITY OF PREPN TO INCR PROTHROMBIC LEVEL OF DEFICIENT CHICKS IS EMPLOYED.

For more General Manufacturing Information (Complete) data for PHYTONADIONE (9 total), please visit the HSDB record page.