2122 Nutritional and Vitamins
Far; Neth.: Vedrop; Norw.: Bio�E; Ido-Et; Nycoplus E-vitamin; Ph. Eur. 8: (Menadione). A pale yellow crystalline powder. Uses and Administration Vedrop; NZ: Micelle Et; Philipp.: Enat; Enervon-E; Evion; It is unstable in light. Practically insoluble in water; Integra-E; Lexivit-E; Myra; Zyme; Pol. : Dermovit E; Tokovit E; sparingly soluble in alcohol and in methyl alcohol; freely Vitamin K is an essential cofactor in the hepatic synthesis of Vedrop; Vitale Et; Port.: Ve; Vedrop; Rus.: Evitol (3sJITon); S. soluble in toluene. Protect from light. prothrombin (factor II) and other blood clotting factors Afr.: Ephynalt; Vitaforce Et; Singapore: Enat; Natopherol; Nat (factors VII, IX, and X, and proteins C and S) and in the USP 36: (Menadione). A bright yellow, practically uree; Rosken Skin Repair Vitamin E; Spain: Auxina E; function of proteins such as osteocalcin important for bone odourless, crystalline powder. It is affected by sunlight. Ephynal; Vedrop; Swed.: E·vidont; E·vimin; Ido·Et; Vedrop; development. Practically insoluble in water; soluble I in 60 of alcohol, 1 in Switz. : ecobiosant; Ephynal; Evit; Optovitt; Thai.: Bio-E; Vitamin K deficiency may develop in neonates (see 50 of vegetable oils, and 1 in 10 of benzene; sparingly Blackmores Bio E; E-Drops; Nat E; Patar E-400; Tupper-E; Vitamin K Deficiency Bleeding, p. 2123.2), but is Turk.: E-400; Eforol; Ephynal; Evicap; Evigen; Evon; Grand· soluble in chloroform. Store at a temperature of 25 degrees, uncommon in adults, although it may occur in patients pherol; Natural Et; UK: Ephynal; Prairie Gold; Vedrop; Vita·E; excursions permitted between 15 degrees and 30 degrees. with malabsorption syndromes, obstructive jaundice or Ukr.: Enat (3HaT); USA: Aqua·E; Aquasol E; Aquavit·E; E· Protect from light. Gems; E-Oil; GRX Vitamin E; Natural E; Nutr-E-Sol; Promega; hepatic disease. Deficiency leads to the development of Vita-Plus E; Vitec; Venez.: Best; Egogyn; Epol; Missecap; Nat-E; hypoprothrombinaemia, in which the clotting time of the Vit-E-Nat; Vit-E-Var; Vitae; Viteral. Handling. Menadione powder is irritating to the respir blood is prolonged and spontaneous bleeding can occur. atory tract and to the skin. The alcoholic solution has vesi Coumarin anticoagulants interfere with vitamin K metab Multi-ingredient Preparations. Numerous preparations are listed cant properties. olism, and their effects can be antagonised by giving vitamin in Volume B. K. Vitamin K compounds are used in the treatment and Homoeopathic Preparations. Ger. : Infi-Symphytum; NeyChon Menadione Sodium Bisulfite (BANM, r/NN) prevention of haemorrhage associated with vitamin K Nr 68; NeyDil Nr 66t; NeyGero Nr 64; NeyGeront Vitalkapsein deficiency. The dose of vitamin K should be carefully l?isul rto _ _.s(Jdi<:p de _ rhe allicih&; Ki;l(itarlu i. (Vl acli l A; NeyLing Nr 66. f . _ . !l fn �h cl controlled by prothrombin-time estimations. $Qqyurn Bisulfit; o/)eqadi All cross-references refer to entries in Volume A Action. References to the action of vitamin K and the role a maximum dose of 40 to 50 mg. However, large doses of as those who had a complicated delivery, those born of vitamin K-dependent coagulation proteins and carboxy vitamin K may result in overcorrection, and increase the prematurely, and those whose mothers were receiving glutamate-containing proteins such as osteocalcin. delay before resumed anticoagulant therapy becomes antiepileptic therapy. Since it is not possible to selectively I. Friedman PA. Vitamin K-dependent proteins. N Eng! 1 Med 1984; 310: effective. In addition, the time to onset of action is a mini identify all neonates that are at risk for VKDB, the routine 1458-60. mum of 1 to 2 hours, irrespective of dose. There is increas use of phytomenadione in all neonates has been advocated. 2. Rick ME. Protein C and protein S: vitamin K-dependent inhibitors of ing evidence that lower doses of vitamin K are effective in However, such practice has been controversial, particularly blood coagulation. JAMA 1990; 263: 701-3. over-anticoagulation, 1-3 and this is reflected in current 2·4 3. Nelsestuen GL, et a!. Vitamin K-dependent proteins. Vitam Horm 2000; as regards the route. 58: 355-89. guidelines (see Treatment of Adverse Effects of Warfarin, Some consider that oral dosage is less invasive and more 4. Saxena SP, et al. Novel vitamin K-dependent pathways regulating cell p. 1529.I). The use of vitamin K lowers the elevated INR acceptable to parents.4 However, there has also been survival. Apoptosis 2001; 6: 57-68. faster than witholding warfarin alone. However, for concern about the adequacy of absorption of oral patients on phenprocoumon, vitamin K had insufficient phytomenadione. In addition, there was some evidence2,5-7 Malignant neoplasms. In a small study in women with effect, and no benefit for those on acenocoumarol; stop to suggest that a single intramuscular dose was more viral cirrhosis of the liver to establish the effects of vitamin ping therapy is more effective.' The route by which vit effective than a single oral dose in preventing late VKDB, K on bone loss, those given menatetrenone were found to amin K is given may also be significant. A meta-analysis4 and that repeated oral doses might be required, which may have a lower incidence of hepatocellular carcinoma; larger of studies of vitamin K for the treatment of over-anticoa be less convenient and carry the risk of poor compliance. controlled studies were advocated, with prevention of gulation found that oral or intravenous vitamin K therapy More recently, a possible increased risk of childhood cancer 1 carcinoma by menatetrenone as a primary end-point. was more effective for warfarin than simply stopping the in neonates treated with intramuscular, but not oral, 2 Another study reported reduced recurrence of hepatocel anticoagulant; however, subcutaneous therapy was not phytomenadione has been reported (see Carcinogenicity, lular carcinoma in patients given menatetrenone. effective. A review5 noted that over-anticoagulated p. 2 I 24.2). Although the association remains controversial, 1. Habu D, et al. Role of vitamin K1 in the development of hepatocellular patients present with a wide range of INR values, and may it led to recommendations for the preferential use of oral carcinoma in women with viral cirrhosis of the liver. JAMA 2004; 292: 358-6 1. respond differently to fixed dosing regimens of vitamin K, vitamin K in neonates at low-risk of VKDB in some 2. Mizuta T, Ozaki I. Hepatocellular carcinoma and vitamin K. Vitam Horm leaving them outside their target INR 24 hours after treat countries, including the UK8 and Germany, 9 whereas other 2008; 78: 435-42. ment and at risk for either haemorrhage or thromboembo countries, including the USA,10•11 still preferred the lism. Patient factors that affect response to vitamin K intramuscular route for all neonates. Neonatal intraventricular haemorrhage. Vitamin K include age, body-weight, co-morbidity or health status, There is still no agreement on the most effective route or crosses the placenta slowly and to a limited extent, but warfarin daily dose, and genetic polymorphism. The dosage regimen, and study of this has been complicated by Sufficiently to warrant studies to assess whether giving authors called for a more individualised approach to the issues concerning the available formulations. A colloidal, phytomenadione to the mother can reduce the incidence reversal of over-anticoagulation. micelle formulation (licensed for oral use in some countries) or severity of intraventricular haemorrhage (p. I I28.3) in A study has shown that dietary vitamin K intake is an was introduced to replace the original preparation which the preterm neonate. Studies have shown conflicting important factor in anticoagulation instability; even brief contained polyoxyl castor oil, propylene glycol, and phenol results. A systematic review concluded that vitamin K periods of increased. or decreased intake had significant (unlicensed for oral use but often given in this way). given to the mother before birth did not significantly pre effects on anticoagulation -' A high intake of green, leafy Although replacing the original formulation has eased vent periventricular haemorrhage, and could not be vegetables or selected oil-based foods can readily provide a concerns about the safety of its exdpients, it is not known if recommended for routine clinical use.1 dietary intake of 500 micrograms of vitamin K. Instead of the new formulation provides sustained protection when I. Crowther CA, et al. Vitamin K prior to preterm birth for preventing restricting dietary vitamin K, maintenance of a stable intake given intramuscularly. Oral absorption of the new neonatal periventricular haemorrhage. Available in The Cochrane may result in improved maintenance of therapeutic formulation has also prompted discussion.12 A report13 of Database of Systematic Reviews; Issue I. Chichester: John Wiley; 2010 {accessed 27105110). anticoagulation.7 the failure of prophylaxis in 3 breast-fed babies (2 of whom Concern has also been expressed about possible effects had unidentified cholestatic liver disease) who received 2 Osteoporosis. The effects of vitamin K on bone, and its on patients taking warfarin if vitamin K is included in their oral doses of the micellar formulation, as recomn1ended in role in osteoporosis (p. 1168. 1) have been reviewed. 1•5 It parenteral nutrition. 8 Switzerland, emphasises the importance of the third, and is widely prescribed for the management of osteoporosis in I. Weibert RT, et a/. Correction of excessive anticoagulation with low-dose possibly, other, follow-up doses. Plasma vitamin K Japan -' A reduced risk of vertebral' and nonvertebral' oral vitamin K1. Ann InternMed 1997; 125: 959-62. concentrations in breast-fed infants receiving 3 oral doses 2. Fetrow CW, et al. Antagonism of warfarin-induced hypoprothrombine fracture has been reported from 2 studies in postmenopau of this formulation were at least equal to concentrations in mia with use of low-dose subcutaneous vitamin K1• J Clin Pharmacal 1 sal women given menatetrenone 45 mg daily by mouth. 1997; 37: 751-7. those receiving a single intramuscular dose. 4 A study in 3. Hanslik T, Prinseau J. The use of vitamin Kin patients on anticoagulant Germany, however, found the mice1lar oral formulation to Vitamin K2 (menaquinones such as menatetrenone) therapy: a practical guide. Am J Cardiovasc Drugs 2004; 4: 43-55. appears to have more marked effects on bone than vit _ be no more efficacious than older vitamin K preparations, 15 4. Delee KJ, et a!. Treatment of excessive anticoagulation with amin K (phytomenadione).3 Oral phytomenadione 5 mg and a pharmacokinetic study found its absorption to be 1 phytonadione {vitamin K): a meta-analysis. Arch Intern Med 2006; 166: dally for 2 to 4 years did not protect against age-related 391-7. unreliable in infants with conjugated hyperbilirubinae decline in bone mineral density (BMD ) in postmenopausal 5. Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms mia; 16 the authors suggest that even 3 oral doses may not Canadian women with osteopenia, although some protec for the reversal of over-anticoagulation with warfarin: the need for a provide sufficient protection against VKDB in infants with more tailored dosing regimen. Bur J Haematol 2006; 77: 457-62. tion against fractures (as well as a reduction in the inci latent cholestasis. 6. Franco V, et al. Role of dietary vitamin K intake in chronic oral dence of cancer) was reported.8 A systematic review9 to anticoagulation: prospective evidence from observational and rando Advice issued in 1998 from the UK Department of assess whether vitamin K supplementation can reduce mized protocols. Am J Med 2004; 116: 651-6. Health17 advocates that all newborn infants should receive bone loss and prevent fractures identified I 3 studies with 7. Bovill EG, et al. Vitamin K and oral anticoagulation: thought for food. vitamin K prophylaxis, both oral and intramuscular routes Am J Med 2004; 116: 711-13. data on bone loss; 7 reported fracture data. Most studies should be available, and that parents should be involved in 8. BernM. Observations on possible effects of daily vitamin K replacement, were conducted in Japan among postmenopausal women. especially upon warfarin therapy. J Parenter Enteral Nutr 2004; 28: 388-- the dedsion on which route is used. In healthy neonates of Vitamin K supplements increased BMD in all but I study. 98. 36 weeks' gestation or over, licensed product information in Meta-analyses of the 7 studies with fracture data showed the UK recommends a dose of I mg phytomenadione as a a reduced fracture incidence with menatetrenone supple Vitamin K deficiency bleeding. Vitamin K deficiency single intramuscular injection soon after birth. Alterna mentation, especially at the hip. The authors advised cau bleeding (VKDB; haemorrhagic disease of the newborn; tively, 2 mg may be given orally soon after birth, followed by tion in interpretation of the data, since the studies were HDN), of which 3 types have been recognised, is asso a second dose of 2 mg at 4 to 7 days; a third oral dose of 2 mg not designed to show fracture effects, and quality of many ciated with a clotting defect due to vitamin K deficiency . 1'2 should be given to exclusively breast-fed babies one month In early VKDB bleeding occurs at the time of delivery or after birth. In preterm neonates of less than 36 weeks' of the trials was poor. In addition, dietary differences in • Japan might confound findings. While patients at risk of during the first 24 hours of life and is typically seen in gestation, an intramuscular or intravenous dose of fracture should be encouraged to consume a diet high in infants whose mothers have taken drugs that affect 400 micrograms/kg (maximum I mg) may be given soon vitamin K, routine supplementation is not justified until vitamin K metabolism such as warfarin, some antiepilep after birth. The BNFC states that the intramuscular route these results can be confirmed in a large randomised study tics, rifampicin, or isoniazid. should be used in those infants considered to be at particular Classic VKDB, the most common type, usually occurs at 2 risk for VKDB, and also suggests that infants with cholestatic with fracture as a primary outcome. • 1. Iwamoto J, et a!. Effects of vitamin K2 on osteoporosis. Curr PharmDes to 5 days of age and breast feeding is an important factor disease should be given either intramuscular or intravenous 2004; 10: 2557-76. as human breast milk has a much lower content of phytomenadione as oral absorption is likely to be impaired. 2. Adams J, Pepping J. Vitamin K in the treatment and prevention of vitamin K than either cow's milk or infant formulas. Additionally, subsequent oral doses are suggested for osteoporosis and arterial calcification. Am J Health-Syst Pharm 2005; 62: Late VKDB presents frequently as intracranial haemorr neonates given an initial intravenous dose, in order to 1574--81. • 3. Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and hage in infants over one month of age. The vitamin-K provide comparable prolonged protection to the intramus osteoporosis. AlternMed Rev 2005; 10: 24--35. deficiency in these cases can be either idiopathic (usually cular route. 4. BOgel S. Vitamin K and bone health in adult humans. Vitam Horm 2008; in breast-fed infants who did not receive vitamin K at Other regimens have been investigated or are in use 78: 393-416. 5. Shea MK, Booth SL. Update on the role of vitamin Kin skeletal health. birth) and/or can be a secondary manifestation of other elsewhere. One hospital in the USA has satisfactorily used, Nutr Rev 2008; 66: 549-57. disorders such as chronic diarrhoea, cystic fibrosis or for many years, a single 2-mg dose given via nasogastric 6. Ishida Y, Kawai S. Comparative efficacy of hormone replacement other malabsorption syndromes, biliary atresia, or - tube to neonates after birth, 18 although the American a 1 therapy, etidronate, calcitonin, alfacalcidol. and vitamin K in antitrypsin deficiency. Academy of Pediatrics still advocates use of the postmenopausal women with osteoporosis: The Yamaguchi Osteo porosis Prevention Study. Am .JMed 2004; 117: 549-5 5. Treatment of VKDB involves use of intravenous phyto intramuscular route.u In Denmark, a 2-mg oral or 7. Sato Y, et al. Menatetrenone and vitamin D2 with calcium supplements menadione, usually I mg initially with further doses intramuscular dose at birth followed by a weekly oral dose prevent nonvertebral fracture in elderly women with Alzheimer's depending on response. More immediate treatment, in the of 1 mg during the first 3 months of life has effectively disease. Bone 2005; 36: 61-8. form of blood transfusion or blood clotting factors, may be prevented any late VKDB in healthy breast-fed babies.19 In 8. Cheung AM, et al. Vitamin K supplementation in postmenopausal women with ostcopenia (ECKO trial): a randomized controlled trial. needed to compensate for severe blood loss and delayed the Netherlands a lower dose regimen of 1 mg orally or PLoS Med 2008; 5: cl96. Available at: http:l/medicine.plosjoumals.org/ response to vitamin K. VKDB, particularly the late type, intramuscularly at birth, followed by 2 5 micrograms daily or archivell549- I676/5/l0/pdfl l O. l 371_journal.pmed.0050196-L.pdf carries a high risk of morbidity or death; therefore, the I mg weekly by mouth from I week to 3 months of age has (accessed 13/03/09) emphasis has been on prevention. been found satisfactory.20 However, a retrospective 9. Cockayne S, et al. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern It has long been known that giving vitamin K to the comparison of dose regimens used in Denmark and the Med 2006; 166: 1256-61. neonate soon after birth can reduce the incidence of VKDB. Netherlands revealed that the lower doses used in the Menadiol sodium phosphate was formerly used, but reports Netherlands did not provide protection against VKDB in Over-anticoagulation. Doses of vitamin K for over-antic in the 1950s of jaundice and kernicterus in infants given this breast-fed infants with unrecognised cholestasis due to oagulation with warfarin have traditionally been large, vitamin K analogue caused concern, and led to the biliary atresia.21 In France, for formula-fed neonates at no and this continues to be reflected in -licensed product preferential use of phytomenadione either intramuscularly risk of haemorrhage, 2 mg is given orally at birth, followed information for these products, where recommended oral or orally. Giving phytomenadione, has been standard by a second dose between day 2 and 7; infants who are or parenteral doses range from 2.5 to 25 mg initially, with practice for neonates considered at high risk of VKDB, such breast-fed are given weekly oral doses of 2 mg until The symbol t denotes a preparation no longer actively marketed 2124 Nutritional and Vitamins cessation of exclusive breast feeding. For neonates at high development in the infant of haemolytic anaemia, ll. McKinney PA, et a!. Case-control study of childhood leukaemia and risk of haemorrhage, however. the first dose is given hyperbilirubinaemia, and kernicterus, and such use is not cancer in Scotland: findings for neonatal intramuscular vitamin K. BMJ 1998; 316: 173-7. intramuscularly, or even by slow intravenous injection, recommended. Phytomenadione has a lower risk of 12. Passmore SJ, et a!. Ecological studies of relation between hospital policies according to the clinical state of the infant. 2 haemolysis. Menadione and menadiol sodium phosphate on neonatal vitamin K administration and subsequent occurrence of Although phytomenadione crosses the placenta slowly have also been reported to cause haemolysis in patients with childhood cancer. BMJ 1998; 316: 184-9. and to a limited extent it is nevertheless recommended that G6PD deficiency or vitamin E deficiency. 13. Passmore SJ, et al. Case-control studies of rel All cross-references refer to entries in Volume A Vitamin K Substances/Zeaxanthin 2125 Porphyria. The Drug Database for Acute Porphyria, com Mex. : Danapril; Dionadion; K-50; Konakiont; Royken; Neth.: Yeast may be enriched by growing it in the presence of piled by the Norwegian Porphyria Centre (NAPOS) and Konakion; Norw.: Konakion; NZ: K-Thrombint; Konakion; various minerals. Chromium-enriched yeast (chromium the Porphyria Centre Sweden, classifies phytomenadione Phz1ipp.: Clotigent; Cycomin; Hema-K; Hemadone; Hemo-Kt; yeast), iron-enriched yeast (iron yeast), selenium-enriched as not porphyrinogenic; it may be used as a drug of first Kona-K; Konakion; Vitakay; Pol. : Vitacon; Port.: Kanakion; S. yeast (selenium yeast), and zinc-enriched yeast (zinc yeast) Afr. : Konakion; Singapore: Konakion; Spain: Kaergona Hidro· choice and no precautions are needed. Menadione is not have been used as dietary supplements. solublet; Konakion; Swed.: Konakion; Switz.: Konakion; Thai.: classified. 1 Yeast is an ingredient of some preparations for treating Glakay; Konakion; KP; Turk. : Konakion MM; Libavit K; Vi haemorrhoids, and some preparations intended to restore 1. The Drug Database for Acute Porphyria. Available at: http:/lwww. Plex K; UK: Konakion; Neokay; USA: Mephyton. drugs-porphyria.org (accessed 07/10/11) normal gastrointestinal flora (see Probiotics, p. 2596.3). Multi-ingredient Prepara�ons. Arg. : Aderogyl; Estreptocarbocaf Yeast is widely used in brewing. Interactions tiazol; Estreptocarbocaftiazol; Kacerutin; Austral.: Bone Matrix Support; Nutribone; OsteoEze Bone & Joint; PM Kiddiecal; PM Antibiotic·assaciated colitis. Although other organisms, Vitamin K decreases the effects of oral anticoagulants (see NextG Cal; Vitalipid N; Austria: Vitalipid; Belg.: Vitalipid; Chz1e: including Candida spp., have been implicated in antibiotic p. 1535.3), and is used to counteract excessive effects of China: Hepabil; K-Gel; Kalin; Microret Kt; Vitalipid N; Vitalipid associated diarrhoea, colonisation of the colon with Clostri these drugs, see Uses and Administration, p. 2122.3. N (ftfl!l>l'Uil!!�); Zhi Wei Baa (lillft!Ji!); Cz. : Vitalipid N; Denm.: dium difficile, a toxin-producing Gram-positive anaerobe, is Vitamin K may reduce the response to resumed therapy Vitalipid; Fin.: Vitalipid; Fr. : Vitalipide; Ger.: Vitalipid; Gr.: the most common identifiable cause of antibiotic-asso with anticoagulants for a week or more. Vitalipid; Hong Kong: Vitalipid N; Hung. : Vitalipid; India: Cadisper C; CKPt; Gynae-CVP; Gystat; Kalpastict; Siochrome; ciated colitis (p. 183.1) and pseudomembranous colitis. Styptocid; Styptocip; Indon.: Biocal-95; Cal-95; Calciviton; Cal There are reports of benefit with dried yeast in patients Pharmacokinetics plex; Calvitos; Hi-Bone; Ossovit Plus; Ossovit; Phoscal; Steopor; with C. difficile-associated diarrhoea;l.2 commerdally avail able brewers' yeast tablets were used, at a dose of 3 tablets The fat-soluble vitamin K compounds phytomenadione and Vitalipid N; IrL : Bio-Calcium + D3 + Kt; Vitlipid N; Israel: Vita menadione require the presence of bile for their absorption lipid N; Ita!. : 3Mil; Dicovit DK; Ditrevit K; Nadione; Vitalipid; three times daily (strength unspecified), in 3 patients from the gastrointestinal tract; the water-soluble derivatives Malaysia: Vitalipid Nt; Mex. : Anadekint; Hemosin-K; Micro refractory to standard treatroent,1 or as adjunctive therapy can be absorbed in the absence of bile. Vitamin K kat; Microret K; Neth.: Vitintra; Norw.: Vitalipid; NZ: Vitalipid; in II patients, using the same dose.2 Pol. : Port.: Rus.: (BeK accumulates mainly in the liver but is stored in the body Vitalipid N; Vitalipid; Vectrum Calcium l. Schellenberg D, et al. Treannent of Clostridium difficile diarrhoea with Tl'YM KaJ!LQuii); Vitalipid N (BHTammH.ll H); S.Afr.: Vitalipid; Sin only for short periods of time. Vitamin K does not appear to brewer's yeast. Lancet 1994; 343: 171-2. gapore: Vitalipid N; Spain: Vitalipid; Swed. : Vitalipid; Switz.: 2. Barthram J, et al. Further research warranted. Pharm J 1997; 259: 371. cross the .placenta readily and it is variably distributed into Vitalipid N; Thai.: Bio-Calcium + D3 + K; Siduol; Vitalipid; ' breast mill<. Phytomenadione is rapidly metabolised to more Turk.: Vitalipid N; UK: Vitlipid N; Ukr. : Osteoartisi Max r polar metabolites and is excreted in bile and urine as (Ocreoaprn:lu Mar �.r�P. The symbol t denotes a preparation no longer actively marketed