Vitamin B12 Substances

Vitamin B12 Substances

Drug Nomenclature

Date of monograph revision: 23-Apr-1998; 06-Sep-1999; 30-Oct-2001; 25-May-2004; 08-Mar-2006; 24-Jul-2006

Drug Profile

Vitamin B12 is the name generally used for a group of related cobalt-containing compounds, also known as cobalamins, of which cyanocobalamin and hydroxocobalamin are the principal forms in clinical use.

Cobamamide

Drug Nomenclature

Date of monograph revision: 03-Mar-2006; 08-Mar-2006; 24-Jul-2006
Synonyms: Adenosylcobalamin; Coenzyme B12; Dibencozide; Dibenzcozamide; Dimebenzcozamide
INN: Cobamamide [pINN (en)]
INN: Cobamamida [pINN (es)]
INN: Cobamamide [pINN (fr)]
INN: Cobamamidum [pINN (la)]
INN: Кобамамид [pINN (ru)]
Chemical name: Inner salt of the Co-(5´-deoxyadenosine-5´) derivative of the 3´-ester of cobinamide phosphate with 5,6-dimethyl-1-αd-ribofuranosylbenzimidazole
Molecular formula: C72H100CoN18O17P =1579.6
CAS: 13870-90-1
ATC code: B03BA04
Pharmacopoeias:

In Chin.

Mecobalamin

Drug Nomenclature

Date of monograph revision: 03-Mar-2006; 08-Mar-2006; 24-Jul-2006
Synonyms: Methylcobalamin
BAN: Mecobalamin
USAN: Mecobalamin
INN: Mecobalamin [pINN (en)]
INN: Mecobalamina [pINN (es)]
INN: Mécobalamine [pINN (fr)]
INN: Mecobalaminum [pINN (la)]
INN: Мекобаламин [pINN (ru)]
Chemical name: Coα-[α-(5,6-Dimethylbenzimidazolyl)]-Coβ-methylcobamide
Molecular formula: C63H91CoN13O14P =1344.4
CAS: 13422-55-4
ATC code: B03BA05
Chemical Structure of Mecobalamin

Chemical Structure of Mecobalamin

Pharmacopoeias:

In Jpn.

Cyanocobalamin

Drug Nomenclature

Date of monograph revision: 23-Apr-1998; 06-Sep-1999; 30-Oct-2001; 25-May-2004; 08-Mar-2006; 24-Jul-2006
Synonyms: Cianocobalamina; Cianokobalamin; Cianokobalaminas; Cobamin; Cyanocobalaminum; Cyanokobalamin; Cycobemin; Kyanokobalamin; Syanokobalamiini
BAN: Cyanocobalamin
INN: Cyanocobalamin [rINN (en)]
INN: Cianocobalamina [rINN (es)]
INN: Cyanocobalamine [rINN (fr)]
INN: Cyanocobalaminum [rINN (la)]
INN: Цианокобаламин [rINN (ru)]
Chemical name: Coα-[α-(5,6-Dimethylbenzimidazolyl)]-Coβ-cyanocobamide
Molecular formula: C63H88CoN14O14P =1355.4
CAS: 68-19-9
ATC code: B03BA01
Chemical Structure of Cyanocobalamin

Chemical Structure of Cyanocobalamin

Pharmacopoeias:

In Chin., Eur. (see Go to European Pharmacopoeia Convention Signatories), Int., Jpn, Pol., US, and Viet.

Ph. Eur. 5.5 (Cyanocobalamin). A dark red, crystalline powder or dark red crystals. The anhydrous substance is very hygroscopic. Sparingly soluble in water and in alcohol; practically insoluble in acetone. Store in airtight containers. Protect from light.

USP 29 (Cyanocobalamin). Dark red crystals or amorphous or crystalline red powder. In the anhydrous form it is very hygroscopic and when exposed to air it may absorb about 12% of water. Soluble 1 in 80 of water; soluble in alcohol; insoluble in acetone, in chloroform, and in ether. Store in airtight containers. Protect from light.

Hydroxocobalamin

Drug Nomenclature

Date of monograph revision: 23-Apr-1998; 06-Sep-1999; 30-Oct-2001; 25-May-2004; 08-Mar-2006; 24-Jul-2006
Synonyms: Hidroxocobalamina; Hydroksikobalamiini; Hydroxikobalamin; Hydroxocobalaminum; Hydroxycobalaminum; Idrossocobalamina
BAN: Hydroxocobalamin
USAN: Hydroxocobalamin
INN: Hydroxocobalamin [rINN (en)]
INN: Hidroxocobalamina [rINN (es)]
INN: Hydroxocobalamine [rINN (fr)]
INN: Hydroxocobalaminum [rINN (la)]
INN: Гидроксокобаламин [rINN (ru)]
Chemical name: Coα-[α-(5,6-Dimethylbenzimidazolyl)]-Coβ-hydroxocobamide
Molecular formula: C62H89CoN13O15P =1346.4
CAS: 13422-51-0
ATC code: B03BA03; V03AB33
Read code: y02qQ
Chemical Structure of Hydroxocobalamin

Chemical Structure of Hydroxocobalamin

NOTE:

The hydrated form of hydroxocobalamin has been referred to as aquocobalamin.
Pharmacopoeias:

In Int. and US.

USP 29 (Hydroxocobalamin). Dark red crystals or red crystalline powder. Is odourless or has not more than a slight acetone odour. The anhydrous form is very hygroscopic. Soluble 1 in 50 of water and 1 in 100 of alcohol; practically insoluble in acetone, in chloroform, in ether, and in benzene; sparingly soluble in methyl alcohol. pH of a 2% solution in water is between 8.0 and 10.0. Store in airtight containers at a temperature of 8 degrees to 15 degrees. Protect from light.

Hydroxocobalamin Acetate

Drug Nomenclature

Date of monograph revision: 25-May-2004; 08-Mar-2006; 24-Jul-2006
Synonyms: Acetatocobalamin; Hidroksokobalamino acetatas; Hidroxocobalamina, acetato de; Hidroxokobalamin-acetát; Hydroksokobalamiiniasetaatti; Hydroxocobalamini Acetas; Hydroxocobalamini acetas; Hydroxokobalamin acetát; Hydroxokobalaminacetat
BAN: Hydroxocobalamin Acetate [BANM]
INN: Hydroxocobalamin Acetate [rINNM (en)]
INN: Acetato de hidroxocobalamina [rINNM (es)]
INN: Hydroxocobalamine, Acétate d' [rINNM (fr)]
INN: Hydroxocobalamini Acetas [rINNM (la)]
INN: Гидроксокобаламина Ацетат [rINNM (ru)]
Molecular formula: C64H93CoN13O17P =1406.4
CAS: 22465-48-1
Pharmacopoeias:

In Eur. (see Go to European Pharmacopoeia Convention Signatories), Jpn, and Viet.

Ph. Eur. 5.5 (Hydroxocobalamin Acetate). A dark red, very hygroscopic, crystalline powder or dark red crystals. Soluble in water. Some decomposition may occur on drying. Store at a temperature between 2 degrees and 8 degrees in airtight containers. Protect from light.

Hydroxocobalamin Chloride

Drug Nomenclature

Date of monograph revision: 25-May-2004; 08-Mar-2006; 24-Jul-2006
Synonyms: Hidroksokobalamino chloridas; Hidroxocobalamina, cloruro de; Hidroxokobalamin-klorid; Hydroksokobalamiinikloridi; Hydroxocobalamini Chloridum; Hydroxocobalamini Hydrochloridum; Hydroxokobalamin hydrochlorid; Hydroxokobalaminklorid
BAN: Hydroxocobalamin Chloride [BANM]
INN: Hydroxocobalamin Chloride [rINNM (en)]
INN: Cloruro de hidroxocobalamina [rINNM (es)]
INN: Hydroxocobalamine, Chlorure d' [rINNM (fr)]
INN: Hydroxocobalamini Chloridum [rINNM (la)]
INN: Гидроксокобаламина Хлорид [rINNM (ru)]
Molecular formula: C62H90ClCoN13O15P =1382.8
Pharmacopoeias:

In Eur. (see Go to European Pharmacopoeia Convention Signatories), Int., and Viet.

Ph. Eur. 5.5 (Hydroxocobalamin Chloride). A dark red, very hygroscopic, crystalline powder or dark red crystals. Soluble in water. Some decomposition may occur on drying. Store at a temperature between 2 degrees and 8 degrees in airtight containers. Protect from light.

Hydroxocobalamin Sulfate

Drug Nomenclature

Date of monograph revision: 25-May-2004; 08-Mar-2006; 24-Jul-2006
Synonyms: Hidroksokobalamino sulfatas; Hidroxocobalamina, sulfato de; Hidroxokobalamin-szulfát; Hydroksokobalamiinisulfaatti; Hydroxocobalamin Sulphate; Hydroxocobalamini Sulfas; Hydroxokobalamin sulfát; Hydroxokobalaminsulfat
BAN: Hydroxocobalamin Sulfate [BANM]
INN: Hydroxocobalamin Sulfate [rINNM (en)]
INN: Sulfato de hidroxocobalamina [rINNM (es)]
INN: Hydroxocobalamine, Sulfate d' [rINNM (fr)]
INN: Hydroxocobalamini Sulfas [rINNM (la)]
INN: Гидроксокобаламина Сульфат [rINNM (ru)]
Molecular formula: C124H180Co2N26O34 P2S =2790.8
Pharmacopoeias:

In Eur. (see Go to European Pharmacopoeia Convention Signatories), Int., and Viet.

Ph. Eur. 5.5 (Hydroxocobalamin Sulphate). A dark red, very hygroscopic, crystalline powder or dark red crystals. Soluble in water. Some decomposition may occur on drying. Store at a temperature between 2 degrees and 8 degrees in airtight containers. Protect from light.

Adverse Effects and Precautions

Allergic hypersensitivity reactions have occurred rarely after parenteral doses of the vitamin B12 compounds cyanocobalamin and hydroxocobalamin. Antibodies to hydroxocobalamin-transcobalamin II complex have developed during hydroxocobalamin therapy.

Arrhythmias secondary to hypokalaemia have occurred at the beginning of parenteral treatment with hydroxocobalamin.

Intranasal cyanocobalamin may cause rhinitis, nausea, and headache.

Cyanocobalamin or hydroxocobalamin should, if possible, not be given to patients with suspected vitamin B12 deficiency without first confirming the diagnosis. Regular monitoring of the blood is advisable. Use of doses greater than 10 micrograms daily may produce a haematological response in patients with folate deficiency; indiscriminate use may mask the precise diagnosis. Conversely, folate may mask vitamin B12 deficiency (see Go to Vitamin B12 deficiency.).

Cyanocobalamin should not be used for Leber's disease or tobacco amblyopia since these optic neuropathies may degenerate further.

Breast feeding.

Vitamin B12 is distributed into breast milk.1 The American Academy of Pediatrics considers its use to be usually compatible with breast feeding.2

  1. 1. Samson RR, McClelland DBL. Vitamin B12 in human colostrum and milk. Acta Paediatr Scand 1980; 69: 93–9. PubMed
  2. 2. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. PubMed Correction. ibid.; 1029. Also available at: online (accessed 09/01/06)

Hypersensitivity.

Analysis, by the Boston Collaborative Drug Surveillance Program, of data on 15 438 patients hospitalised between 1975 and 1982 detected 3 allergic skin reactions attributed to cyanocobalamin among 168 recipients of the drug.1 For the purposes of the study, reactions were defined as being generalised morbilliform exanthems, urticaria, or generalised pruritus only.

In a patient with a generalised pruritic reaction to hydroxocobalamin (with subsequent urticaria, bronchospasm, and oropharyngeal angioedema), cyanocobalamin was relatively well-tolerated, with only one episode of delayed urticaria.2

  1. 1. Bigby M, et al Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15 438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63. PubMed
  2. 2. Heyworth-Smith D, Hogan PG. Allergy to hydroxycobalamin, with tolerance of cyanocobalamin. Med J Aust 2002; 177: 162–3. PubMed

Local reactions.

After 3 years of monthly intramuscular vitamin B12 injections, a patient presented with a sclerotic plaque at the injection site, which was successfully treated by excision and local fat transfer. It was unclear as to whether the patient had reacted to the vehicle, the preservative, or to the cyanocobalamin.1 Fascial haematoma after vitamin B12 injection leading to local compression (posterior arm compartment syndrome) has also been reported.2

  1. 1. Ho J, et al. Vitamin B12-associated localized scleroderma and its treatment. Dermatol Surg 2004; 30: 1252–5. PubMed
  2. 2. Knapke D, Truumees E. Posterior arm and deltoid compartment syndrome after vitamin B12 injection. Orthopedics 2004; 27: 520–1. PubMed

Interactions

Absorption of vitamin B12 from the gastrointestinal tract may be reduced by neomycin, aminosalicylic acid, histamine H2-antagonists, and colchicine. Serum concentrations may be decreased by concurrent use of oral contraceptives. Many of these interactions are unlikely to be of clinical significance but should be taken into account when performing assays for blood concentrations. Parenteral chloramphenicol may attenuate the effect of vitamin B12 in anaemia.

Pharmacokinetics

Vitamin B12 substances bind to intrinsic factor, a glycoprotein secreted by the gastric mucosa, and are then actively absorbed from the gastrointestinal tract. Absorption is impaired in patients with an absence of intrinsic factor, with a malabsorption syndrome or with disease or abnormality of the gut, or after gastrectomy. Absorption from the gastrointestinal tract can also occur by passive diffusion; little of the vitamin present in food is absorbed in this manner although the process becomes increasingly important with larger amounts such as those used therapeutically. After intranasal dosage, peak plasma concentrations of cyanocobalamin have been reached in 1 to 2 hours. The bioavailability of the intranasal preparation is about 7 to 11% of that by intramuscular injection.

Vitamin B12 is extensively bound to specific plasma proteins called transcobalamins; transcobalamin II appears to be involved in the rapid transport of the cobalamins to tissues. Vitamin B12 is stored in the liver, excreted in the bile, and undergoes extensive enterohepatic recycling; part of a dose is excreted in the urine, most of it in the first 8 hours; urinary excretion, however, accounts for only a small fraction in the reduction of total body stores acquired by dietary means. Vitamin B12 diffuses across the placenta and also appears in breast milk.

Retention in the body.

After injection of cyanocobalamin a large proportion is excreted in the urine within 24 hours; the body retains only 55% of a 100-microgram dose and 15% of a 1000-microgram dose. Body stores of vitamin B12 amount to 2000 to 3000 micrograms which is believed to be enough for 3 to 4 years. If 1000 micrograms is injected monthly, the 150 micrograms retained lasts for about 1 month. Hydroxocobalamin is better retained than cyanocobalamin; 90% of a 100-microgram dose and 30% of a 1000-microgram dose are retained and that range is believed to be enough for 2 to 10 months.1

  1. 1. Anonymous. Time to drop cyanocobalamin? Drug Ther Bull 1984; 22: 43. PubMed

Human Requirements

For adults, the daily requirement of vitamin B12 is probably about 1 to 2 micrograms and this amount is present in most normal diets. Vitamin B12 occurs only in animal products; it does not occur in vegetables, therefore strict vegetarian (vegan) diets that exclude dairy products may provide an inadequate amount although it has been said that many years of vegetarianism are necessary before a deficiency is produced, if at all. Meats, especially liver and kidney, milk, eggs, and other dairy products, and fish are good sources of vitamin B12.

UK and US recommended dietary intake.

In the UK1 dietary reference values (see Go to Human requirements.) have been published for vitamin B12 and similarly in the USA recommended dietary allowances (RDAs) have been set.2 Differing amounts are recommended for infants and children of varying ages, adults and pregnant and lactating women. In the UK the reference nutrient intake (RNI) is 1.5 micrograms daily for adult males and females and the estimated average requirement (EAR) is 1.25 micrograms daily. In the USA the RDA for adults is 2.4 micrograms daily.

  1. 1. DoH. Dietary reference values for food energy and nutrients for the United Kingdom: report of the panel on dietary reference values of the committee on medical aspects of food policy. Report on health and social subjects 41. London: HMSO, 1991.
  2. 2. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press, 2000. Also available at: online (accessed 06/01/06)

Uses and Administration

Vitamin B12, a water-soluble vitamin, occurs in the body mainly as methylcobalamin (mecobalamin) and as adenosylcobalamin (cobamamide) and hydroxocobalamin. Mecobalamin and cobamamide act as coenzymes in nucleic acid synthesis. Mecobalamin is also closely involved with folic acid in several important metabolic pathways.

Vitamin B12 deficiency can occur in strict vegetarians with an inadequate dietary intake, although it may take many years before a deficiency is produced. Deficiency is more likely in patients with malabsorption syndromes or metabolic disorders, nitrous oxide-induced megaloblastosis, or after gastrectomy or extensive ileal resection. Deficiency leads to the development of megaloblastic anaemias and demyelination and other neurological damage. A specific anaemia known as pernicious anaemia develops in patients with an absence of the intrinsic factor necessary for good absorption of the vitamin from dietary sources.

Vitamin B12 preparations are used in the treatment and prevention of vitamin B12 deficiency. It is essential to identify the exact cause of deficiency, preferably before starting therapy. Hydroxocobalamin is generally preferred to cyanocobalamin; it binds more firmly to plasma proteins and is retained in the body longer (see under Pharmacokinetics, Go to Retention in the body.). Cyanocobalamin and hydroxocobalamin are generally given by the intramuscular route, although cyanocobalamin may be given by mouth or intranasally (see also under Administration, Go to Administration.). Oral cyanocobalamin may be used in treating or preventing vitamin B12 deficiency of dietary origin.

In the UK, recommended doses for pernicious anaemia and other macrocytic anaemias without neurological involvement are hydroxocobalamin (or cyanocobalamin) 250 to 1000 micrograms intramuscularly on alternate days for 1 to 2 weeks, then 250 micrograms weekly until the blood count returns to normal. Maintenance doses of 1000 micrograms of hydroxocobalamin are given every 2 to 3 months (or monthly for cyanocobalamin). If there is neurological involvement, hydroxocobalamin or cyanocobalamin may be given in doses of 1000 micrograms on alternate days and continued for as long as improvement occurs. For the prophylaxis of anaemia associated with vitamin B12 deficiency resulting from gastrectomy or malabsorption syndromes hydroxocobalamin may be given in doses of 1000 micrograms intramuscularly every 2 or 3 months or cyanocobalamin in doses of 250 to 1000 micrograms intramuscularly each month. For vitamin B12 deficiency of dietary origin, cyanocobalamin 50 to 150 micrograms may be taken daily by mouth between meals.

Lower doses of both cyanocobalamin and hydroxocobalamin are recommended in the USA. For the treatment of deficiency, the usual intramuscular dose of cyanocobalamin is 100 micrograms daily for 7 days, then on alternate days for 7 further doses, then every 3 to 4 days for 2 to 3 weeks. For hydroxocobalamin the dose is 30 to 50 micrograms daily for 5 to 10 days. For maintenance, both cyanocobalamin and hydroxocobalamin are given at a dose of 100 to 200 micrograms monthly, based on haematological monitoring. An intranasal preparation of cyanocobalamin is also available for maintenance therapy, the recommended dose being 500 micrograms once weekly. Oral doses of up to 1000 micrograms of cyanocobalamin have also been used. In patients with normal gastrointestinal absorption, doses of 1 to 25 micrograms daily are considered sufficient as a dietary supplement.

Treatment usually results in rapid haematological improvement and a striking clinical response. However, neurological symptoms respond more slowly and in some cases remission may not be complete.

Hydroxocobalamin may also be given in the treatment of tobacco amblyopia and Leber's optic atrophy; initial doses are 1000 micrograms daily for 2 weeks intramuscularly followed by 1000 micrograms twice weekly for as long as improvement occurs. Thereafter, 1000 micrograms is given every 1 to 3 months.

Cyanocobalamin and hydroxocobalamin are also used in the Schilling test to investigate vitamin B12 absorption and deficiency states. They are given in a non-radioactive form together with cyanocobalamin radioactively-labelled with cobalt-57 (Go to Cobalt-57) or cobalt-58 (Go to Cobalt-58) and the amount of radioactivity excreted in the urine can be used to assess absorption status. A differential Schilling test, in which the forms of cyanocobalamin are given under different conditions can provide information concerning the cause of the malabsorption. Cobamamide and mecobalamin may also be used for vitamin B12 deficiency.

Administration.

The small amounts of vitamin B12 present in the diet are absorbed from the gastrointestinal tract by an active process that involves binding with intrinsic factor. As intrinsic factor is absent in patients who have developed pernicious anaemia it has often been assumed that oral vitamin B12 preparations will therefore be ineffective. However, about 1% of an oral dose is absorbed by passive diffusion, and with large doses this amount may be sufficient for therapy. Thus attention has been given again to the use of oral cobalamins for the treatment of pernicious anaemia.1-3 Oral cyanocobalamin 2000 micrograms daily was as effective as intramuscular therapy in patients with vitamin B12 deficiency in a comparative study.4 Some now consider that oral doses of 1000 micrograms daily,3,5 or every 2 weeks for children,6 are a suitable alternative to injections given at monthly or so intervals; others still deem oral use to be unjustified on the grounds of negligible oral absorption.7 A review8 concluded that, while there is substantial evidence to support the use of 1000 to 2000 micrograms daily of oral cobalamin as maintenance therapy, parenteral therapy is preferable for initial treatment of those with neurological symptoms. Cyanocobalamin is also effective when given intranasally,9 with peak plasma concentrations greater than those achievable orally, and this may offer another alternative to injection. The intranasal absorption of hydroxocobalamin has been studied.10,11 Cobalamin has also been given sublingually. Normalisation of serum cobalamin concentration has been reported in 18 patients given cyanocobalamin 2000 micrograms sublingually for 7 to 12 days;12 500 micrograms sublingually was found to be as effective as the same dose given orally in correcting cobalamin deficiency.13

  1. 1. Lederle FA. Oral cobalamin for pernicious anemia: medicine's best kept secret? JAMA 1991; 265: 94–5. PubMed
  2. 2. Hathcock JN, Troendle GJ. Oral cobalamin for treatment of pernicious anemia? JAMA 1991; 265: 96–7. PubMed
  3. 3. Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998; 352: 1721–2. PubMed
  4. 4. Kuzminski AM, et al. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92: 1191–8. PubMed
  5. 5. Andrès E, et al. Usefulness of oral cyanocobalamin therapy in severe hematologic manifestations related to vitamin B12 deficiency. Ann Pharmacother 2004; 38: 1086–7. PubMed
  6. 6. Çetin M, Altay C. Efficacy of oral vitamin B12 treatment in children. J Pediatr 2001; 139: 754. PubMed
  7. 7. Van der Kuy P-HM, et al. Bioavailability of oral hydroxocobalamin. Br J Clin Pharmacol 2000; 49: 395P–396P.
  8. 8. Lane LA, Rojas-Fernandez C. Treatment of Vitamin B12-deficiency anemia: oral versus parenteral therapy. Ann Pharmacother 2002; 36: 1268–72. PubMed
  9. 9. Romeo VD, et al. Intranasal cyanocobalamin. JAMA 1992; 268: 1268–9. PubMed
  10. 10. van Asselt DZB, et al. Nasal absorption of hydroxocobalamin in healthy elderly adults. Br J Clin Pharmacol 1998; 45: 83–6. PubMed
  11. 11. Slot WB, et al. Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients. Gastroenterology 1997; 113: 430–3. PubMed
  12. 12. Delpre G, et al. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet 1999; 354: 740–1. PubMed
  13. 13. Sharabi A, et al. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol 2003; 56: 635–8. PubMed

Amino acid metabolic disorders.

References to the use of hydroxocobalamin in the treatment of inborn errors of vitamin B12 metabolism.1-3 Some patients with homocystinuria (Go to Amino acid metabolic disorders.) or methylmalonic aciduria have responded to cobalamins—the BNFC suggests an initial intramuscular dose of 1 mg daily, for 5 to 7 days, in patients from one month of age; this is reduced, according to response, to 1 mg once or twice weekly. Some children respond to maintenance with 5 to 10 mg once or twice weekly by mouth.

  1. 1. Linnell JC, Bhatt HR. Inherited errors of cobalamin metabolism and their management. Baillieres Clin Haematol 1995; 8: 567–601. PubMed
  2. 2. Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr 1998; 132: 121–4. PubMed
  3. 3. Smith DL, Bodamer OA. Practical management of combined methylmalonicaciduria and homocystinuria. J Child Neurol 2002; 17: 353–6. PubMed

Cyanide toxicity.

Hydroxocobalamin combines with cyanide to form cyanocobalamin, and thus may be used as an antidote to cyanide toxicity (Go to Treatment of Adverse Effects). Hydroxocobalamin is reported to be effective in controlling cyanide toxicity due to nitroprusside infusion,1 and after exposure to inhaled combustion products in residential fires.2

It has been hypothesised that the amount of cyanocobalamin formed is limited by the number of cyanide ions present and the amount of hydroxocobalamin given. For a given dose of hydroxocobalamin a maximum concentration of cyanocobalamin would be reached, allowing measurement of cyanocobalamin as a surrogate emergency marker for cyanide levels, which are difficult and time-consuming to measure. For a 5-g dose of hydroxocobalamin given intravenously over 30 minutes, the authors of one study considered a cyanocobalamin concentration of about 300 micromoles/litre a sign that all the hydroxocobalamin had been used, and more should be given.2 They cautioned, however, that, unless antidote regimen and blood sampling were similar to that in their study, this concentration should not be extrapolated to other patient populations.

In another patient given hydroxocobalamin 5 g intravenously over 2 hours,3 plasma concentrations of cyanide rose 1 hour after treatment with hydroxocobalamin. The authors attributed this to hydroxocobalamin extracting cyanide from red blood cells to form cyanocobalamin in plasma, which was then measured as cyanide.

  1. 1. Zerbe NF, Wagner BKJ. Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity. Crit Care Med 1993; 21: 465–7. PubMed
  2. 2. Houeto P, et al. Relation of blood cyanide to plasma cyanocobalamin concentration after a fixed dose of hydroxocobalamin in cyanide poisoning. Lancet 1995; 346: 605–8. PubMed
  3. 3. Weng T-I, et al. Elevated plasma cyanide after hydroxocobalamin infusion for cyanide poisoning. Am J Emerg Med 2004; 22: 492–3. PubMed

Deficiency states.

The emergence of newer metabolic assays for homocysteine and methylmalonic acid has led to the identification of subtle vitamin B12 deficiency1-3 without the overt manifestations of megaloblastic anaemia (see Go to Megaloblastic anaemia.) or neurological disease; this condition appears to be particularly common in the elderly.1,4,5 At present, there is no clear clinical rationale for treating subtle deficiency.1,6 However, there have been suggestions that it may be linked to some immunological impairment, identified as impaired antibody responses to pneumococcal vaccine.7 Moreover, raised homocysteine concentrations have been identified as a risk factor for atherosclerosis and ischaemic heart disease, and there is increasing interest in the potential of B vitamins, including B12, to reduce homocysteine concentrations and therefore atherosclerotic outcomes (see Cardiovascular Disease, under Uses of Folic Acid, Go to Cardiovascular disease.). Evidence that hyperhomocysteinaemia may be a risk factor for dementia is limited.5 A systematic review concluded that evidence for efficacy of vitamin B12 in improving cognitive function of people with dementia (and low serum vitamin B12 concentrations) was lacking.8

Dietary vitamin B12 deficiency in infants may lead to developmental abnormalities.9,10

The issue of fortification of food with folic acid to reduce the number of infants born with neural tube defects has created debate on the risks of masking vitamin B12 deficiency, and fortification with vitamin B12 has also been recommended, see under Folic Acid, Go to Vitamin B12 deficiency..

  1. 1. Carmel R. Subtle cobalamin deficiency. Ann Intern Med 1996; 124: 338–40. PubMed
  2. 2. Green R. Screening for vitamin B12 deficiency: caveat emptor. Ann Intern Med 1996; 124: 509–11. PubMed
  3. 3. Carmel R, et al. Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program) 2003; 62–81. PubMed
  4. 4. Andrès E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. Can Med Assoc J 2004; 171: 251–9. PubMed
  5. 5. Clarke R. Prevention of vitamin B-12 deficiency in old age. Am J Clin Nutr 2001; 73: 151–2. PubMed
  6. 6. Metz J. What's the use of oral vitamin B12? A neglected but valid treatment route may have new uses in the future. Med J Aust 1999; 170: 407. PubMed
  7. 7. Fata FT, et al. Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels. Ann Intern Med 1996; 124: 299–304. PubMed
  8. 8. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2003 (accessed 09/01/06). PubMed
  9. 9. Emery ES, et al. Vitamin B12 deficiency: a cause of abnormal movements in infants. Pediatrics 1997; 99: 255–6. PubMed
  10. 10. von Schenck U, et al. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child 1997; 77: 137–9. PubMed

Eczema.

A small study found that topical application of a preparation containing vitamin B12 was more effective than placebo in patients with atopic eczema.1

  1. 1. Stücker M, et al. Topical vitamin B12—a new therapeutic approach in atopic dermatitis—evaluation of efficacy and tolerability in a randomized placebo-controlled multicentre clinical trial. Br J Dermatol 2004; 150: 977–83. PubMed

Ischaemic heart disease.

For mention of the possible link between vitamin B12, hyperhomocysteinaemia, and atherosclerosis and ischaemic heart disease, see under Folic Acid Go to Cardiovascular disease..

Megaloblastic anaemia.

The megaloblastic anaemias are characterised by macrocytosis (an increased mean cell volume) and the production of distinctive morphological changes and abnormal maturation in developing haematopoietic cells in the bone marrow: white cell and platelet lines are affected as well as erythroid precursors, and in severe cases anaemia may be associated with leucopenia and thrombocytopenia. Megaloblastic anaemia is a consequence of impaired DNA biosynthesis in the bone marrow, usually due to a deficiency of vitamin B12 (cobalamins) or folate, both of which are essential for this process. Although the haematological symptoms of B12 deficiency and folate deficiency are similar it is important to distinguish between them since the use of folate alone in B12-deficient megaloblastic anaemia can improve haematological symptoms without preventing aggravation of accompanying neurological symptoms, and may lead to severe nervous system sequelae such as subacute combined degeneration of the spinal cord. Where it is desirable to start therapy immediately, combined treatment for both deficiencies may be started once suitable samples have been taken to permit diagnosis of the deficiency, and the patient converted to the appropriate treatment once the cause of the anaemia is known.

Vitamin B12 deficiency anaemia. Vitamin B12 deficiency and its associated symptoms may be due to malabsorption (including following gastrectomy), dietary deficiency (mainly in strict vegetarians), competition with intestinal bacteria or parasites, or to the effect of drugs such as nitrous oxide. In populations of northern European origin pernicious anaemia, in which atrophy of the gastric mucosa results in a lack of the intrinsic factor essential for B12 absorption, is the most frequent cause. As body stores of the vitamin are large, it may take several years for signs of deficiency to manifest once the defect in absorption occurs.

In addition to megaloblastic anaemia, vitamin B12 deficiency may result in neurological damage, including peripheral neuropathy and effects on mental function ranging from mild neurosis to dementia.

treatment. The treatment is with vitamin B12, almost always by the intramuscular or sometimes the deep subcutaneous route since in most patients absorption from the gastrointestinal tract is inadequate. Hydroxocobalamin is generally preferred to cyanocobalamin since it need be given less often. Regimens may vary, but hydroxocobalamin 1 mg every few days for 6 doses will restore normal body stores of the vitamin (see also Uses and Administration, Go to Uses and Administration). Dosage has not been well established in children; the BNFC recommends similar doses to those licensed in adults. The haematological response to therapy is rapid, with improvement in most parameters and symptoms beginning within 48 hours. Neurological abnormalities may take much longer to respond, and may not do so completely.

prophylaxis. Where the defect in B12 handling is irreversible, as in pernicious anaemia, maintenance therapy must continue for life to prevent a recurrence of the deficiency. Therapy must also be given prophylactically after total gastrectomy or total ileal resection, or where gastrointestinal surgery is shown to have impaired absorption of the vitamin. Typically, injection of hydroxocobalamin 1 mg every 2 to 3 months is used. In patients whose diet supplies inadequate B12, deficiency may be prevented, in the absence of other causes, by much lower oral doses given as a supplement; up to 150 micrograms of cyanocobalamin daily has been recommended.

Folate-deficiency anaemia. Deficiency of folate may be due to inadequate diet, or malabsorption syndromes (such as coeliac disease or sprue), to increased need (as in pregnancy, one of the most common causes of megaloblastic anaemia, or the increased haematopoiesis of haemolytic syndromes), to increased urinary loss or loss due to haemodialysis, or to an adverse effect of alcohol, antiepileptics, or other drugs.

The clinical features of folate-deficient megaloblastic anaemia are similar to those of disease due to vitamin-B12 deficiency except that the accompanying severe neuropathy does not occur, and deficiency may develop much more rapidly. Deficiency may also be associated with neural tube defects (Go to Neural tube defects.) if it occurs in pregnancy.

treatment. Once folate deficiency has been established the usual treatment in the UK is folic acid 5 mg by mouth daily. Lower doses of up to 1 mg are suggested in the USA. It is customary to continue therapy for at least 4 months, the time necessary for complete red cell replacement. In patients with malabsorption, therapy may require higher doses, up to 15 mg of folic acid daily. As in B12-deficiency anaemia, the response to therapy is rapid.

prophylaxis. Long-term maintenance is rarely needed, except in a few patients in whom the underlying cause of folate deficiency cannot be treated (for example in some severe haemolytic syndromes). Doses of 5 mg daily or even weekly have been suggested for prophylaxis in patients undergoing dialysis or with chronic haemolytic states, depending on the diet and rate of haemolysis; a dose of 400 micrograms daily is recommended in the USA.

For primary prophylaxis of megaloblastic anaemia in pregnancy, folic acid is given in the UK in usual doses of 200 to 500 micrograms daily, often with a ferrous salt for prophylaxis of iron deficiency.

Drugs that act as inhibitors of dihydrofolate reductase, such as methotrexate, may produce severe megaloblastic anaemia which cannot be reversed by therapy with folic acid. The adverse effects of such drugs may be largely prevented or reversed by therapy with folinic acid, which can be incorporated into folate metabolism without the need for reduction by the inhibited enzyme. For details of such 'folinic acid rescue', see under Folinic Acid, Go to Uses and Administration.

General references.

For further information on the substances mentioned above, see:

  • Cyanocobalamin (see Vitamin B12 Substances, Go to Vitamin B12 Substances)
  • Folic Acid, Go to Folic Acid
  • Folinic Acid, Go to Folinic Acid
  • Hydroxocobalamin (see Vitamin B12 Substances, Go to Vitamin B12 Substances)
  1. 1. Wickramasinghe SN. Folate and vitamin B12 deficiency and supplementation. Prescribers' J 1997; 37: 88–95.
  2. 2. Wickramasinghe SN. The wide spectrum and unresolved issues of megaloblastic anemia. Semin Hematol 1999; 36: 3–18. PubMed
  3. 3. Rasmussen SA, et al. Vitamin B12 deficiency in children and adolescents. J Pediatr 2001; 138: 10–17. PubMed
  4. 4. Hoffbrand V, Provan D. Macrocytic anaemias. In: Provan D, ed. ABC of clinical haematology. 2nd ed. London: BMJ Publishing Group, 2003.
  5. 5. Stabler SP, Allen RH. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 2004; 24: 299–326. PubMed

Neural tube defects.

There is abnormality in homocysteine metabolism in many women who give birth to children with neural tube defects (Go to Neural tube defects.); the enzyme methionine synthase, which converts homocysteine to methionine, requires both folate and vitamin B12 as cofactors, and low maternal vitamin B12 concentrations may be an independent risk factor for neural tube defects.1 A case-control study found elevated mid-trimester methylmalonic acid concentrations in women with pregnancies affected by neural tube defects, suggesting that abnormalities of cobalamin metabolism, and subsequent methylation, may be involved in the aetiology of neural tube defects.2 Decreased vitamin B12 concentrations, but no folate deficiency, were found in 3 women with pregnancies affected by neural tube defects.3 A review4 of case-control studies found a moderate association between low maternal vitamin B12 status and the risk of fetal neural tube defects. If confirmed, this would suggest that additional supplementation with cobalamins may be warranted.3-5

  1. 1. Mills JL, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995; 345: 149–51. PubMed
  2. 2. Adams MJ, et al. Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects. Teratology 1995; 51: 311–17. PubMed
  3. 3. Candito M, et al. Anomalies du tube neural et vitamine B12: à propos de trois cas. Ann Biol Clin (Paris) 2004; 62: 235–8. PubMed
  4. 4. Ray JG, Blom HJ. Vitamin B12 insufficiency and the risk of fetal neural tube defects. Q J Med 2003; 96: 289–95. PubMed
  5. 5. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr 2001; 85 (suppl): S109–S113. PubMed

Osteoporosis.

An elevated serum homocysteine concentration appears to be a risk factor for osteoporotic fractures in older men and women.1-3 Treatment with vitamin B12 and folate can reduce plasma homocysteine concentrations (see Cardiovascular Disease, under Folic Acid, Go to Cardiovascular disease.). In a placebo-controlled study of patients with hemiplegia following stroke (and at increased risk of hip fracture),4 those given folate and vitamin B12 were found to have a significantly reduced risk of hip fracture despite a lack of effect on bone mineral density. Vitamin B12 status has been associated with bone health in a number of studies,3,5 and it was suggested that the observed effects on fracture might be due to increased concentrations of vitamin B12 rather than the lowering of plasma homocysteine.3,6

  1. 1. van Meurs JBJ, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004; 350: 2033–41. PubMed
  2. 2. McLean RR, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004; 350: 2042–9. PubMed
  3. 3. van Meurs JBJ, Uitterlinden AG. Homocysteine and fracture prevention. JAMA 2005; 293: 1121–2. PubMed
  4. 4. Sato Y, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005; 293: 1082–8. PubMed
  5. 5. Dhonukshe-Rutten RAM, et al. Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr 2003; 133: 801–7. PubMed
  6. 6. Sugiyama T, et al. Folate and vitamin B12 for hip fracture prevention after stroke. JAMA 2005; 294: 792. PubMed

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Benzoral¤; Lisoneurin B12; Methycobal¤; Reedvit; SL B12; Vitam Doce; Australia: Cytacon¤; Cytamen; Neo-Cytamen; Austria: Diclo-B; Erycytol; Hepavit; Belgium: Forta B; Hydroxo¤; Novobedouze¤; Brazil: Bedozil; Cianon B12; Cronobe; Enzicoba; Methycobal¤; Rubranova; Vitadoze; Xantox¤; Zinabol; Canada: Anacobin¤; Bedoz¤; Rubion¤; Rubramin¤; Czech Republic: B12 Ankermann; Neurobene; Denmark: Behepan¤; Betolvex; Vibeden; Finland: Betolvex; Cohemin; France: Algobaz¤; Cobanzyme; Cyanokit; Dibencozan¤; Docemine¤; Dodecavit; Dolonevran¤; Epithea; Heraclene¤; Hydroxo¤; Indusil T¤; Nevrizide¤; Novobedouze¤; Paxom¤; Germany: Ambe 12; Aquo-Cytobion; B 12-L 90¤; B12 Depot-Rotexmedica; B12 Ehrl¤; B12 Rotexmedica; B12 Steigerwald; B12-Horfervit¤; B12 Ankermann; B12 Depot-Hevert; B12 Depot-Vicotrat¤; B12 Vicotrat; B12-ASmedic; Berubi-long¤; Chibro B12¤; Cobalparen-Depot¤; Cobalparen¤; Cytobion; Depogamma¤; Hamo-Vibolex; Hydroxobase¤; Lophakomp-B 12 Depot; Lophakomp-B 12; Millevit¤; Neurotrat B12¤; Novidroxin¤; Novirell B Mono; Vicapan N¤; Vit-Alboform¤; Vita-Brachont¤; Greece: Articlox; Idroxocobalamina¤; Hong Kong: Cobamin; Cyanokit; Methycobal; Triniscon¤; India: Mecovit; Methycobal; Myelogen; Ireland: Cytacon; Cytamen; Neo-Cytamen; Israel: Bedodeka; Bevitex; Nascobal; Italy: Anabasi¤; Cobaforte; Cobamide¤; Cobergon¤; Dobetin; Eritrovit B12¤; Fravit B12¤; Idrobamina¤; Idrossamina¤; Indusil; Maximal¤; Natur B12¤; Neo-Cytamen; OH B12; Reticulogen¤; Zidovit¤; Japan: Calomide-S¤; Methycobal; Malaysia: Methycobal; Mexico: Axofor¤; Biocobal; Biotrefon L; Compensal; Doprit¤; Droxivit¤; Duradoce; Exorvit¤; Hidrowil¤; Hidroxovit; Lentorem¤; Leo-Doce; Maxibol; Nebal; Neribax¤; Neurofor¤; Parol¤; Rubrina; Sanovit; Selectofort; Valamin 12¤; Vidavit¤; Netherlands: Betolvex¤; Hydrocobamine; Norway: Betolvex; New Zealand: Neo-Cytamen; Portugal: Bedoze; Co-Vibedoze¤; Cobamet; Cobaxid; Jaba B12; Made B12¤; OH B12; Permadoze; Tridocemine; South Africa: Betolvex¤; Cobalatec; Cytacon¤; Cytamen¤; Norivite-12; Nubee 12¤; Singapore: Hidomin¤; Methycobal; Neuromethyn; Spain: Ambritan¤; Anabolizante Hermes¤; Asimil B12¤; B12 Latino Depot¤; Co Vitam B12¤; Cobaldocemetil¤; Cromatonbic B12; Indusil¤; Isopto B 12; Lifaton B12¤; Megamilbedoce; Optovite B12; Panhor¤; Reticulogen Fortificado; Sorbevit B12¤; Surgevit B12¤; Zimadoce; Sweden: Behepan; Behepan; Betolvex; Betolvidon; Switzerland: Arcored¤; Betolvex; Cobazymase¤; Hydroxo¤; Novobedouze¤; Vitarubin; Thailand: Ampavit; Hitocobamin; Methycobal; Neuromet; Redisol¤; Sicobal¤; United Arab Emirates: Cynovit; United Kingdom: Cemac B12¤; Cobalin-H; Cytacon; Cytamen; Neo-Cytamen; United States: Cobolin-M¤; Crystamine; Crysti 1000; Cyanoject¤; Cyomin; Ener-B¤; Hydro Cobex; Hydro-Crysti-12; Hydrobexan¤; LA-12¤; Nascobal; Redisol¤; Rubesol-1000¤; Rubramin PC¤; Twelve Resin-K; Venezuela: Bedovit Simple; Cristadoce; Dobetin; Docebe B12; Droxofor; Hidro-Doce; Ibedox; Maxibol;

Multi-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Acifol-B12; Algio Nervomax Fuerte; Algio Nervomax; Anemidox-Ferrum; Anemidox-Solutab; Bioneural B12¤; Blastop; Blokium B12; Buta Rut B12; Cobenexol Forte; Cobenexol Fuerte; Corteroid Gesic; CVP B1 B6 B12; Dastonil; Delta Tomanil B12; Dexabion; Dexabion; Dioxaflex B12; Dolo Nervobion 10000; Dolo Nervobion; Dorixina B1 B6 B12; Factofer B12; Ferranin Complex; Ferrocebrina; Flexicamin B12; Flogiatrin B12; ITE B12 Forte; Klosidol B1 B6 B12; Nervobion Fuerte; Nervomax TB12; Nucleo CMP¤; Oxa B12; Presterin; QX 10; Rubiron; Sindrolen¤; Tenvic; Tunik B12; Vesalion B12; Virobron B12 NF; Xedenol B12; Yectafer Complex; Australia: Medinat PMT-Eze; Austria: Ambene N; Ambene N; Ambene; Arca-Be; Beneuran compositum; Clinit¤; Delta-Tomanol¤; Diclovit; Neurobion; Neuromerck; Neuromultivit; Pronerv; Rheumesser; Trinsicon¤; Belgium: Ferrifol B12¤; Neo Genyl¤; Neurobion; Rubraton¤; Vioneurin; Brazil: Aminocid; Anemofer; Betinjectol¤; Bituelve¤; Calcifix B12; Calcinol Complexo; Cianotrat-Dexa; Citoneurin; Cobactin; Cobaglobal; Cobavit; Cobavital; Coraben; Dexa-Citoneurin; Dexa-Cronobe; Dexa-Neuriberi; Dexacobal; Dexador; Dexadoze; Dexagil; Dexalgen; Dexaneurin; Dexanevral; Dozeneurin; Ergohepat B12¤; Ferroplex; Ferrotrat; Fol Sang; Hematiase B12; Hepasedan¤; Hepatotris; Iloban; Infiltran B12¤; Lisan; Lisotox; Metiocolin B12; Metiocolin Composto; Nucleo CMP; Rubizuel¤; Trinalgen¤; Trinevral¤; Trirubin; Vi-Ferrin; Vibetrat Dexa¤; Vibetrat¤; Vipirim¤; Vitaneuron; Xantinon Complex; Canada: Acti-B12; Folacin 12¤; Fortiplex¤; Heparos¤; Methischol¤; Penta-3B + C; Penta-3B; Trinsicon¤; Chile: Betonvit; Citoneuron; Cronoferril; Dolotol 12; Ferranem; Ferranim; Folifer; Nefersil B; Neurobionta; Neurocam; Tol 12; Czech Republic: Aktiferrin Compositum; Dicopac; Ferro-Folgamma; Milgamma N; Milgamma N; Milgamma; Neuromultivit; Finland: Neurobion; Neurovitan; France: Algimax¤; Ascorbamine¤; Biovaline¤; Forcapil¤; Inadrox¤; Neoparyl-B12¤; Nergitone¤; Nuclevit B12¤; Thiobanzyme¤; Vibalgan¤; Vitanevril B6-B12¤; Germany: Ambene Comp¤; AntiFocal N; B 12 compositum N¤; B 12 Nervinfant¤; B12 Fol-Vicotrat; B12-Intrinsic-Vicotrat¤; Causat B12 N¤; Corneregen N¤; Dimaestad plus¤; Dodecatol N¤; Dodecatol¤; Dolo-Neurobion forte; Eryfer comp; Eukalisan forte¤; Eukalisan N; Ferro sanol comp; Ferro-B 12 Ehrl¤; Ferro-Folgamma; Folgamma; Hepa-Uvocal¤; Hepagrisevit Forte-N¤; Hepagrisevit-Depot¤; Hepasteril¤; Hepatofalk¤; Hepavis¤; Hepsan¤; Hewedolor B¤; Magopsor¤; Medivitan N; Medyn; Milgamma N; mono-Hepagrisevit¤; Neuro-Demoplas¤; Neuro-ratiopharm¤; Neurobion; Neurotrat¤; NeyNormin N (Revitorgan-Dilutionen N Nr 65); NeyTumorin N (Revitorgan-Dilutionen N Nr 66)¤; Novirell B¤; Nurdelin¤; Pernaemyl¤; Pernical¤; Prohepar¤; Rulofer¤; Rutibal¤; Selectafer N; Supertendin 3000¤; Telbibur N¤; Vitaject¤; Vitasprint B12; Greece: Neurobion; Hong Kong: 3B; Epargriseovit¤; Hepatofalk¤; Neuro B1-6-12¤; Neurobion; Neurorubine; Nevramin; Princi-B Fort; Trabit¤; Vida Neurotab; Vidaclofen-Plus; Hungary: Ferro-Folgamma; Milgamma N; Milgamma; Neurobion; India: Alcrin-M; Anemidox; Blosyn; Calcinol; Carboflot; Conviron-TR; Delphicol; Dexorange; Elferri-Z; Ferrochelate; Fervit¤; Genfol; Globac-Z; Hepasules; Hepatoglobine; Hepatoglobine; Jectocos Plus; Macalvit; Ostocalcium B-12; Plastules; Sioneuron; Tonoferon; Tonoferon; Vitamon; Vitneurin; Ireland: Cyfol¤; Israel: Betrivit¤; Tribemin; Tricardia; Italy: Adeneurina¤; Adenobeta¤; Adenoplex Forte; Adenovit; Adinepar¤; Artrobetin¤; Benexol B12; Benexol B12; Beta-Cortex B12¤; Betascor B12¤; Bio-Rex¤; Briogen; Calci-ostelin B12¤; Calcio Colloidale con Ostelin con Vit¤; Calcio Dobetin; Cebran¤; Cerebrix¤; Citicortex¤; Citoglutar¤; CO-B12 (Cobidodici)¤; Co-Carnetina B12; Cobalton¤; Cortepar B12¤; Cromex¤; Dinamozim¤; Disintox Cortex¤; Dobetin con Vitamina B1; Dobetin Totale; Dopatox¤; Efargen¤; Emazian B12¤; Emazian Cortex¤; Emoantitossina¤; Emofol¤; Emonucleosina Cortex¤; Emopon; Endoepacort B12¤; Energon Rende¤; Epaglifer¤; Epaplex¤; Epargriseovit; Eparmefolin; Epartonno¤; Exepin Cortex¤; Fegacorten¤; Fegato¤; Ferrofolin Venti¤; Fevital¤; Fibronevrina; Firmavit¤; Fitepar Cortex¤; Folepar B12; Folinemic Cortex¤; Folinemic¤; For Liver¤; Fosfo Plus; Fosfoutipi Vitaminico¤; Fosfozimin¤; Fruttidasi¤; Gliviton¤; Globuleno¤; Gluserin B12¤; Gluta Complex¤; Glutacortin¤; Glutamin Fosforo; Glutestere B-Complesso¤; Hepa-Factor Complex¤; Hepa-Factor; Hepatos B12; Liedasi¤; Liverasten¤; Liverest¤; Memoserina S¤; Memovisus; Memovit B12; Menalgon B6¤; Menalgon¤; Mionevrasi Forte¤; Mionevrasi¤; Mnemina Fosforo¤; NE 300¤; Neo-Cromaton Cortex¤; Neo-Epa¤; Neo-Eparbiol; Neo-Geynevral¤; Nepatim¤; Neuraben; Neurobionta¤; Nevril¤; Nevrostenina B12¤; Nevrum¤; Novaneurina B12¤; Nucleodoxina¤; Nucleonevrina¤; OH B12 B1¤; Oro B12¤; Oromag B12¤; Porfirin 12¤; Porfirin 12; Protidepar 100¤; Protidepar¤; Redinon Cortex¤; Ribocort B12¤; Ricoliver¤; Ricortex¤; Rossocorten¤; Rubrocortex¤; Sideritrina¤; Sinevrile¤; Tonogen; Tonoliver 10000¤; Tonoliver Ferro¤; Toxepasi Complex¤; Trebi¤; Tricortin; Tridodilan¤; Triferon¤; Trinevrina B6; Trivitepar B12¤; Uridinvit Forte¤; Urimiodin¤; Vitalion¤; Vitamucin con Ferro¤; Vitamucin Semplice¤; Vitasprint Complex; Vitasprint; Japan: Neurovitan¤; Malaysia: 3B; Alinamin B12¤; Flavettes Neuroforte; Neuro B¤; Neurobion; Neurorubine; Neurovit; Nevramin; Nevramin; Princi-B Fort; Sangobion; Mexico: B1-12-15; Bedocil¤; Benexol B12; Ciprolisina; Cobotiaxina; Dexabion; Dolo Pangavit; Dolo-Neurobion; Dolo-Tiaminal; Duciclon; Forvin; Gonakor; Intrafer F-800; Iodarsolo B12¤; Macrox-5; Milbeta; Neuralin; Neurobion; Neuroflax; Orafer Comp; Pangavit B; Pangavit Hypak; Pangavit Pediatrico; Selectadoce; Suma-B; Tiabexol¤; Tiamidexal; Tiaminal B12 Trivalente; Tiaminal B12; Tribedoce Compuesto; Tribedoce; Tribedoxyl¤; Uni-Dox; Portugal: Linamin Plus¤; Neurobion¤; Tridocemine¤; Russia: Ambene (Амбене); Ferro-Folgamma (Ферро-Фольгамма); Milgamma (Мильгамма); Neuromultivit (Нейромультивит); South Africa: Foliglobin; Neurobion; Prohep; Revaton¤; Sentinel Ulcer Mixture; Trinsicon¤; Singapore: 3B¤; Aktiferrin-F; Alinamin B12; Neogobion; Neurobion; Neurodex; Neuroforte; Neurorubine; Neurovit; Nevramin; Princi-B Fort; Sangobion; Wanse; Spain: Acinetil Bebible¤; Anemotron¤; Antineurina; Benexol B1 B6 B12; Besinergial¤; Bester Complex; Betriple¤; Biomax¤; Calcio 20 Coenzimas¤; Calcio 20 Complex; Cocardoce¤; Cotrizima¤; Covitasa B12; Cromaton Cortex¤; Cromatonbic 5000 Ferro¤; Cromatonbic 5000¤; Dalamon¤; Doneurina¤; Duplicalcio B12; Enoton; Ferriwas B12 Fuerte¤; Foli Doce; Gammamida Complex¤; Hegama¤; Hepa Factor; Hidroxil B12 B6 B1; Histiotone¤; Imferon B12¤; Inzitan; Ledovit C B12¤; Malandil; Mederebro Compuesto¤; Mederebro; Menalgil B6; Menalgil¤; Meneparol Sol¤; Meneparol¤; Metabolicum¤; Metilema¤; Milbedoce Anabolico¤; Nervobion; Neurocatavin¤; Neuromade; Neurostop Complex; Prodessal¤; Rakivit Hepatico¤; Raquivit¤; Refulgin; Rubrocortin¤; Sedionbel¤; Sorbeglucal¤; Sugarceton¤; Taurobetina¤; Teovit¤; Toniasten¤; Tonico Juventus; Tonozime UTP¤; Trinsicon¤; Trofalgon; Trofi Milina¤; Ultravital¤; Viadetres¤; Vitafardi C B12; Vitallon 3B¤; Vitonisan B¤; Yectofer Compuesto¤; Sweden: Neurobion; Switzerland: Arconeurine¤; Benexol B12; Clinit¤; Ferrum Fol B Hausmann¤; Neurotrat¤; Resoferon fol B¤; Tribeton¤; Trilagavit¤; Vitasprint Complex; Thailand: 3B; Alinamin B12¤; Beromin; Cilfer-12-F¤; Cydoxmine-B¤; Cyriamine; Douzabox; Genavit; Hemolax; Neubee; Neurobex; Neurobion; Nevramin; Nuro-B; Nuvit; Ostone-B12; Princi-B; Re-B Forte; Sangobion¤; Trabit; Trabit; Tribesian; Tricortin¤; Trinsicon¤; Trivit-B; Vioneurin¤; Vita-B; Vitamedin; Vitron; United Arab Emirates: 3V; United Kingdom: Ce-Cobalin¤; Dicopac; Hematinic; United States: Anemagen¤; Bevitamel; Cerefolin; Chromagen FA; Chromagen Forte; Chromagen; Contrin; Fe-Tinic Forte; FeoGen; Ferotrinsic; Ferralet Plus¤; Ferrex Forte Plus; Ferrex Forte; Ferrogels Forte; Fetrin; FOLTX; Fumatinic; Hem Fe; Hemocyte-F; Icar-C Plus; Livitrinsic-f; Nervidox 6¤; Nervidox¤; Neuro B-12¤; Neurobion¤; Niferex Forte; Nu-Iron Plus¤; Nutra Tear¤; Perihemin¤; Poly-Iron Forte; PremesisRx; Pronemia Hematinic; Tia Doce¤; Tolfrinic; TriHEMIC; Trinsicon; Vita-Feron¤; Venezuela: Autrin; Be-Fosfin; Bedoyecta; Beferron; Briomet; Cianofer; Cobalfer; Deca-Lentermina Complex; Dobetin Compuesto; Fercobre B-12; Fercor; Ferroce con B12; Folifer B-12; Hepafol; Lentermina Complex; Mega-Neubion; Miovit; Neubion; Tres-Be; Tres-Be;


  • kAI BISHOP  2012-08-02

    do you carry Axofor hydroxocobalaimn B1 injeectable? how much are thet? our phone is 2538468684. thank you reply

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