How we wish to be cited:
Nilsson M. Safe dosage of oral vitamin B12 – verdict confirms present documentation [editorial]. Rondel 2005; 23. URL: http://www.rondellen.net

The intense debate on correct indications and correct dosage of oral vitamin B12 therapy has stormed in The Rondel (Table 1) and in The Journal of the Swedish Medical Association (Läkartidningen 2005; 102:1160-62, 1459-60, 1509,51837-8) for a year. The legal decision on the marketing of TrioBe by Recip AB was made by verdict No 720/05 of the regulatory authority (1). The company was found guilty of marketing their preparation outside approved indications and documentation (1). Mats Nilsson (publisher15_eng.htm), statistician with a special interest in Swedish cobalamin communication, finalizes the discussion.

Previous contributions to the debate.

1. Rosenberg P, Hernborg A, Håkansson J, Skoglund I, Svartholm R, Söderström U, Wahlström L. B vitamins and dementia – lack of evidence in Cochrane analysis [debate]. Rondel 2004; 19. URL: http://www.rondellen.net/debate19_eng.htm
2. Norberg B. Cobalamin and folate for better and worse [editorial]. Rondel 2004; 20. URL: http://www.rondellen.net/publisher20_eng.htm
3. Norberg B. Safety and reliability of oral cobalamin [editorial]. Rondel 2004; 21. URL: http://www.rondellen.net/publisher21_eng.htm
4. Nilsson-Ehle H. High homocysteine – prophylaxis and treatment [debate]. Rondel 2004; 21. URL: http://www.rondellen.net/debate21_eng.htm
5. Jansson J-H. Hypothesis on shaky pillars –homocysteine and vascular disease [evaluation]. Rondel 2004; 21. URL: http://www.rondellen.net/evaluation21_eng.htm
6. Norberg B. Treatment of vitamin B12 deficiency – documentation of oral cyanocobalamin [editorial]. Rondel 2005; 22. URL: http://www.rondellen.net/publisher22_eng.htm
7. Lindgren A. Deficiency of cobalamin and folate – current knowledge about diagnosis and treatment [health]. Rondel 2005; 22. URL: http://www.rondellen.net/health22_eng.htm
8. Nilsson-Ehle H. Reply: Treatment of vitamin B12 deficiency – documentation of oral cyanocobalamin [debate]. Rondel 2005; 22. URL: http://www.rondellen.net/debate22_eng.htm

Oral cyanocobalamin, 1 mg daily, was registered in Sweden Nov 25, 1964, brand Behepan (2, 3). The second brand (Betolvex) was registered 1983 in Denmark and Sweden. These brands represent the bulk of oral high-dose cobalamin in the world. For historical reasons, Behepan has dominated with approximately 80% of the market in the period 1964-2000 (4). By now, there are four brands of oral cyanocobalamin, 1 mg, on the Swedish market. The indication is prophylaxis and treatment of B12 deficiency. Remission dosage is 2 mg twice daily during the first month of therapy. The maintenance dosage is 1-2 mg daily.

During the period 1998-2004, some operators on the B12 market have asserted that oral cyanocobalamin, 0.5 mg daily, is sufficient for treatment of B12 deficiency (Table 1). The legal aspects of this claim were elucidated by the verdict of the regulatory authority May 6, 2005 (1). Recip AB was found guilty of marketing TrioBe with non-approved indications, non-approved dosage, and non-documented and insidious teaching on under-treatment of B vitamin deficiency and its consequence (1).

As an independent "expert", I was asked to analyze the basic documentation (2, 3) on oral cyanocobalamin, 0.5 and 1 mg, half a year ago. The texts have to be interpreted with due regard to time and context. The Berlin group wrote two reports on mainly the same patients (2, 3). Tables and figures suggest that at least 5, at most 12 patients (n=64) had been switched from 0.5 mg cyanocobalamin daily to 1 mg daily, when Behepan was registered 1964. In case there is a more exact answer to the question, we - my co-workers and me - will try to find it.

During the period 1950-1965, clinical researchers used oral B12 preparations lower than 1 mg daily; the trials led to frequent relapses of deficiency symptoms (2, 3). It is reasonable to assume that this experience produced the scepsis against oral cobalamin therapy still found wide over the wold. However, the Berlin trial gained in confidence among physicians and patients. The Swedish experience with oral cyanocobalamin, 1 mg daily, was approximately 1 million patient years in the period 1990-2000 (4). From about 1990, B vitamin combinations with lower content of cobalamin were tried for homocysteine lowering. The effect on morbidity and mortality is now challenged (Table 1, e). The latest turn of tide is cobalamin dosage, 1-2 mg daily (5-9). Thus, the play is back on square one.

Previous debate is summarized in Table 1. It is obvious that some participants are closer to truth than others. The verdict of the regulatory authority closes the case (1). It is reasonable to assume that the past debate of Sweden is the future debate of the world.

1. NBL verdict No. 720/05 (pdf)
2. Berlin H, Berlin R, Brante G. Peroral behandling av perniciös anemi med höga doser vitamin B12 utan intrinsic factor. Läkartidningen 1965; 62:773-81
3. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand 1968; 184:247-58
4. Nilsson M. Cobalamin communication in Sweden 1990-2000. Views, knowledge, and practice among Swedish physicians. Dissertation, Umeå University 2005
5. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1191-8
6. Nilsson K, Gustafson L, Hultberg B. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. Internat J Geriatr Psychiatry 2001; 16:609-14
7. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S, Nightingale P, et al. Oral vitamin B12 can change our practice. Postgraduate Medical Journal 2003;79(930):218-9
8. Sato Y, Honda Y, Iwamotu J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke. A randomized controlled trial. JAMA 2005; 293:1082-8
9. Eussen SJPM, Groot LCPG, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency. A dose-finding trial. Arch Intern Med 2005; 165:1167-72

Published June 20, 2005