Download Oral versus Injectable Vitamin B12 Supplementation

Title: Oral versus Injectable Vitamin B12 Supplementation: Clinical and CostEffectiveness
Date: November 30, 2007
Context and policy issues:
Vitamin B12 (cobalamin) is essential for the formation of red blood cells and maintaining the
integrity of the nervous system.1 Vitamin B12 deficiency causes megaloblastic anemia, loss of
appetite, mood disturbances, and potentially irreversible neurological complications.1 Vitamin
B12 deficiency has also been linked to an increased risk of myocardial infarction and stroke.1
Vitamin B12 deficiency may be due to poor dietary intake of meat and dairy products and
inadequate absorption as a result of pernicious anemia, gastritis, bariatric surgery, ileal
resection, inflammatory bowel disease, certain drugs (e.g. metformin or proton pump inhibitors),
or food-cobalamin malabsorption (characterized by the inability to release vitamin B12 from food
or from its binding proteins).2 The prevalence of vitamin B12 deficiency is not clear, but the
incidence increases with age.1
In North America, vitamin B12 deficiency is typically treated with intramuscular (IM) injections.3
The dose and duration of therapy is dependent on the severity and cause of deficiency, but
injections every one to three months are usually required.4 Efficacy of therapy is monitored by
the regression of neurological symptoms, levels of vitamin B12 in the blood, and formation of
red blood cells (as indicated by hemoglobin level, the hematocrit, and the mean corpuscular
volume).4 However, there are several drawbacks to IM administration including pain on injection,
difficulty in patients with a tendency to bleed or in very thin patients, and the inconvenience and
cost of frequent visits to health care professionals for injections.3 There is a growing body of
evidence that vitamin B12 administered orally at doses greater than 500 μg may be efficacious
for various types of vitamin B12 deficiency.1,2,5 Furthermore, there is evidence that switching
patients from injection to oral therapy is both feasible and acceptable largely due to increased
convenience.6 Vitamin B12 supplementation has not been associated with any serious adverse
effects as amounts given in excess of need are excreted in the urine.4 Several single ingredient
oral vitamin B12 preparations ranging in dose from 25 μg to 1200 μg are licensed by Health
Canada as over the counter natural health products.7 This report will present the evidence
evaluating the clinical and cost effectiveness of oral versus IM vitamin B12 supplementation.
Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in
Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of
sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS
responses should be considered along with other types of information and health care considerations. The information included in this response is
not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health
technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the
case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While
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Research questions:
1. What is the clinical effectiveness of oral Vitamin B12 supplementation compared to IM
Vitamin B12 supplementation?
2. What is the cost-effectiveness of oral Vitamin B12 supplementation compared to IM Vitamin
B12 supplementation?
Methods:
A limited literature search was conducted on key health technology assessment resources,
including PubMed, the Cochrane Library (Issue 4, 2007), University of York Centre for Reviews
and Dissemination (CRD) databases, ECRI’s HTIS, EuroScan, international HTA agencies, and
a focused Internet search. Results include articles published between 1997 and the present,
and are limited to English language publications only. Search filters were applied to limit the
retrieval to systematic reviews, guidelines, economic studies, and randomized controlled trials.
Internet links to full-text and abstracts are provided, where available. Bibliographies of reports
were scanned to identify other relevant evidence.
Summary of findings:
A Cochrane systematic review published in 2005 was identified.1 The report compared the
clinical effectiveness of oral versus IM vitamin B12 therapy in patients with vitamin B12
deficiency. Studies that included patients with primary folate deficiency, end stage renal
disease, or those receiving treatment for cardiovascular disease were excluded. Meta-analysis
was not performed because of study heterogeneity. Two randomized controlled trials (RCTs)
conducted in outpatient hospital clinics met the inclusion criteria for the review (Table 1).
Findings from the first study indicated statistically higher levels of serum cobalamin in the oral
group at two months (p<0.001) and at four months (p<0.0005) compared with the IM group.8
The groups did not differ significantly in neurological response (improvement or clearing of
parasthaesias, ataxia or memory loss). No timeframe was provided specifying how rapidly
improvement in neurological symptoms occurred. Results from the second trial indicated
significant differences (p<0.001) in serum cobalamin, hemoglobin level and mean corpuscular
volume in both groups of participants from baseline.9 However, statistical analysis for between
group comparisons were not conducted. The authors reported greater tolerability with oral
vitamin B12 therapy but did not indicate how tolerability was evaluated. Improvements in
cognitive function, sensory neuropathy and vibration sense were also reported but differences
between the two groups were not statistically significant. Neither trial reported any adverse
effects with the use of oral or IM vitamin B12 therapy. The studies did not analyze the effect of
the intervention on the quality of life of the participants.
Based on the RCTs identified, the authors of the systematic review concluded that doses
between 1000-2000 μg of oral vitamin B12 therapy may be as effective as IM therapy in
producing hematologic and neurologic responses. However, the length of follow-up in both
trials was insufficient (ranging from 90 days to four months) since the biological half-life of body
stores of vitamin B12 is greater than thirty months.1 Furthermore, neither study was conduced
in a primary care setting where most vitamin B12 deficient patients are treated. There is also
uncertainty regarding the long-term efficacy of oral vitamin B12 therapy in patients with
malabsorption as no patients with inflammatory bowel disease were included in either study.1
Oral vs. Injectable Vitamin B12 Supplementation
2
Table 1: Details of Trials Included in Cochrane Review1
Study
Kuziminski et
al., 19988
Design
RCT, open-label
Participants:
Patients with chronic
atrophic gastritis (17),
pernicious anemia
(7), ileal resection (3),
poor dietary intake
(4), gastric stapling
(1), and omeprazole
therapy(1)
Bolaman et
al., 20039
Intervention:
Oral B12: 2000 μg
once daily
for 120 days
(n=18)
vs.
IM B12: 1000 μg
on days
1,3,7,10,14,21,30,60
and 90
(n=15)
RCT, open-label
Participants:
Patients with
megaloblastic anemia
due to vitamin B12
deficiency
Intervention:
Oral B12*: 1000 μg
once daily for 10
days
(n=26)
vs.
IM B12: 1000μg
daily for 10 days
(n=34)
Followed by both
treatments
administered once a
week for four weeks
then, once a month
indefinitely
Results
Vitamin B12 Level (pg/mL) at 4months:
Oral B12: 1005 ± 595
IM B12: 325 ± 165
(p<0.0005)
Hematocrit (%) at 4 months:
Oral B12: 40.5 ± 2.9
IM B12: 40.6 ± 4.4
(p value not reported)
Limitations
Short follow-up,
small sample size
(5 withdrawals),
method of
randomization not
clearly described,
ITT analysis not
reported.
MCV (fL) at 4 months:
Oral B12: 90 ± 7
IM B12: 91 ± 7
(p value not reported)
Neurologic Improvement at 4 months:
Oral B12: 22.2%
IM B12: 26.7%
(p=NS)
Vitamin B12 Level (pg/mL):
Oral B12:
Day 0: 72.9 ± 54.8 Day 90: 213.8 ± 30.2
(p<0.001)
IM B12:
Day 0: 70.2 ± 59.1 Day 90: 225.5 ± 40.2
(p<0.001)
Short follow-up,
small sample size
(10 withdrawals),
ITT analysis not
reported, authors
did not analyze the
differences
between the oral
and IM groups.
Hemoglobin level(g/dL):
Oral B12:
Day 0: 8.4 ± 2.1 Day 90: 13.8 ± 0.7
(p<0.001)
IM B12:
Day 0: 8.3 ± 2.3 Day 90: 13.7 ± 0.9
(p<0.001)
Mean corpuscular volume(fL):
Oral B12:
Day 0: 112.3 ± 11.4 Day 90: 86.9 ± 3.9
(p<0.001)
IM B12:
Day 0: 114.8 ± 10.9 Day 90: 86.7 ± 4.1
(p<0.001)
RCT=Randomized Controlled Trial, IM=Intramuscular, NS=Non-significant, ITT=Intention-to-treat
* Oral cobalamin was administered as the contents of a 1000 μg ampule mixed with 20 mL of fruit juice
since tablets were not available in Turkey at the time of the study.
Oral vs. Injectable Vitamin B12 Supplementation
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Results from observational trials suggest comparable efficacy of the IM and oral route for
treating vitamin B12 deficiency. A prospective case series of 50 patients with vitamin B12
deficiency in an out-patient setting was conducted to measure the effectiveness, safety and
acceptability of oral vitamin B12 as a replacement therapy.10 Duration of oral therapy ranged
from 3 to 18 months. At the beginning of the study, all patients received 1000 μg of vitamin B12
administered as a IM injection. When the patient’s serum level dropped to lower than 418
pg/mL, they were switched to 1000 μg of oral vitamin B12 daily. Results indicated that oral
therapy was effective maintaining satisfactory serum B12 levels for all patients in the study and
most patients (87%) demonstrated a preference for oral therapy compared with IM injections.
Moreover, there were no significant changes in hemoglobin (p=0.4) or mean corpuscular
volume (p=0.42), and no new neurological complications developed over the study period. This
study did not indicate whether the length of oral vitamin B12 treatment had a significant impact
on the overall clinical outcomes measured.
Another study conducted in a community setting analyzed retrospective data from 60 patients
with vitamin B12 deficiency who were switched from IM to oral therapy.11 The dosing range for
oral vitamin B12 supplementation was not specified. After three years of oral therapy there was
no significant difference in vitamin B12 levels (p=0.62), hemoglobin levels (p=0.67) or mean
corpuscular volume (p=0.44) between IM and oral vitamin B12 supplementation. Two cohort
studies also indicate similar efficacy in correcting serum B12 levels and hematological
abnormalities in patients with food-cobalamin malabsorption.12,13
Economic evaluations:
Two costing studies were retrieved in the search.14,15 The first study estimated the cost savings
that would be achieved if all elderly patients were switched from IM injections to a 1000 μg
tablet.14 A third-party perspective was adopted. Patients over 65 years old who received IM
vitamin B12 during 1995 and 1996 were identified using population-based administrative
databases in Ontario. The cost for each patient included drugs, injections, pharmacists’ fees
and injection-associated physician visits and was estimated in Canadian dollars. Potential
savings to the provincial healthcare system from switching was estimated to be substantial
(between $2.9 and $17.6 million) over five years in Ontario alone, depending on the number of
injection visits avoided.14
Another study conducted in the UK also examined whether savings could be made by changing
patients from IM injections to high doses of oral vitamin B12 in a primary care setting.15 The
dose for oral vitamin B12 supplementation was not reported. The analysis was carried out from
the perspective of the third-party payer but the price year was not defined. Data obtained from a
literature review and expert opinion were used to determine the costs associated with the drug
(including the needle and syringe) and administration (mainly the costs of nursing time). The
cost of the resources used to administer IM vitamin B12 was calculated at between £56 and
£100 per patient per year. Initial conversion costs arising from frequent monitoring (increased
laboratory tests and visits to a health care professional) considerably increased the cost of
switching patients to high-dose oral vitamin B12. Home visits had the highest impact on
conversion costs. These costs were estimated to be between £126 and £249 but were only
applicable during the first year, and were not necessary in newly diagnosed patients started on
oral treatment from the outset. However, once patients receiving IM treatment had been
converted to oral treatment, or in new patients treated orally from the outset, the cost was £36
per patient per year. These savings were mainly the result of a decrease in nursing time
required with oral therapy. These results suggest that switching patients from IM to oral therapy
and treating newly diagnosed patients with oral vitamin B12 from the outset could save health
care resources in the long term.
Oral vs. Injectable Vitamin B12 Supplementation
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Guidelines:
Guidelines from the British Columbia Medical Association (2003) recommend that oral
supplementation of vitamin B12 is the treatment of choice in most cases including pernicious
anemia.16
However, the guidelines state that in patients with significant neurological
complications IM injections at a dose of 1000 μg should be used to help prevent irreversible
complications followed by oral doses of 1000-2000 μg per day.16
Conclusions and implications for decision or policy making:
Overall, evidence to suggest that oral supplementation may be as effective as IM therapy for
vitamin B12 deficiency is limited. Results from economic evaluations suggest that potential
savings made by switching patients from IM to oral vitamin B12 could be substantial but may not
be realized immediately due to high conversion costs. Although oral therapy is more
convenient, symptoms and laboratory measurements would need to be monitored closely,
especially during the first months of therapy to ensure efficacy and compliance. IM
administration is more appropriate for patients unable to take medications by mouth, those
presenting with severe neurological symptoms, and when compliance to a daily dosage regimen
is a concern. 16 Caution is particularly warranted when using timed-release preparations (whose
dissolution can take up to 6 hours) when prompt treatment is required to prevent progressive,
irreversible neurologic and cognitive impairment.17
Further research is needed to confirm long-term efficacy for clinically important outcomes,
dosing and treatment duration for different causes of deficiency, and economic benefit of oral
vitamin B12 supplemenation in order to help establish guidelines for use in primary care
settings.11,18
Prepared by:
Sarah Ndegwa, BScPharm, Research Officer
Kelly Farrah, MLIS, Information Specialist
Health Technology Inquiry Service (HTIS)
E-mail: [email protected]
Toll free phone: 1-866-898-8439
Oral vs. Injectable Vitamin B12 Supplementation
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References:
1. Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, Hood K, McCaddon A, et al. Oral
vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane
Database Syst Rev 2005;(3):CD004655. Available:
http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004655/pdf_fs.html
(accessed 2007 Nov 22).
2. Andrès E, Vidal-Alaball J, Federici L, Loukili NH, Zimmer J, Kaltenbach G. Clinical aspects
of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations,
and treatment with special focus on oral cobalamin therapy. Eur J Intern Med
2007;18(6):456-62.
3. Graham ID, Jette N, Tetroe J, Robinson N, Milne S, Mitchell SL. Oral cobalamin remains
medicine's best kept secret. Arch Gerontol Geriatr 2007;44(1):49-59.
4. Schrier SL. Diagnosis and treatment of vitamin B12 and folic acid deficiency. In: UpToDate
[database online]. Version 15.1. Waltham (MD): UpToDate; 2007.
5. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, et al. Oral
cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dosefinding trial. Arch Intern Med 2005;165(10):1167-72.
6. Kwong JC, Carr D, Dhalla IA, Tom-Kun D, Upshur RE. Oral vitamin B12 therapy in the
primary care setting: a qualitative and quantitative study of patient perspectives. BMC Fam
Pract 2005;6(1):8. Available: http://www.biomedcentral.com/content/pdf/1471-2296-6-8.pdf
(accessed 2007 Nov 22).
7. List of licensed natural health products. In: Drug and health products [web site]. Ottawa:
Health Canada; 2007. Available: http://www.hc-sc.gc.ca/dhpmps/prodnatur/applications/licen-prod/lists/listapprnhp-listeapprpsn_e.html#V (accessed
2007 Nov 22).
8. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of
cobalamin deficiency with oral cobalamin. Blood 1998;92(4):1191-8. Available:
http://www.bloodjournal.org/cgi/reprint/92/4/1191 (accessed 2007 Nov 22).
9. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T. Oral versus
intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective,
randomized, open-label study. Clin Ther 2003;25(12):3124-34.
10. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S, Nightingale P, et al. Oral vitamin
B12 can change our practice. Postgrad Med J 2003;79(930):218-20.
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12. Andrès E, Perrin AE, Demangeat C, Kurtz JE, Vinzio S, Grunenberger F, et al. The
syndrome of food-cobalamin malabsorption revisited in a department of internal medicine.
A monocentric cohort study of 80 patients. Eur J Intern Med 2003;14(4):221-6.
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13. Andrès E, Affenberger S, Zimmer J, Vinzio S, Grosu D, Pistol G, et al. Current
hematological findings in cobalamin deficiency. A study of 201 consecutive patients with
documented cobalamin deficiency. Clin Lab Haematol 2006;28(1):50-6.
14. van Walraven C, Austin P, Naylor CD. Vitamin B12 injections versus oral supplements.
How much money could be saved by switching from injections to pills? Can Fam Physician
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B
16. Guidelines and Protocols Advisory Committee. B12 deficiency - investigation &
management of vitamin B12 and folate deficiency. Victoria: The Committee; 2006.
Available: http://www.health.gov.bc.ca/gpac/pdf/b12.pdf (accessed 2007 Nov 2).
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18. Andrès E, Noel E, Kaltenbach G. Comment: treatment of vitamin B12 deficiency anemia:
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