Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

symptomatic

1st line – parenteral cyanocobalamin or hydroxocobalamin

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ACUTE
|
symptomatic
|
severe symptoms
1st line – 

parenteral cyanocobalamin or hydroxocobalamin

Patients with severe hematologic (pancytopenia and marked symptomatic anemia) or neurologic (subacute combined spinal degeneration, dementia, or cognitive impairment) symptoms of vitamin B12 deficiency require hospital admission and acute and urgent treatment.[108]

An acute regimen of parenteral cyanocobalamin is given daily for 1-2 weeks, and then once a week for up to 1 month, until significant reticulocytosis is seen in the marrow.[109]

Brisk bone marrow reticulocytosis can be measured in 1-2 weeks as a response to treatment. Other markers of deficiency, including methylmalonic acid, homocysteine, and mean corpuscular volume, should normalize in 8 weeks with adequate treatment.

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms intramuscularly/subcutaneously once daily for 1-2 weeks, followed by 1000 micrograms once weekly for 1 month

OR

hydroxocobalamin: 1000 micrograms intramuscularly three times weekly for 2 weeks, followed by 1000 micrograms once every 3 months

Plus – referral to neurologist and/or hematologist

Back
ACUTE
|
symptomatic
|
severe symptoms
Plus – 

referral to neurologist and/or hematologist

Treatment recommended for ALL patients in selected patient group

Patients with severe neurologic symptoms may require neurologic and psychogeriatric referral and evaluation while commencing the acute parenteral treatment regimen. Unfortunately, neurologic disease associated with vitamin B12 deficiency may be irreversible, despite adequate therapy.[79][80]

Patients with symptomatic anemia and pancytopenia require hospital admission and hematologic specialist referral.

Pregnant women should be managed in consultation with their obstetrician.

Consider – blood transfusion ± low-dose diuretic

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ACUTE
|
symptomatic
|
severe symptoms
Consider – 

blood transfusion ± low-dose diuretic

Treatment recommended for SOME patients in selected patient group

Patients with symptomatic anemia and pancytopenia require hospital admission and hematologic specialist referral and, rarely, may require red blood cell (RBC) transfusion.

If there are signs of congestive cardiac failure, cardiac monitoring is advised and packed RBCs should be given together with low-dose diuretic therapy.

Diuretics should generally be avoided in pregnancy unless the benefits outweigh the risks, and only under specialist guidance.

Primary options

bumetanide: 0.5 to 2 mg orally/intravenously once or twice daily initially, increase according to response, maximum 10 mg/day

Consider – oral folic acid

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ACUTE
|
symptomatic
|
severe symptoms
Consider – 

oral folic acid

Treatment recommended for SOME patients in selected patient group

Folate supplementation can help reverse the hematologic abnormalities.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

Plus – lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Back
ACUTE
|
symptomatic
|
severe symptoms
Plus – 

lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Treatment recommended for ALL patients in selected patient group

Most patients with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin.

Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. Parenteral cyanocobalamin may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[120]

Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[121] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[122][123][124]

Absorption can be maximized by administration on an empty stomach.

Patients treated with oral cyanocobalamin should respond within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms orally once daily

Secondary options

cyanocobalamin (vitamin B12): 1000 micrograms intramuscularly/subcutaneously once monthly

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

1st line – oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Back
ACUTE
|
symptomatic
|
mild to moderate symptoms
1st line – 

oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Treatment of patients with mild to moderate symptoms of vitamin B12 deficiency (e.g., mild anemia, dysesthesia/paresthesias, polyneuropathy, depression) is with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin, depending on clinician preference.

Patients treated with oral cyanocobalamin should respond within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms orally once daily; 1000 micrograms intramuscularly/subcutaneously once monthly

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

Plus – lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Back
ACUTE
|
symptomatic
|
mild to moderate symptoms
Plus – 

lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Treatment recommended for ALL patients in selected patient group

Most patients with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin.

Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. Parenteral cyanocobalamin may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[120]

Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[121] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[122][123][124]

Absorption can be maximized by administration on an empty stomach.

Patients treated with oral cyanocobalamin should respond within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms orally once daily

Secondary options

cyanocobalamin (vitamin B12): 1000 micrograms intramuscularly/subcutaneously once monthly

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

asymptomatic or borderline deficiency

1st line – dietary supplementation + multivitamins

Back
ACUTE
|
asymptomatic or borderline deficiency
|
patients aged >65 years with poor diet
1st line – 

dietary supplementation + multivitamins

Older patients who present with clinical features of deficiency may have vitamin B12 levels within the reference range. Conversely, low serum vitamin B12 (<200 picograms/mL) may not be associated with symptoms.

Dietary advice should be given on the importance of eating animal-derived foods (such as meat, fish, eggs, and milk), and taking vitamin B12-containing supplements.

Combined diet and vitamin B12-containing supplements should meet the recommended dietary allowance of 2.4 micrograms/day.[72]

2nd line – lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Back
ACUTE
|
asymptomatic or borderline deficiency
|
patients aged >65 years with poor diet
2nd line – 

lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

If diet and vitamin B12-containing supplements do not help, or if the diet cannot be improved, cyanocobalamin treatment is advised.

Most patients with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin.

Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to high-dose oral therapy. Parenteral cyanocobalamin may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[120]

Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[121] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[122][123][124]

Absorption can be maximized by administration on an empty stomach.

Patients treated with oral cyanocobalamin should respond within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms orally once daily

Secondary options

cyanocobalamin (vitamin B12): 1000 micrograms intramuscularly/subcutaneously once monthly

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

1st line – dietary supplementation + multivitamins

Back
ACUTE
|
asymptomatic or borderline deficiency
|
vegan or strict vegetarian diet
1st line – 

dietary supplementation + multivitamins

Vegans or strict vegetarians should be counseled to supplement their diet with appropriate vitamin B12-fortified foods and supplements containing vitamin B12 in order to meet the recommended dietary allowance of 2.4 micrograms/day.[72][111]

Pregnant and breastfeeding women who have a strict vegetarian or vegan diet should be counseled about adequate intake of vitamin B12 and supplementation.[125]​ Breastfeeding women who adhere to a vegan diet will only provide adequate vitamin B12 for her infant if the mother satisfies vitamin B12 requirements through supplementation.[119]

2nd line – lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Back
ACUTE
|
asymptomatic or borderline deficiency
|
vegan or strict vegetarian diet
2nd line – 

lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin

Lifelong maintenance treatment with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin is advised.

Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. Parenteral cyanocobalamin may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[120]

Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[121] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[122][123][124]

Absorption can be maximized by administration on an empty stomach.

Patients treated with oral cyanocobalamin should respond within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms orally once daily

Secondary options

cyanocobalamin (vitamin B12): 1000 micrograms intramuscularly/subcutaneously once monthly

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

1st line – parenteral or oral cyanocobalamin or hydroxocobalamin

Back
ACUTE
|
asymptomatic or borderline deficiency
|
with chronic gastrointestinal illness
1st line – 

parenteral or oral cyanocobalamin or hydroxocobalamin

Patients with a chronic gastrointestinal (GI) illness at high risk of vitamin B12 deficiency (e.g., extensive ileal disease, ileal surgery) should be monitored annually for vitamin B12 deficiency.[112][113]

Patients with a chronic GI illness that can cause malabsorption or inadequate absorption (e.g., pernicious anemia, Crohn disease with more than 20 cm of terminal ileum resected, celiac disease) or who have undergone gastric surgery or terminal ileectomy, may be treated with parenteral or oral cyanocobalamin.[1][114]​ Guidelines recommend parenteral administration, based on expert opinion.[114]

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]

Primary options

cyanocobalamin (vitamin B12): 1000 micrograms intramuscularly/subcutaneously once monthly; 1000 micrograms orally once daily

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

1st line – oral, parenteral, or intranasal cyanocobalamin or parenteral hydroxocobalamin

Back
ACUTE
|
asymptomatic or borderline deficiency
|
after bariatric surgery
1st line – 

oral, parenteral, or intranasal cyanocobalamin or parenteral hydroxocobalamin

Patients who have had bariatric surgery may not be able to adequately maintain serum vitamin B12 levels with vitamin B12-containing supplements.​[115]​​ US guidance recommends oral, parenteral, or intranasal cyanocobalamin to prevent deficiency.[94]​ European guidance recommends vitamin B12 supplementation in addition to multivitamins.[116]

An oral multivitamin supplement optimized for bariatric surgery has shown potential benefit in reducing vitamin deficiencies following Roux-en-Y gastric bypass surgery, but the evidence is limited.[117]

In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.

Self-administration of vitamin B12 by intramuscular injection may be appropriate in some patients, and can lead to improved patient satisfaction and health outcomes.[80]​ 

Primary options

cyanocobalamin (vitamin B12): 350-1000 micrograms orally once daily; or 1000 micrograms intramuscularly/subcutaneously once monthly; or 3000 micrograms intramuscularly/subcutaneously every 6 months; or 500 micrograms intranasally once weekly

OR

hydroxocobalamin: 1000 micrograms intramuscularly once every 3 months

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer