What is the recommended vitamin B12 (cobalamin) replacement regimen, including dose, route (oral versus intramuscular), schedule, and monitoring, for patients with confirmed or suspected deficiency such as older adults, vegans, those with pernicious anemia, malabsorptive gastrointestinal disease, chronic proton‑pump inhibitor use, or post‑bariatric surgery?

Vitamin B12 Replacement Regimen

Direct Recommendation by Clinical Scenario

For patients with confirmed B12 deficiency and neurological symptoms (paresthesias, neuropathy, cognitive changes, gait disturbance, glossitis), administer hydroxocobalamin 1 mg intramuscularly on alternate days until neurological improvement plateaus, then transition to 1 mg intramuscularly every 2 months for life. 1, 2, 3, 4

For patients with confirmed B12 deficiency without neurological involvement, give hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, followed by maintenance of 1 mg intramuscularly every 2–3 months lifelong. 1, 2, 3

For post-bariatric surgery patients (sleeve gastrectomy, Roux-en-Y gastric bypass, or malabsorptive procedures), initiate routine prophylactic hydroxocobalamin 1 mg intramuscularly every 3 months indefinitely, regardless of documented deficiency. 1, 2

---

Route Selection: Intramuscular vs Oral

Intramuscular therapy is mandatory for:

• Pernicious anemia (intrinsic factor deficiency) 5
• Post-bariatric surgery (especially RYGB, BPD/DS) 1, 2
• Ileal resection >20 cm 2, 3
• Severe neurological involvement 1, 2
• Patients requiring rapid correction 1

High-dose oral therapy (1000–2000 mcg daily) is acceptable for:

• Dietary insufficiency (vegans, vegetarians) 6, 7
• Food-cobalamin malabsorption 7
• Patients refusing injections without severe neurological symptoms 8, 7

The oral route achieves equivalent biochemical correction in most malabsorption states, but intramuscular administration produces faster clinical improvement and remains the guideline standard for pernicious anemia and neurological disease. 8, 7

---

Formulation Selection

Hydroxocobalamin is the preferred injectable form because it has superior tissue retention, established dosing protocols across all major guidelines, and avoids cyanide metabolism. 2, 3

Avoid cyanocobalamin in patients with renal dysfunction (eGFR <50 mL/min) because the cyanide moiety requires renal clearance and doubles cardiovascular event risk (hazard ratio 2.0) in diabetic nephropathy. 2, 4

Use methylcobalamin or hydroxocobalamin instead of cyanocobalamin when:

• Estimated GFR <50 mL/min 2, 4
• Diabetic nephropathy is present 2
• Chronic kidney disease exists 2

For patients with normal renal function, cyanocobalamin is acceptable but hydroxocobalamin remains guideline-preferred for intramuscular maintenance. 2, 5

---

Dosing Schedules by Population

Pernicious Anemia

• Initial: Hydroxocobalamin 1 mg IM three times weekly × 2 weeks 1, 3
• Maintenance: 1 mg IM every 2–3 months for life 1, 2, 3
• FDA-labeled cyanocobalamin alternative: 100 mcg IM daily × 6–7 days, then alternate days × 7 doses, then every 3–4 days × 2–3 weeks, then 100 mcg monthly for life 5

Post-Bariatric Surgery

• Prophylactic: Hydroxocobalamin 1 mg IM every 3 months indefinitely 1, 2
• Alternative oral: 1000–2000 mcg daily 2, 6
• Pregnancy monitoring: Check B12 every 3 months throughout gestation 2, 3

Ileal Resection or Crohn's Disease

• Resection >20 cm: Hydroxocobalamin 1 mg IM monthly for life 2, 3
• Ileal involvement >30–60 cm without resection: Annual screening; prophylactic supplementation if deficiency develops 2, 3

Chronic PPI or Metformin Use

• Screen after >4 months metformin or >12 months PPI use 6
• If deficient: Treat per neurological involvement protocol above 1, 3
• Consider prophylactic oral 1000 mcg daily in high-risk elderly on chronic PPIs 6

Older Adults (>75 years)

• Screen for deficiency 6
• If deficient: Treat per neurological involvement protocol 1, 3
• Prophylactic oral 1000 mcg daily is reasonable for those >50 years with risk factors 6

Vegans and Strict Vegetarians

• Prophylactic oral 1000 mcg daily or foods fortified with B12 6
• If deficient: High-dose oral 1000–2000 mcg daily is effective 6, 7

---

Monitoring Strategy

Initial phase (first year):

• Serum B12 at 3,6, and 12 months after starting therapy 2, 3
• Complete blood count at each visit to assess resolution of macrocytosis 2
• Methylmalonic acid (MMA) if B12 remains borderline (target <271 nmol/L) 2, 3
• Homocysteine targeting <10 μmol/L for optimal outcomes 2, 3

Maintenance phase (after stabilization):

• Annual serum B12 and homocysteine 2, 3
• Iron studies (ferritin, transferrin saturation) at every visit, as iron deficiency frequently coexists 2

Post-bariatric surgery patients:

• B12 every 3 months if planning pregnancy 2
• Additional micronutrients (vitamin D ≥75 nmol/L, thiamine, calcium, vitamin A) every 6 months 2

High-risk populations (ileal disease, post-surgery):

• Annual screening even if asymptomatic 2, 3

---

Critical Pitfalls to Avoid

Never administer folic acid before correcting B12 deficiency. Folic acid masks megaloblastic anemia while allowing irreversible subacute combined degeneration of the spinal cord to progress. 1, 2, 3, 4 Once B12 is repleted, add folic acid 5 mg daily only if folate deficiency is documented. 1

Do not discontinue therapy when symptoms resolve or B12 levels normalize in patients with permanent malabsorption (pernicious anemia, post-bariatric surgery, ileal resection >20 cm). These patients require lifelong supplementation. 2, 3

Do not assume one normal B12 result means cure. Patients with malabsorption relapse without ongoing therapy; continue monitoring annually. 2, 3

Recognize that neurological damage can become irreversible if undertreated. Aggressive alternate-day dosing is mandatory when neurological symptoms are present. 1, 2, 4

In thrombocytopenia, do not withhold IM injections. Use smaller gauge needles (25–27G) and apply prolonged pressure (5–10 minutes) for platelet counts 25–50 × 10⁹/L; consider platelet transfusion support if <10 × 10⁹/L. 2

Avoid the buttock as an injection site due to sciatic nerve injury risk; if used, inject only the upper outer quadrant with the needle directed anteriorly. 2

---

Special Considerations

Renal dysfunction: Methylcobalamin or hydroxocobalamin are safer than cyanocobalamin because they avoid cyanide accumulation and associated cardiovascular risk. 2, 4

Pregnancy after bariatric surgery: Measure B12 each trimester; do not start high-dose folic acid (5 mg) until B12 adequacy is confirmed. 2

Neurological symptoms persisting despite normal B12: Measure MMA (target <271 nmol/L) and homocysteine (target <10 μmol/L) to confirm functional adequacy; consider increasing injection frequency to monthly. 2, 3

Concomitant folate deficiency: Treat B12 first, then add folic acid 5 mg daily for ≥4 months. 1

Unexplained anemia or fatigue despite B12 correction: Investigate protein, zinc, copper, selenium, and iron deficiency. 1, 2