Vitamin B12

Introduction Overview

Generic Name

Vitamin B12

Brand Name

Nascobal

Dosage Form

Oral tablets, intranasal spray, intramuscular injection, subcutaneous injection, intravenous infusion

Drug Class

Vitamin B Complex

Pharmacokinetics

Absorption:
Vitamin B12 is irregularly absorbed in the distal small intestine after oral administration due to its reliance on intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells, for efficient active absorption. Only a small percentage of orally administered vitamin B12 is absorbed via passive diffusion independently of IF. Parenteral administration bypasses gastrointestinal absorption, with hydroxocobalamin absorbed more slowly than cyanocobalamin when given intramuscularly (IM) or subcutaneously (sub-Q). The bioavailability of cyanocobalamin nasal spray is approximately 6.1% compared to IM administration. Absorption can be impaired in conditions causing lack of IF (such as pernicious anemia), gastrointestinal surgery, or malabsorption syndromes. Clinical implication includes the necessity for parenteral administration in individuals with absorption defects.

Distribution:
Vitamin B12 distributes extensively into body tissues, particularly accumulating in the liver, bone marrow, and other tissues. It crosses the placenta, supporting fetal development, and is secreted into human milk, which is vital for nourishing breastfed infants. The vitamin binds to transcobalamin II for cellular uptake and transport. It is stored predominantly in the liver, with body stores sufficient to delay deficiency for several years under normal circumstances. Distribution kinetics are important for maintaining adequate hematologic and neurologic function.

Metabolism:
Vitamin B12 undergoes minimal metabolic transformation; its primary forms in the body are methylcobalamin and adenosylcobalamin, which function as cofactors for critical enzymatic reactions in DNA synthesis and fatty acid metabolism. Exogenously administered cyanocobalamin and hydroxocobalamin are converted intracellularly into active coenzyme forms. Hydroxocobalamin also acts as a cyanide scavenger by binding cyanide to form cyanocobalamin, which is subsequently excreted. Enzymatic conversion is essential for the vitamin's role in erythropoiesis and neurological function. Metabolic activity is influenced by physiological status, the form of vitamin B12 administered, and patient-specific factors.

Elimination:
Vitamin B12 is primarily eliminated via renal excretion, with 50–98% of administered vitamin excreted unchanged in urine. Hepatobiliary recycling through enterohepatic circulation aids in conservation of the vitamin. Clinical elimination rates can vary with renal function; accumulation occurs in impaired renal function but toxicity is rare. Hydroxocobalamin’s ability to form cyanocobalamin facilitates detoxification of cyanide and subsequent urinary excretion. The elimination profile guides dosing intervals, particularly in deficiency states and cyanide poisoning management.

Dosage Forms

Available Dosage Forms:
- Intranasal Spray: Metered-dose pump delivering 500 mcg per actuation (Brand name: Nascobal; contains benzalkonium chloride preservative).
- Parenteral Injection: Hydroxocobalamin for injection (2.5 g vial; Brand name: Cyanokit) administered intramuscularly or intravenously.
- Oral formulations (commonly available but not specified in strengths here): tablets and capsules.

Dosages for Adults and Adolescents:
- Vitamin B12 Deficiency:
- Cyanocobalamin IM/Sub-Q: Initial dosage is 100 mcg daily for 6–7 days; if improvement, then 100 mcg every other day for 7 doses, followed by 100 mcg every 3–4 days for 2–3 weeks. Maintenance dosing is 100 mcg monthly.
- Hydroxocobalamin IM: Initial 30 mcg daily for 5–10 days, maintenance 100–200 mcg monthly.
- Intranasal cyanocobalamin: 500 mcg once weekly; dose adjustment may be needed based on serum levels.
- Cyanide Poisoning (off-label): Hydroxocobalamin IV infusion of 5 g initially, with a potential second 5-g dose based on clinical response.

Dosages for Pediatric Patients:
- Vitamin B12 Deficiency:
- Hydroxocobalamin IM: 100 mcg initial single doses totaling 1–5 mg over ≥2 weeks; maintenance 30–50 mcg every 4 weeks.
- Dietary and Replacement Requirements:
- Oral administration for infants born to vegan mothers (AI from birth).
- Infants ≤6 months: AI 0.4 mcg daily.
- Infants 7–12 months: AI 0.5 mcg daily.
- Children 1–3 years: RDA 0.9 mcg daily.
- Children 4–8 years: RDA 1.2 mcg daily.
- Children 9–13 years: RDA 1.8 mcg daily.
- Children 14–18 years: RDA 2.4 mcg daily.

Specific Patient Populations:
- Pregnant Women: RDA 2.6 mcg daily.
- Lactating Women: RDA 2.8 mcg daily, increased to ensure adequate milk concentrations.
- Geriatric Patients: Same dosing as adults; absorption may be impaired necessitating fortified foods or supplements.
- Patients with malabsorption syndromes require parenteral administration as RDAs are insufficient.

Additional Notes:
- Oral cyanocobalamin is less effective than parenteral routes for treating deficiency due to absorption limitations.
- Hydroxocobalamin is preferred for initial treatment and cyanide poisoning.
- Nasal spray should be administered at least 1 hour before or after hot foods/liquids; efficiency reduced with nasal congestion or rhinitis.

Mechanism Of Action

Vitamin B12 functions as a crucial cofactor in enzymatic reactions essential for nucleoprotein synthesis and myelin formation, which are fundamental for DNA synthesis, cell reproduction, and neurologic function. Its bioactive forms, methylcobalamin and adenosylcobalamin, participate in two major enzymatic pathways: methylmalonyl-CoA mutase and methionine synthase. Methionine synthase catalyzes the conversion of homocysteine to methionine, essential for methylation reactions and DNA synthesis, while methylmalonyl-CoA mutase converts methylmalonyl-CoA to succinyl-CoA, a critical step in fatty acid and energy metabolism.

Cellular uptake is mediated by intrinsic factor-dependent absorption in the ileum, followed by transport bound to transcobalamin II, facilitating cellular internalization. Once inside cells, vitamin B12 acts as a coenzyme facilitating nucleic acid synthesis and myelin sheath maintenance, crucial to hematopoiesis and nervous system integrity.

Hydroxocobalamin has an additional mechanism when used in cyanide poisoning; it binds to cyanide ions with high affinity, rapidly forming cyanocobalamin which is non-toxic and excreted via the kidneys, thus detoxifying cyanide and preventing mitochondrial cytochrome oxidase inhibition that leads to cellular hypoxia.

Compared to other B vitamins, vitamin B12 uniquely requires intrinsic factor for absorption and is distinctive in its cobalt central atom, essential for its biochemical functions. Clinical studies have underscored its importance in preventing megaloblastic anemia, neuropathy, and supporting metabolic pathways necessary for neurodevelopment and erythropoiesis. Deficiency disrupts these pathways leading to ineffective DNA synthesis, resultant anemia, and neurologic symptoms. Therapeutic administration replenishes stores, restores biochemical function, and reverses deficiency-related clinical manifestations.

Pharmacological Actions

Serves as an essential cofactor for enzymes involved in nucleic acid synthesis and methylation reactions.
Facilitates conversion of homocysteine to methionine, critical for DNA methylation and synthesis.
Supports conversion of methylmalonyl-CoA to succinyl-CoA, integral to fatty acid metabolism and energy production.
Maintains integrity of the myelin sheath and proper neurologic function.
Exogenous administration corrects deficiencies causing megaloblastic anemia and neurologic impairments.
Hydroxocobalamin binds cyanide ions to form cyanocobalamin, enabling renal excretion and detoxification.
Enhances erythropoiesis by supporting DNA synthesis in hematopoietic cells.
Parenteral formulations bypass GI absorption barriers ensuring bioavailability in malabsorption syndromes.
May improve neurological symptoms related to vitamin B12 deficiency when administered adequately.
Nasal spray formulation supports maintenance therapy in stable patients with pernicious anemia.

Therapeutic Or Clinical Uses

Treatment of pernicious anemia and other vitamin B12 deficiency states.
Management of vitamin B12 deficiency due to inadequate intrinsic factor secretion, impaired absorption, or dietary deficiency.
Maintenance treatment of adults with pernicious anemia without nervous system involvement using nasal spray.
Supplementation in individuals with dietary deficiency, including strict vegetarians and breastfed infants of vegan mothers.
Management of hereditary transcobalamin II deficiency.
Use as an antidote for cyanide poisoning via hydroxocobalamin administration.
Supportive treatment during Schilling test for assessing vitamin B12 absorption.
Preventative supplementation in elderly individuals with impaired absorption.
Replacement therapy during pregnancy and lactation to prevent neonatal deficiency.
Off-label use for acute cyanide toxicity following smoke inhalation or industrial exposure.

Side Or Adverse Effects

Mild transient diarrhea following large or parenteral doses.
Peripheral vascular thrombosis reported in rare cases.
Pruritus and transient exanthema (skin rash) and urticaria.
Body swelling in some patients receiving parenteral preparations.
Anaphylaxis and hypersensitivity reactions, especially with parenteral administration.
Hydroxocobalamin-associated rash, mainly acneiform, in 20–44% of high-dose recipients.
Transient elevations in blood pressure during intravenous hydroxocobalamin infusion.
Red discoloration of skin lasting up to 2 weeks post-injection.
Red or reddish-brown discoloration of urine lasting up to 5 weeks.
Potential hypokalemia during intensive treatment of megaloblastic anemia due to increased erythropoiesis.
Rare reports of rapid optic nerve atrophy in patients with early Leber's hereditary optic neuropathy.
Benzyl alcohol preservative toxicity ('gasping syndrome') risk in neonates receiving certain formulations.
Local injection site reactions may occur with intramuscular or subcutaneous administration.

Precautions

Monitor serum potassium closely during early phases of intensive vitamin B12 therapy to prevent fatal hypokalemia.
Administer intradermal sensitivity testing prior to parenteral administration in patients suspected of cobalt or vitamin B12 hypersensitivity.
Exercise caution in patients with polycythemia vera as vitamin B12 therapy may unmask the condition.
Avoid use in patients with early Leber’s disease due to risk of optic nerve atrophy.
Monitor hematologic parameters including hematocrit, reticulocyte count, and vitamin B12 levels prior to and during therapy.
Use with caution in patients with impaired renal function due to aluminum content in some injection formulations and risk of aluminum toxicity.
Avoid formulations containing benzyl alcohol in neonates and monitor for toxicity.
Advise patients receiving intranasal spray to avoid use during nasal congestion or upper respiratory infections.
Advise patients on intranasal therapy to administer doses at least 1 hour before or after hot liquids or foods.
Monitor blood pressure during intravenous hydroxocobalamin administration due to transient hypertension risk.
In patients receiving folic acid, exercise caution as folate can mask hematologic manifestations of vitamin B12 deficiency but not neurologic damage.
Pregnant and lactating women should ensure adequate vitamin B12 intake to prevent deficiency in mother and infant.
Patients must be counseled on the necessity of lifelong maintenance therapy in pernicious anemia to prevent irreversible neurologic complications.
Be aware of potential interference of hydroxocobalamin with certain laboratory tests due to blood and urine discoloration.
Use extreme caution when administering vitamin B12 in patients with undiagnosed anemia.

Warnings

Fatal hypokalemia has occurred in patients with megaloblastic anemia undergoing intensive vitamin B12 therapy; potassium levels should be monitored and supplemented if needed.
Vitamin B12 deficiency may mask signs of polycythemia vera, potentially delaying diagnosis until after treatment.
Rapid and severe optic nerve atrophy reported in patients with early Leber's hereditary optic neuropathy; avoid use in this population.
Anaphylaxis and severe hypersensitivity reactions may occur, particularly with parenteral administration; test dose recommended in sensitive individuals.
Hydroxocobalamin administration may cause skin and urine discoloration that can persist for weeks; patients should be advised accordingly.
Transient blood pressure elevations can occur with intravenous hydroxocobalamin; monitor cardiovascular status during administration.
Use caution in patients with impaired renal or hepatic function as safety and efficacy data are limited; excretion primarily renal.
Avoid administering cyanocobalamin intravenously as it is rapidly excreted and may not be effective for deficiency treatment.
Benzyl alcohol-preserved formulations can cause toxicity in neonates; avoid use in this population when possible.
Defer intranasal administration in patients with nasal congestion, allergic rhinitis, or upper respiratory infections to ensure efficacy.
Concomitant folic acid administration may obscure diagnosis of vitamin B12 deficiency, allowing neurologic damage to progress unnoticed.
Monitor for potential interference of hydroxocobalamin with colorimetric laboratory assays, which can affect clinical interpretation.
Vitamin B12 therapy should not be discontinued abruptly in patients with pernicious anemia to prevent irreversible neurological damage.
Adjust therapeutic approach in pregnant and lactating women due to increased requirements and potential effects on fetus and infant.
Avoid administration of hydroxocobalamin through IV lines shared with blood products due to incompatibility.

Contraindication

Known hypersensitivity or allergy to vitamin B12, cobalt, or any component of the formulation.
No contraindications for hydroxocobalamin when used for cyanide poisoning.
Avoid intranasal administration in patients with active nasal congestion or upper respiratory tract infections.
Patients with history of hypersensitivity to parenteral vitamin B12 formulations should not receive further parenteral doses without appropriate precautions.
Caution or avoidance in patients with early Leber's hereditary optic neuropathy due to risk of rapid optic nerve atrophy.
Avoid intravenous administration of cyanocobalamin for deficiency treatment due to rapid renal excretion and ineffectiveness.
Use caution or avoid use in neonates sensitive to benzyl alcohol preservatives in certain injectable formulations.
Avoid concurrent administration of incompatible drugs with parenteral hydroxocobalamin or cyanocobalamin injections.
Contraindicated to mix parenteral vitamin B12 with oxidizing or reducing agents, alkaline or strongly acidic solutions.
Avoid use if patient has a known allergy to benzalkonium chloride in nasal spray preparation.

Drug Interactions

Colchicine may reduce gastrointestinal absorption of vitamin B12, potentially lowering therapeutic efficacy.
Aminosalicylic acid and its salts can impair vitamin B12 absorption from the GI tract.
Chloramphenicol antagonizes hematopoietic response to vitamin B12 in deficient patients; alternative anti-infectives should be considered.
Excessive alcohol intake over two weeks impairs vitamin B12 absorption and utilization.
Ascorbic acid in large doses may destroy substantial amounts of dietary vitamin B12 if ingested within one hour of oral administration.
Methotrexate invalidates diagnostic microbiologic blood assays for vitamin B12, complicating monitoring.
Pyrimethamine also invalidates diagnostic microbiologic blood assays for vitamin B12.
Prednisone may increase vitamin B12 absorption and intrinsic factor secretion in some patients with pernicious anemia but has no effect in patients with gastrectomy.
Hydroxocobalamin (Cyanokit) may have unestablished safety for concomitant use with other cyanide antidotes; caution recommended.
Hydroxocobalamin causes red discoloration of blood and urine, potentially interfering with laboratory tests including clinical chemistry, hematology, coagulation, and urine analysis.
Prior administration of cyanocobalamin can result in false-positive test results for intrinsic factor antibodies.
Vitamin B12 injections are incompatible with multiple drugs including ascorbic acid, diazepam, dobutamine, dopamine, fentanyl, nitroglycerin, pentobarbital, propofol, sodium nitrite, sodium thiosulfate, thiopental, chlorpromazine hydrochloride, phytonadione, prochlorperazine edisylate, warfarin sodium, dextrose, heavy metals, oxidizing or reducing agents.
Vitamin B12 is compatible with heparin sodium, hydrocortisone sodium succinate, potassium chloride, and vitamin B complex with C for injection admixtures.
Concurrent use with drugs that interfere with renal function may affect vitamin B12 elimination.

Preparations Of The Drug

Nasal spray: Nascobal, delivering 500 mcg per metered spray, containing benzalkonium chloride as preservative; marketed by QOL Medical.
Parenteral injection: Hydroxocobalamin for injection (2.5 g vials), Brand: Cyanokit, manufactured by Dey.
Parenteral injection: Cyanocobalamin for injection available from multiple manufacturers in various strengths, typically for IM or subcutaneous use.
Oral tablets and capsules (not specified in this monograph but widely available commercially).
Reconstituted hydroxocobalamin solution prepared by adding 100 mL of 0.9% sodium chloride injection to 2.5 g vial, with concentration 25 mg/mL, stable up to 6 hours at ≤40°C.
Adjunct excipients may vary and some formulations contain benzyl alcohol (avoid in neonates) or preservatives requiring caution in specific populations.
Intranasal spray requires priming before use and administration with nasal spray adapter inserted approximately 1 cm into nostril.
Parenteral formulations have specific incompatibilities with various drugs; see product labeling for detailed compatibility information.
Intravenous hydroxocobalamin infusion requires a dedicated IV line, avoid co-administration with blood products in the same line.
Oral formulations should be stored in a cool dry place, nasal sprays should be protected from light and freezing, parenteral solutions stored protected from light at 20–25°C or specified conditions.