Adequate intake (AI): Oral: 0.4 mcg/day (~0.05 mcg/kg/day) (Ref); Note: Neonates born to vegan mothers should be supplemented with the AI for vitamin B12 from birth; they may have low vitamin B12 stores at birth and, if breastfeeding, may only receive a small amount of the vitamin from the mother's milk (Ref).
Anemia of prematurity: Limited data available: IM: 100 mcg once monthly for 4 months with concomitant folic acid administration produced higher hemoglobin in 34 preterm neonates (GA <36 weeks; birth weight <1,800 g) when compared to placebo or folate monotherapy; all patients received vitamin E and iron supplementation (Ref).
Pernicious anemia; treatment of deficiency: Limited data available: IM, SubQ: Initial: 1,000 mcg/day for 2 to 7 days based upon clinical response; followed by 100 mcg once weekly for 4 weeks and then maintenance dose: 100 mcg/month; Note: For severe anemia, a lower initial dose of 0.2 mcg/kg/dose for 2 days followed by the above regimen has been recommended due to potential hypokalemia observed during initial treatment of adults with severe anemia (Ref); however, in more recent experience, while some adult patients may experience hypokalemia with initial treatment, this is unlikely to be clinically significant (Ref). Some experts have recommended doses as low as 50 to 100 mcg (Ref).
Pernicious anemia: Note: Concurrent folic acid supplementation may also be needed.
Manufacturer's labeling: Infants, Children, and Adolescents: IM, SubQ: 100 mcg once daily for 6 to 7 days; if improvement occurs, administer 100 mcg on alternate days for 7 doses, then every 3 to 4 days for 2 to 3 weeks; once hematologic values have returned to normal, maintenance dose: 100 mcg monthly.
Alternate dosing: Limited data available: Infants, Children, and Adolescents: IM, SubQ: Initial: 1,000 mcg/day for 2 to 7 days based upon clinical response; followed by 100 mcg once weekly for 4 weeks and then maintenance dose: 100 mcg/month; for severe anemia, a lower initial dose of 0.2 mcg/kg/dose for 2 days followed by the above regimen has been recommended due to potential hypokalemia observed during initial treatment of adults with severe anemia (Ref); however, in more recent experience, while some adult patients may experience hypokalemia with initial treatment, this is unlikely to be clinically significant (Ref). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Ref).
Vitamin B12 deficiency, severe: Limited data available; dosing regimens variable:
Dietary deficiency: Infants (breastfed with vitamin B12 deficient mothers): IM: 250 to 1,000 mcg once daily for 1 to 2 weeks, followed by weekly dosing until patient recovers (Ref); patients with neurologic symptoms have been treated with doses of 1,000 mcg (Ref).
Malabsorption: Infants, Children, and Adolescents: IM: 250 to 1,000 mcg daily or every other day for 1 week, then weekly for 4 to 8 weeks, and then monthly for life; younger children should receive monthly doses of 100 mcg (Ref). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Ref).
There are no dosage adjustments provided in the manufacturer's labeling. Some formulations may also contain aluminum, which may accumulate in renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Cyanocobalamin (vitamin B12): Drug information")
Dosage guidance:
Dosage form information: The cyanocobalamin content of over-the-counter products varies; it is generally higher in B-complex products (eg, 50 to 500 mcg) or products containing only vitamin B12 (eg, 500 to 1,000 mcg) than in multivitamin products (eg, 5 to 25 mcg) (Ref).
Aphthous stomatitis, simple, recurrent (off-label use):
Note: May consider use regardless of serum vitamin B12 levels (Ref).
Oral (sublingual): 1,000 mcg once daily for 6 months (Ref).
IM: 1,000 mcg once daily for 7 days, then 1,000 mcg once weekly for 1 month, then 1,000 mcg once monthly for 6 months (Ref).
Drug toxicity reduction:
Pemetrexed:
IM: 1,000 mcg every 9 weeks, beginning 1 to 3 weeks prior to pemetrexed treatment initiation (Ref); in patients without preexisting anemia, some data suggest that pemetrexed and cyanocobalamin may be started simultaneously to avoid delaying pemetrexed initiation (Ref). After the initial dose, may administer cyanocobalamin on the same day as pemetrexed; administer with oral folic acid supplementation.
Pralatrexate:
IM: 1,000 mcg every 8 to 10 weeks, beginning within 10 weeks prior to pralatrexate treatment initiation; administer with oral folic acid supplementation (Ref). After the initial dose, may administer cyanocobalamin on the same day as pralatrexate.
Vitamin B12 deficiency, treatment:
Note: Folic acid supplementation may also be required.
Severe/Symptomatic anemia or neurologic/neuropsychiatric findings:
Initial therapy:
IM, deep SUBQ: 1,000 mcg 1 to 3 times/week or once daily for 1 week, then 1,000 mcg once weekly for 4 to 8 weeks (Ref). Alternatively, if neurologic symptoms are present, may initiate 1,000 mcg every other day for up to 3 weeks or until no further improvement in signs or symptoms, then switch to 1,000 mcg once weekly for up to 12 weeks (Ref).
Maintenance therapy:
Note: Continue parenteral therapy until the deficiency has been corrected and signs and symptoms have resolved before switching to oral therapy (Ref).
IM, deep SUBQ: 1,000 mcg once monthly (Ref).
Oral, Sublingual: 1,000 to 2,000 mcg once daily (Ref).
Mild symptoms or asymptomatic:
IM, deep SUBQ: Initial: 1,000 mcg once weekly for 4 to 8 weeks; maintenance dose: 1,000 mcg once monthly (Ref).
Oral, Sublingual: 1,000 to 2,000 mcg once daily (Ref). Note: In patients with impaired GI absorption (eg, pernicious anemia, bariatric surgery), or in whom adherence must be assured, parenteral administration may be required (Ref).
Intranasal (Nascobal): Initial: 500 mcg (1 spray) in 1 nostril once weekly. Consider an alternative route if vitamin B12 levels are persistently low after 1 month of treatment. Note: Some experts do not use intranasal formulations due to variable absorption (Ref).
Duration of therapy: Continue indefinitely in patients with pernicious anemia or other irreversible cause of deficiency (eg, bariatric surgery); may discontinue therapy if a reversible cause of deficiency (eg, reduced dietary intake) has been addressed (Ref).
Vitamin B12 deficiency, prevention:
Note: For use in patients with risk factors for vitamin B12 deficiency (eg, bariatric or gastric surgery, disorders of the stomach or terminal ileum, vegan or vegetarian diet) (Ref).
Oral, Sublingual: 350 to 1,000 mcg once daily; in patients with pernicious anemia, higher doses (eg, 1,000 to 2,000 mcg/day) are required (Ref).
IM, deep SUBQ: 1,000 mcg once monthly or 1,000 to 3,000 mcg once every 6 to 12 months (Ref). Note: May be preferred in patients with impaired GI absorption (eg, pernicious anemia, bariatric surgery), or for whom adherence to oral therapy is challenging (Ref).
Intranasal (Nascobal): 500 mcg (1 spray) in 1 nostril once weekly. Consider an alternative route if adequate vitamin B12 levels cannot be maintained. Note: Some experts do not use intranasal formulations due to variable absorption (Ref).
Duration of therapy: Continue indefinitely in patients with pernicious anemia or other irreversible cause of deficiency (eg, bariatric surgery); may discontinue therapy if a reversible cause of deficiency (eg, reduced dietary intake) has been addressed (Ref).
There are no dosage adjustments provided in the manufacturer's labeling. Some formulations may also contain aluminum, which may accumulate in renal impairment.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Central nervous system: Headache (IM: 20%; intranasal: 4%)
Infection: Infection (12% to 13%)
Neuromuscular & skeletal: Asthenia (IM: 16%; intranasal: 4%)
1% to 10%:
Central nervous system: Paresthesia (4%)
Gastrointestinal: Glossitis (nasal: 4%), nausea (4%)
Respiratory: Rhinitis (4% to 8%)
Frequency not defined:
Cardiovascular: Cardiac failure, thrombosis (peripheral)
Dermatologic: Pruritus, skin rash (transient)
Endocrine & metabolic: Hypokalemia
Gastrointestinal: Diarrhea
Hematologic & oncologic: Polycythemia vera, thrombocythemia
Hypersensitivity: Anaphylactic shock (IM/SubQ)
Respiratory: Pulmonary edema
Miscellaneous: Swelling
Hypersensitivity to cyanocobalamin (vitamin B12), cobalt, or any component of the formulation
Concerns related to adverse effects:
• CNS effects: Vitamin B12 deficiency for >3 months results in irreversible degenerative CNS lesions; neurologic manifestations will not be prevented with folic acid unless vitamin B12 is also given. Spinal cord degeneration might also occur when folic acid used as a substitute for vitamin B12 in anemia prevention.
• Hypokalemia: According to the manufacturer, treatment of severe vitamin B12 megaloblastic anemia may result in severe hypokalemia, sometimes fatal, due to intracellular potassium shift upon anemia resolution; however, in more recent experience, while some patients may experience hypokalemia with initial treatment, this is unlikely to be clinically significant (Carmel 2008).
• Thrombocytosis: Treatment of severe vitamin B12 megaloblastic anemia may result in thrombocytosis.
Disease-related concerns:
• Leber disease: Patients with Leber disease who received vitamin B12 treatment have suffered from severe rapid optic atrophy. Use of cyanocobalamin in these patients is not recommended.
• Megaloblastic anemia: Vitamin B12 doses >10 mcg daily may produce a hematologic response in patients with folate deficient megaloblastic anemia and mask previously unrecognized folate deficiency; vitamin B12 is not a substitute for folic acid.
• Polycythemia vera: Vitamin B12 deficiency masks signs of polycythemia vera; vitamin B12 administration may unmask this condition.
Dosage form specific issues:
• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturer's labeling.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Intranasal administration: The effectiveness of intranasal cyanocobalamin in patients with allergic rhinitis, nasal congestion, and upper respiratory tract infections has not been determined. Defer treatment until symptoms have subsided.
Other warnings/precautions:
• IV administration: Avoid intravenous route; anaphylactic shock has occurred.
• Test dose: Intradermal test dose of vitamin B12 is recommended for any patient suspected of cyanocobalamin hypersensitivity prior to administration.
Note: Not all available strengths or formulations may be represented in Dosage Forms.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Kit, Injection:
B-12 Compliance Injection: 1000 mcg/mL [DSC] [contains benzyl alcohol]
Physicians EZ Use B-12: 1000 mcg/mL [contains benzyl alcohol]
Vitamin Deficiency System-B12: 1000 mcg/mL [contains benzyl alcohol]
Liquid, Sublingual:
Generic: 3000 mcg/mL (52 mL)
Lozenge, Oral:
Generic: 50 mcg (100 ea); 100 mcg (100 ea); 250 mcg (100 ea, 250 ea); 500 mcg (100 ea, 250 ea)
Solution, Injection:
Dodex: 1000 mcg/mL (1 mL, 10 mL, 30 mL) [contains benzyl alcohol]
Generic: 1000 mcg/mL (1 mL, 10 mL, 30 mL)
Solution, Nasal:
Nascobal: 500 mcg/0.1 mL (1 ea) [contains benzalkonium chloride]
Generic: 500 mcg/0.1 mL (1 ea)
Tablet, Oral:
True Vitamin B12: 500 mcg, 1000 mcg
Generic: 100 mcg, 250 mcg, 500 mcg, 1000 mcg
Tablet, Oral [preservative free]:
Generic: 1000 mcg
Tablet Extended Release, Oral:
Generic: 1000 mcg
Tablet Sublingual, Sublingual [preservative free]:
Generic: 2500 mcg
Yes
Solution (Cyanocobalamin Injection)
1000 mcg/mL (per mL): $3.28 - $8.74
Solution (Cyanocobalamin Nasal)
500 mcg/0.1 mL (per each): $191.51
Solution (Dodex Injection)
1000 mcg/mL (per mL): $8.52
Solution (Nascobal Nasal)
500 mcg/0.1 mL (per each): $212.79
Tablet, controlled release (Vitamin B-12 ER Oral)
1000 mcg (per each): $0.07
Tablets (Vitamin B-12 Oral)
1000 mcg (per each): $0.04 - $0.22
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Injection:
Cobex: 1000 mcg/mL ([DSC])
Generic: 100 mcg/mL ([DSC]); 1000 mcg/mL (1 mL, 10 mL, 30 mL)
Oral: Not generally recommended for treatment of severe vitamin B12 deficiency due to poor oral absorption (lack of intrinsic factor); oral administration may be used in less severe deficiencies and maintenance therapy; may be administered without regard to food
Parenteral: IM or deep SubQ are preferred routes of administration: Avoid IV administration due to a more rapid system elimination with resulting decreased utilization
Injection solution: For IM or deep SUBQ administration only; do not administer IV.
Intranasal: Nasal spray (Nascobal): Administer 1 hour before or 1 hour after ingestion of hot foods/liquids.
Oral: Some tablets are available for sublingual administration.
Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not cut, crush, or chew. Switch to an IR tablet, chewable tablet, orally disintegrating or sublingual tablet, oral solution drops, or a nonoral formulation such as injection or nasal spray.
Injection: Store between 20°C and 25°C (68°F and 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light.
Intranasal spray: Store at 15°C to 30°C (59°F to 86°F); do not freeze. Protect from light.
Treatment of pernicious anemia; vitamin B12 deficiency due to dietary deficiencies or malabsorption diseases; inadequate secretion of intrinsic factor, inadequate utilization of B12 (eg, during neoplastic treatment); increased B12 requirements due to pregnancy, thyrotoxicosis, hemorrhage, malignancy, liver or kidney disease (FDA approved in pediatric patients [age not specified] and adults)
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Chloramphenicol (Systemic): May diminish the therapeutic effect of Vitamin B12. Risk C: Monitor therapy
Heavy ethanol consumption >2 weeks may impair vitamin B12 absorption.
Strict vegetarian or vegan diets (eg, without eggs or dairy products) may result in vitamin B12 deficiency (NIH 2021; manufacturer's labeling).
Adequate intake (IOM 1998):
1 to 6 months: 0.4 mcg daily.
7 to 12 months: 0.5 mcg daily.
Recommended intake (IOM 1998):
1 to 3 years: 0.9 mcg daily.
4 to 8 years: 1.2 mcg daily.
9 to 13 years: 1.8 mcg daily.
≥14 years: 2.4 mcg daily.
Pregnancy: 2.6 mcg daily.
Lactation: 2.8 mcg daily.
Water soluble vitamins cross the placenta. Absorption of vitamin B12 may increase during pregnancy. Vitamin B12 requirements may be increased in pregnant women compared to nonpregnant women. Serum concentrations of vitamin B12 are higher in the neonate at birth than the mother (IOM 1998).
Vitamin B12, hemoglobin, hematocrit, erythrocyte and reticulocyte count, folate and iron levels should be obtained prior to treatment; vitamin B12 and peripheral blood counts should be monitored 1 month after beginning treatment, then every 3 to 6 months thereafter.
Evaluate serum methylmalonic acid (MMA) and total homocysteine levels at baseline (prior to supplementation) in untreated patients to confirm vitamin B12 deficiency (and extent of deficiency); repeat to confirm adequate supplementation (Stabler 2013).
Megaloblastic/pernicious anemia: In addition to normal hematological parameters, serum potassium and platelet counts should be monitored during therapy. Note: Some patients may develop hypokalemia during initial treatment; however, this is unlikely to be clinically significant (Carmel 2008).
Serum vitamin B12 levels: Normal: >300 pg/mL (SI: >221.2 pmol/L); vitamin B12 deficiency: <200 pg/mL (SI: <147.5 pmol/L) (200 to 300 pg/mL [SI: 147.5 to 221.2 pmol/L] borderline result, possible deficiency); megaloblastic anemia: <100 pg/mL (SI: <73.7 pmol/L).
Coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis, used in cell replication and hematopoiesis
Onset of action:
Megaloblastic anemia: IM:
Conversion of megaloblastic to normoblastic erythroid hyperplasia within bone marrow: 8 hours.
Increased reticulocytes: 2 to 5 days,
Complicated vitamin B12 deficiency: IM, SUBQ: Resolution of:
Psychiatric sequelae: 24 hours.
Thrombocytopenia: 10 days.
Granulocytopenia: 2 weeks.
Absorption: Oral: Variable from the terminal ileum; requires the presence of calcium and gastric "intrinsic factor" to transfer the compound across the intestinal mucosa.
Distribution: Principally stored in the liver and bone marrow, also stored in the kidneys and adrenals.
Protein binding: Transcobalamins.
Metabolism: Converted in tissues to active coenzymes, methylcobalamin and deoxyadenosylcobalamin; undergoes some enterohepatic recycling.
Bioavailability: Intranasal (Nascobal): 6.1% (relative to IM); Oral: Pernicious anemia: 1.2%.
Time to peak, serum: IM, SUBQ: 30 minutes to 2 hours; Intranasal: 1.25 ± 1.9 hours.
Excretion: Urine (50% to 98%, unchanged drug).
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