Cyanocobalamin

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 [contains benzyl alcohol]

Physicians EZ Use B-12: 1000 mcg/mL [contains benzyl alcohol]

Vitamin Deficiency System-B12: 1000 mcg/mL [contains benzyl alcohol]

Generic: 1000 mcg/mL [DSC]

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:

Generic: 1000 mcg/mL (1 mL, 10 mL, 30 mL)

Solution, Nasal:

Nascobal: 500 mcg/0.1 mL (1 ea) [contains benzalkonium chloride]

Tablet, Oral:

Generic: 100 mcg, 250 mcg, 500 mcg, 1000 mcg

Tablet, Oral [preservative free]:

Generic: 100 mcg [DSC], 500 mcg [DSC], 1000 mcg

Tablet Extended Release, Oral:

Generic: 1000 mcg

Tablet Sublingual, Sublingual:

Generic: 2500 mcg [DSC]

Tablet Sublingual, Sublingual [preservative free]:

Generic: 2500 mcg

Pharmacology

Mechanism of Action

Coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis, used in cell replication and hematopoiesis

Pharmacokinetics/Pharmacodynamics

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

Metabolism

Converted in tissues to active coenzymes, methylcobalamin and deoxyadenosylcobalamin; undergoes some enterohepatic recycling

Excretion

Urine (50% to 98%, unchanged drug)

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

Time to Peak

Serum: IM, SubQ: 30 minutes to 2 hours; Intranasal: 1.25 ± 1.9 hours

Protein Binding

Transcobalamins

Use: Labeled Indications

Vitamin B₁₂ deficiency: Treatment of pernicious anemia, vitamin B₁₂ deficiency due to dietary deficiencies, gastrointestinal malabsorption, folic acid deficiency, parasitic infestation, inadequate secretion of intrinsic factor, and inadequate utilization of B₁₂ (eg, during neoplastic treatment); treatment of increased B₁₂ requirements due to pregnancy, thyrotoxicosis, hemorrhage, malignancy, liver or kidney disease

Use: Off Label

Aphthous ulcers (recurrent)b

Data from 2 small studies support the use of cyanocobalamin in reducing the frequency of recurrent aphthous ulcers in patients with normal or low serum vitamin B₁₂ levels at baseline Gulcan 2008, Volkov 2009.

Contraindications

Hypersensitivity to cyanocobalamin (vitamin B₁₂), cobalt, or any component of the formulation

Dosage and Administration

Dosing: Adult

Aphthous ulcers, recurrent (off-label use):

Oral (sublingual): 1,000 mcg once every evening for 6 months (Volkov 2009)

IM: 1,000 mcg once daily for 7 days, followed by weekly for 1 month, followed by monthly for 6 months (Gulcan 2008)

Vitamin B₁₂ deficiency: Note: Folic acid supplementation may also be required.

Intranasal (Nascobal): 500 mcg in 1 nostril once weekly; may increase dose if vitamin B₁₂ levels decline after 1 month of treatment. Alternate route (eg, IM, SubQ) should be considered if B₁₂ levels are persistently low.

Oral: 1,000 to 2,000 mcg daily for 1 to 2 weeks; maintenance: 1,000 mcg daily (Langan 2011; Oh 2003)

IM, deep SubQ: May use initial treatment similar to that for pernicious anemia depending on severity of deficiency: 100 mcg daily for 6 to 7 days; if improvement, administer same dose 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 dosage: 100 mcg monthly.

Note: Higher doses may be preferred, especially in cases of severe deficiency; consider alternate dosing regimens with initial doses ranging from 100 to 1,000 mcg every day or every other day for 1 to 2 weeks and maintenance doses of 100 to 1,000 mcg every 1 to 3 months (Oh 2003) or 1,000 mcg once a week for 8 weeks followed by 1,000 mcg once a month (Langan 2011).

Mild B₁₂ deficiency (eg, malabsorption, atrophic gastritis, metformin use, chronic acid reducing medication use):

Oral: 500 to 1,000 mcg orally once daily (Stabler 2013)

IM: 1,000 mcg once daily or every other day for 1 week, then 1,000 mcg weekly for 4 to 8 weeks, and then 1,000 mcg monthly for life (Stabler 2013)

Pernicious anemia:

IM: 1,000 mcg once daily or every other day for 1 week, then 1,000 mcg weekly for 4 to 8 weeks, then 1,000 mcg once monthly for life (Stabler 2013) or 100 to 1,000 mcg every day or every other day for 1 to 2 weeks followed by 100 to 1,000 mcg every 1 to 3 months (Oh 2003) or 1,000 mcg once a week for 8 weeks followed by 1,000 mcg once a month for life (Langan 2011)

Oral: 1,000 to 2,000 mcg once daily for life (Stabler 2013)

IM, deep SubQ: Initial: 100 mcg once daily for 6 to 7 days; if improvement, administer same dose on alternate days for 7 doses, then every 3 to 4 days for 2 to 3 weeks; maintenance (once hematologic values have returned to normal): 100 mcg once monthly for life

Severe B₁₂ deficiency (due to gastrectomy, ileal resection, inflammatory bowel disease, sprue):

IM: 1,000 mcg once daily or every other day for 1 week, then 1,000 mcg weekly for 4 to 8 weeks, then 1,000 mcg once monthly for life (Stabler 2013)

Oral: 1,000 to 2,000 mcg once daily for life (Stabler 2013).

Vitamin B₁₂ repletion in gastric bypass surgery patients: IM or SubQ: 1,000 mcg once daily until normal B₁₂ levels are achieved and then resume supplementations dosage (ASBMS [Parrott 2017]) or 1,000 mcg IM once daily or every other day for 1 week, then 1,000 mcg IM weekly for 4 to 8 weeks, followed by supplementation dosing (Stabler 2013).

Vitamin B₁₂ supplementation in gastric bypass surgery patients:

IM or SubQ: 1,000 mcg once monthly (ASMBS [Parrott 2017]) or 1,000 mcg once monthly to 1,000 to 3,000 mcg once every 6 to 12 months (if oral or intranasal therapy are ineffective) (AACE/TOS/ACE [Mechanick 2013]) or 1,000 mcg IM once monthly for life (Stabler 2013).

Oral: 350 to 500 mcg (disintegrating tablet, sublingual, or liquid) once daily (ASMBS [Parrott 2017]) or ≥1,000 mcg once daily (AACE/TOS/ACE [Mechanick 2013]) or 1,000 to 2,000 mcg orally once daily for life (Stabler 2013)

Intranasal: 500 mcg in one nostril once weekly (ASMBS [Parrott 2017]; AACE/TOS/ACE [Mechanick 2013]).

Vitamin B₁₂ supplementation to reduce toxicity associated with pemetrexed: IM: 1,000 mcg every 9 weeks, beginning 1 to 3 weeks prior to pemetrexed treatment initiation; continue for 3 weeks after last pemetrexed dose; administer with oral folic acid supplementation (Scagliotti 2008; Vogelzang 2003); may administer cyanocobalamin on the same day as pemetrexed.

Vitamin B₁₂ supplementation to reduce toxicity associated with pralatrexate: IM: 1,000 mcg every 8 to 10 weeks; administer with oral folic acid supplementation (O'Connor 2011); begin cyanocobalamin within 10 weeks prior to pralatrexate treatment initiation. After the initial dose, may administer cyanocobalamin on the same day as pralatrexate.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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 (Orkin 2015; Rasmussen 2001; Stabler 2013); however, in more recent experience, while some adult patients may experience hypokalemia with initial treatment, this is unlikely to be clinically significant (Carmel 2008). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Orkin 2015).

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 (Stabler 2013); patients with neurologic symptoms have been treated with doses of 1,000 mcg (Guez 2012; Roumeliotis 2012)

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 (Bjørke-Monsen 2011; Kliegman 2016; Stabler 2013). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Orkin 2015).

Administration

IM, SubQ: IM or deep SubQ are the preferred routes of administration. IV administration is not recommended.

Intranasal: Nasal spray (Nascobal): Administer 1 hour before or 1 hour after ingestion of hot foods/liquids.

Oral: Not generally recommended due to variable absorption; however, oral therapy in appropriate doses has been effective for anemia if IM/SubQ routes refused or not tolerated. Some tablets are available for sublingual administration.

Dietary Considerations

Strict vegetarian diets (eg, without eggs or dairy products) may result in vitamin B₁₂ deficiency.

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

Storage

Injection: Clear pink to red solutions are stable at room temperature. Protect from light.

Intranasal spray: Store at 15°C to 30°C (59°F to 86°F); do not freeze. Protect from light.

Drug Interactions

Chloramphenicol (Systemic): May diminish the therapeutic effect of Vitamin B12. Monitor therapy

Colchicine: May decrease the serum concentration of Cyanocobalamin. Monitor therapy

Test Interactions

Methotrexate, pyrimethamine, and most antibiotics invalidate folic acid and vitamin B₁₂ diagnostic blood assays

Adverse Reactions

>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

Warnings/Precautions

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 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.
• Pernicious anemia: Appropriate use: IM/SubQ routes are used to treat pernicious anemia; oral and intranasal administration are not indicated until hematologic remission and no signs of nervous system involvement.
• 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 intranasal or injectable administration.

Monitoring Parameters

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 (and vitamin B₁₂ 1 month after each dosage adjustment if using intranasal formulation), then every 3 to 6 months thereafter.

Evaluate serum methylmalonic acid 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).

Bariatric surgery: Vitamin B₁₂ levels at baseline and once a year postoperatively then every 3 to 6 months if supplemented; every trimester in pregnant females (Mechanick 2013). In patients on chronic administration of medications known to increase risk of B₁₂ deficiency (eg, colchicine, metformin, neomycin, nitrous oxide, proton pump inhibitors, seizure medication), screen every 3 months for the initial postoperative year and then annually (Parrott 2017). Serum methylmalonic acid (MMA) is the recommended assay to evaluate vitamin B₁₂ levels for patients who are asymptomatic, symptomatic, have a history of B₁₂ deficiency, or preexisting neuropathy (Parrott 2017). Monitor for early signs/symptoms of B₁₂ deficiency, including pernicious anemia (pale skin/eyes, glossitis, fatigue, anorexia, diarrhea) or neuropathy (numbness, paresthesia in extremities, ataxia, decreased reflexes), lightheadedness or vertigo, dyspnea, tinnitus, palpitations, and /or increased HR; monitor for advanced signs/symptoms of B₁₂ deficiency, including angina, HF symptoms and/or mental status changes (Parrott 2017).

Pregnancy

Pregnancy Considerations

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).

Patient Education

What is this drug used for?

• It is used to help with some kinds of anemia.
• It is used to treat or prevent low vitamin B₁₂.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Dizziness
• Headache
• Loss of strength and energy
• Anxiety
• Common cold symptoms
• Runny nose
• Diarrhea
• Vomiting
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.
• DVT like edema, warmth, numbness, change in color, or pain in the extremities.
• Vision changes
• Shortness of breath
• Burning or numbness feeling
• Excessive weight gain
• Change in balance
• Swelling of arms or legs
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.