Cyanocobalamin

A11D - Vitamin B1, plain and in combination with B6 and B12 ATC B03BA01 Small molecule approved 1982 Oral Parenteral Topical

JFDA label: Cyanocobalamin (Vit.B12Inj.)

Mechanism of Action

— Supplement

Indications

Approved

Vitamin B12 deficiency

Off-label

Aphthous ulcers (recurrent)

Contraindications

Source: Lexicomp

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

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Not Known Cardiac failure · peripheral vascular disease · thrombosis (peripheral)

Nervous system disorders (9)

Not Known Abnormal gait · anxiety · ataxia · dizziness · headache · hypoesthesia · nervousness · pain · paresthesia

Blood and lymphatic system disorders (1)

Not Known Polycythemia vera

Immune system disorders (1)

Not Known Anaphylaxis (parenteral)

Gastrointestinal disorders (6)

Not Known Diarrhea · dyspepsia · glossitis · nausea · sore throat · vomiting

Skin and subcutaneous tissue disorders (3)

Not Known Pruritus · skin rash (transient) · urticaria

Musculoskeletal and connective tissue disorders (4)

Not Known Arthritis · back pain · myalgia · weakness

Infections and infestations (1)

Not Known Infection

Respiratory, thoracic and mediastinal disorders (3)

Not Known Dyspnea · pulmonary edema · rhinitis

Dosing

Source: Lexicomp

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 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 month

(For additional information see "Cyanocobalamin (vitamin B12): Pediatric drug information") Vitamin B12 deficiency: Note: Folic acid supplementation may also be required. Pernicious anemia: Infants, Children, and Adolescents (based on limited data): 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; initial low dosage recommended due to potential hypokalemia observed during initial treatment of adults with severe anemia (Orkin 2015; Rasmussen 2001; Stabler 2013). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Orkin 2015). Severe B12 deficiency: Based on limited data; 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 (Bjorke-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).

Refer to adult dosing.

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.

Warnings & Precautions

Source: Lexicomp

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.

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

Efficacy in patients with nasal pathology or with other concomitant intranasal therapy has not been determined. Use with caution. 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 sensitivity prior to intranasal or injectable administration.

Pregnancy & Lactation

Pregnancy

Animal reproduction studies have not been conducted. 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).

Lactation

Vitamin B12 is found in breast milk. Milk concentrations are similar to maternal serum concentrations and concentrations may be decreased in women who are vegetarians. Vitamin B12 requirements may be increased in nursing women compared to non-nursing women (IOM 1998).

Monitoring

Clinical pearl	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 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 earl

Clinical pearl

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 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 earl

Chemistry & Properties

Formula	C63H89CoN14O14P
Molecular weight	1356.4 g/mol
PubChem CID	166596686

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.556 h
Volume of distribution	0.567 L/kg
Protein binding	62.8%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (15, DDInter)

Interacting drug	Severity	Management
Arsenic trioxide	moderate
Chloramphenicol	moderate
Aminosalicylic acid	minor
Cimetidine	minor
Dexlansoprazole	minor
Esomeprazole	minor
Famotidine	minor
Lansoprazole	minor
Nizatidine	minor
Omeprazole	minor
Pantoprazole	minor
Potassium chloride	minor
Rabeprazole	minor
Ranitidine	minor
Ranitidine (bismuth citrate)	minor

Registered Products (14)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Poly-B-Bion	Ampoule 1 mg, 100 mg, 100 mg	3 amp pack varies	شركة مستودع ادوية جرينلاند	1.120
Neurorubine Forte	Tablet 1 mg, 50 mg, 200 mg	20 tab	Khoury Drug Store	2.050
Nervovit tablet	Tablet 200 mcg, 200 mg, 200 mg	20 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	2.110
Neurorubine Amp	Ampoule 1 mg/3 ml, 100.00 mg/3 ml, 100.00 mg/3 ml	3 ml	Khoury Drug Store	2.300
vitamist Nasal Spray	Spray 0.025 %	11 ml	Amman Pharmaceutical Industries Co	2.560
B Complete Ampoules	Ampoule 1 mg, 100 mg, 100 mg	5 amp	Hikma Pharmaceuticals Co.Ltd/Jordan	3.070
Jectin-12 Amp	Ampoule 1000 mcg	5 amp	Hikma Pharmaceuticals Co.Ltd/Jordan	3.520
B-YOSEF	Ampoule 100 mcg, 100 mg, 100 mg	10 amp	moon light drugs store	4.420
Pronatal	Tablet 0.6 mg, 2.6 mcg, 18 mg, 0.03 mg, 2 mg, 85 mg, 15 mg, 0.06 mg, 150 mg, 0.03 mg, 0.2 mg, 0.05 mg, 11 mg, 1.9 mg, 27 mg, 1 mg, 53 mg, 1.4 mg, 200 IU, 1.4 mg	30 tab	THE ARAB DRUG STORE P.S.C	5.570
Cyanocobalamin (Vit.B12Inj.)	Ampoule 1000 mcg/ml	10 amp pack varies	AL Rahma Drug Store	6.700
Elevit Pronatal film-coated tablets	Film-Coated Tablet 0.80 mg, 4.00 mcg, 19.00 mg, 10.00 mg, 200 mcg, 100.00 mg, 1080 mcg, 12.5 mcg, 125.00 mg, 7.50 mg, 2.60 mg, 60.00 mg, 1.00 mg, 125 mg, 1.00 mg, 1.80 mg, 100.00 mg, 1.60 mg, 15.00 mg	30 tab	The Jordan Drugstore Co	8.330
Medivitan injection	Powder for Injection 1.05 mg, 1 mg, 5 mg	8 amp	Karmel Drug Store	11.770
Poly-B-Bion	Ampoule 1 mg, 100 mg, 100 mg	100 amp pack varies	شركة مستودع ادوية جرينلاند	31.730
Cyanocobalamin (Vit.B12Inj.)	Ampoule 1000 mcg/ml	100 amp pack varies	AL Rahma Drug Store	52.960