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Mechanism of Action
US Drug Names
NOTE: Hematocrit, reticulocyte count, vitamin B12, folate, and iron concentrations should be obtained prior to treatment. If folate concentrations are low in a patient with low B12 concentrations, folic acid should only be administered in combination with B12. Vitamin blood concentrations and peripheral blood counts should be monitored at one month of treatment and then at intervals of 3 to 6 months.
2.6 mcg orally daily.
2.8 mcg orally daily.
2.4 mcg PO daily. NOTE: Due to malabsorption of food-bound vitamin B12, individuals older than age 50 years are advised to meet their recommended daily allowance mainly by taking vitamin B12-containing supplements or through foods fortified with vitamin B12.
1.8 mcg PO daily.
1.2 mcg PO daily.
0.9 mcg PO daily.
0.5 mcg/day PO is the adequate intake. Recommended daily allowance has not been established.
0.4 mcg/day PO is the adequate intake. Recommended daily allowance has not been established.
500 mcg intranasally into 1 nostril once weekly. The intranasal route is for maintenance of adequate nutritional intake in patients who cannot absorb vitamin B12 via the oral route.
Safety and efficacy of intranasal use have not established; see oral dosage guidelines from the Institute of Medicine.
1,000 to 2,000 mcg/day PO for 1 to 2 weeks, followed by 500 to 1,000 mcg/day PO. 
1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is the usual dosage.   100 mcg IM/subcutaneously once daily for 6 or 7 days is the FDA-approved dosage. After clinical improvement and if a reticulocyte response is seen, give 100 mcg IM/subcutaneously on alternate days for 7 doses, then every 3 to 4 days for another 2 to 3 weeks, then 100 mcg IM/subcutaneously monthly. Administer with folic acid, if needed.
1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is the usual dosage. 
Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements.  1,000 mcg IM daily for 2 to 7 days, then 100 mcg IM/subcutaneously weekly for 4 weeks, then monthly until recovery has been recommended and used in children.     The adult dosage (1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly) has also been used in children.  
Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements.  250 to 1,000 mcg IM daily for 4 to 10 days, followed by 100 to 1,000 mcg IM weekly or monthly until recovery, has been recommended and used in infants in case reports.      
Initial dose is 500 mcg intranasally into 1 nostril once weekly. Consider increasing the dose if serum concentrations of B12 decrease after one month of therapy. Assess serum B12 concentrations one month after each dosage adjustment. Continued low serum concentrations may indicate that the patient may need alternative therapy (i.e., IM or subcutaneous B12 administration).
NOTE: Patients with pernicious anemia are 3 times more likely to develop carcinoma of the stomach than the general population, necessitating an appropriate work-up.
1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly for life is the usual dosage.   100 mcg IM/subcutaneously once daily for 6 or 7 days is the FDA-approved dosage. After clinical improvement and if a reticulocyte response is seen, give 100 mcg IM/subcutaneously on alternate days for 7 doses, then every 3 to 4 days for another 2 to 3 weeks, then 100 mcg IM/subcutaneously monthly for life. Administer with folic acid, if needed.
1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly for life is the usual dosage. 
Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements.  1,000 mcg IM daily for 2 to 7 days, then 100 mcg IM weekly for 4 weeks, then monthly has been recommended and used in children.     The adult dosage (1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly for life) has also been used in children.    
Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements.  250 to 1,000 mcg IM daily for 4 to 10 days, followed by 100 to 1,000 mcg IM weekly or monthly, has been recommended and used in infants in case reports.      
1,000 to 2,000 mcg/day PO for life. 
Initial dose is 500 mcg intranasally into 1 nostril once weekly. Consider increasing the dose if serum concentrations of B12 decrease after one month of therapy. Assess serum B12 concentration one month after each dosage adjustment. Continued low serum concentrations may indicate that the patient may need alternative therapy (i.e., IM or subcutaneous B12 administration).
1,000 mcg intramuscularly once daily for 11 days with a protein-restricted diet.
1,000 mcg IM once is the flushing dose for Schilling test/vitamin B12 absorption test.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines are not available; it appears that no dosage adjustments are needed.
Cyanocobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although cyanocobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product. Cyanocobalamin is available nasally, orally, and parenterally, and is equal in biologic activity to hydroxocobalamin. Cyanocobalamin is used to treat pernicious anemia and prevent and treat vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur. Oral therapy is not always effective, as some persons lack intrinsic factor, an endogenous substance produced by the stomach and necessary for oral B12 absorption. Other patients may not be able to absorb oral vitamin B12 due to surgical removal or dysfunction of the intestines in the area where absorption of vitamin B12 occurs. Thus, parenteral or nasal therapy may be needed; however, intranasal therapy should only be instituted for maintenance treatment after control of the condition has been obtained by the parenteral route. 
For storage information, see the specific product information within the How Supplied section.
In most cases, cyanocobalamin is nontoxic, even in large doses. Pruritus, transitory exanthema (rash), and a feeling of swelling (edema) of the entire body have been reported after IM injection.  Some patients have also experienced a hypersensitivity reaction after IM injection that has resulted in anaphylactic shock and death.
Pulmonary edema and congestive heart failure have been reported early in treatment with parenteral cyanocobalamin. Peripheral vascular thrombosis and peripheral vascular disorder have also occurred. 
Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with intensive cyanocobalamin therapy. Monitor platelet count and serum potassium concentrations during therapy. Polycythemia vera has also been reported with parenteral cyanocobalamin. 
Musculoskeletal adverse reactions associated with cyanocobalamin administration include arthritis, asthenia, back pain, generalized pain, myalgia, abnormal gait.
Respiratory adverse reactions reported with cyanocobalamin administration include dyspnea and rhinitis. Infection (i.e., common cold, sore throat) has also been reported.
Gastrointestinal adverse reactions reported with cyanocobalamin administration include dyspepsia, glossitis, nausea, vomiting, and mild transient diarrhea. 
CNS adverse reactions including anxiety, dizziness, headache, hypoesthesia, incoordination, nervousness, and paresthesias have been reported with cyanocobalamin administration.
Cyanocobalamin injection contains aluminum, and aluminum toxicity may occur with prolonged administration in high-risk patients, including those with renal impairment and premature neonates. Premature neonates are at particular risk for aluminum toxicity because of immature renal function, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with renal impairment, who receive parenteral aluminum at more than 4 to 5 mcg/kg/day, may develop aluminum-related CNS and bone toxicities. Tissue loading may occur at lower administration rates.
Cyanocobalamin is contraindicated in patients with cyanocobalamin hypersensitivity or hypersensitivity to any of the medication components. Cyanocobalamin is also contraindicated in patients with cobalt hypersensitivity because cyanocobalamin contains cobalt. In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered because anaphylactic shock and death have followed parenteral administration of cyanocobalamin.
Intranasal formulations of cyanocobalamin are not suitable for vitamin B12 absorption test (Schilling Test).
Cyanocobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber's disease). Optic nerve atrophy can worsen in patients whose cyanocobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population.
Most formulations of cyanocobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Cyanocobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Cyanocobalamin preparations containing benzyl alcohol should be avoided in premature neonates because benzyl alcohol has been associated with 'gasping syndrome,' a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction.
Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with cyanocobalamin may unmask this condition.
Folic acid is not a substitute for cyanocobalamin in the treatment of vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. However, exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. Additionally, exclusive use of cyanocobalamin in treating folate deficient megaloblastic anemia could delay or mask the real diagnosis. Before receiving folic acid or cyanocobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. The intranasal formulations are not approved to treat acute B12 deficiency; all hematologic parameters should be normal before beginning the cyanocobalamin intranasal formulations. Concurrent iron-deficiency anemia and folate deficiency may result in a blunted or impeded response to cyanocobalamin therapy. Secondary to an increase in red cell production with cyanocobalamin therapy, there is a corresponding increase in iron requirements; thus, patients should be closely monitored for the development of iron deficiency and treated accordingly.
Certain conditions may blunt or impede therapeutic response to cyanocobalamin therapy, such as serious infection, uremia or renal failure, or drugs with bone marrow suppression properties (e.g., chloramphenicol). The mechanism appears to be interference with erythropoiesis.
Patients with rhinorrhea (rhinitis) who are receiving the intranasal formulations of cyanocobalamin may experience decreased medication absorption secondary to nasal discharge. These patients may experience a blunted or impeded response to the intranasal medication. Treatment with intranasal cyanocobalamin should be delayed until symptoms resolve in patients with nasal congestion, allergic rhinitis, and upper respiratory infection. Intranasal cyanocobalamin therapy is not ideal for patients with chronic nasal symptoms or significant nasal pathology. If used in these patients, more frequent monitoring is required because of the potential for erratic or blunted absorption.
Adequate studies in humans have not been conducted; however, no maternal or fetal complications have been associated with doses that are recommended during pregnancy, and appropriate treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Conversely, pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of vegetarian mothers whose diets contain no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy. The usual daily recommended amounts of cyanocobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy.
Cyanocobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of cyanocobalamin by breast-feeding infants. Adequate maternal intake is important for both the mother and infant during nursing, and maternal requirements for vitamin B12 increase during lactation. According to the manufacturer, the usual daily recommended amounts of cyanocobalamin, vitamin B12 for lactating women should be taken maternally during breast-feeding. The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Studies of intranasal cyanocobalamin did not include sufficient numbers of geriatric patients aged >= 65 years to determine whether the clinical response differs from that of younger patients. Other clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution. Elderly patients tend to have a greater frequency of decreased hepatic, renal, or cardiac function, and also have concomitant disease or receiving other drug therapy. Start with doses at the lower end of the dosing range.
Treatment of severe megaloblastic anemia with cyanocobalamin results in the conversion to normal erythropoiesis. The change to normal erythropoiesis may cause secondary development of hypokalemia and thrombocytosis, therefore, potassium levels and platelet counts should be closely monitored.
Vitamin B12, or cyanocolbalamin, is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for cyanocobalamin. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which also requires folate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.
Cyanocobalamin is administered intranasally, orally, and parenterally, while hydroxocobalamin is administered only parenterally. Once absorbed, vitamin B12 is highly bound to transcobalamin II, a specific B-globulin carrier protein and is distributed and stored primarily in the liver as coenzyme B12. The bone marrow also stores a significant amount of the absorbed vitamin B12. Vitamin B12 crosses the placenta and is distributed into breast milk. Enterohepatic recirculation conserves systemic stores. Elimination is primarily through the bile; however, excess cyanocobalamin is excreted unchanged in the urine.
Oral absorption of vitamin B12 from the GI tract depends on the presence of adequate intrinsic factor, which is secreted from gastric mucosa. Drugs like the proton pump inhibitors (PPIs) (e.g., omeprazole and lansoprazole) have the potential for interfering with B12 absorption, presumably by impairing gastric acid and pepsin secretion, which are thought to be necessary for releasing B12 from its protein-binding sites in food. A vitamin B12-intrinsic factor complex is formed in the stomach following removal of cobalamin from dietary sources. This complex passes to the small intestine where attachment to receptor sites occurs on the ileal mucosa, and vitamin B12 is actively transported to portal plasma. Calcium and a pH greater than 6 are required for attachment to the receptor sites. When the receptor sites become saturated, absorption through passive diffusion occurs. Initially, oral doses of B12 and intrinsic factor (IF) will increase cobalamin levels in patients with pernicious anemia; however, 50% of patients develop intestinal antibodies to IF. After oral administration, peak plasma levels are attained in 8 to 12 hours.
Peak plasma levels of cyanocobalamin are achieved within 1 hour after intramuscular injection. Within 48 hours after injection, 50% to 98% of the dose is excreted in the urine, with the majority within the first 8 hours.
Cyanocobalamin is passively absorbed through the highly vascular nasal mucosa. In a pharmacokinetic study (n = 25) comparing the bioavailability of vitamin B12 intranasal spray to the intranasal gel, peak concentrations for the nasal spray were achieved within 1 to 2 hours of administration with a mean peak plasma concentration of approximately 748 +/- 549 pg/mL. Bioavailability of the intranasal spray was found to be 10% less than the intranasal gel. Because the intranasal forms have a lower absorption than the IM dosage form, intranasal B12 forms are administered once weekly. After 1 month of treatment in pernicious anemia patients, once weekly dosing of 500 mcg of B12 intranasal gel resulted in a statistically significant increase in B12 concentrations when compared to a once monthly 100 mcg IM dose.
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