ATC Class:B03BA

VA Class:VT100

AHFS Class:

• Vitamin B Complex 88:08

Generic Name(s):

• Cyanocobalamin

• Hydroxocobalamin

• Intrinsic Factor

Vitamin B₁₂, a cobalt-containing B complex vitamin, is commercially available as cyanocobalamin and hydroxocobalamin, which are synthetic forms of vitamin B₁₂.

Hydroxocobalamin (Cyanokit^®) is an antidote for cyanide poisoning.104

Vitamin B12 Deficiency

Vitamin B₁₂ is used in the treatment of pernicious anemia and other vitamin B₁₂ deficiency states. Cyanocobalamin is usually considered the vitamin B₁₂ preparation of choice. Hydroxocobalamin may, however, be preferred for the initial treatment of vitamin B₁₂ deficiencies. Although hydroxocobalamin produces a more sustained increase in plasma vitamin B₁₂ concentrations after parenteral administration than does parenteral administration of cyanocobalamin, hydroxocobalamin offers no therapeutic advantage over cyanocobalamin when given for maintenance in recommended doses every 2 or 4 weeks; serum cobalamin concentrations attained using these intervals are about the same with both drugs.

Vitamin B₁₂ deficiency is likely to occur in patients with conditions characterized by abnormalities of the gastric or ileal mucosa. Common causes of vitamin B₁₂ deficiency in temperate climates are Crohn's disease, colitis, and pernicious anemia. Other populations at risk for vitamin B₁₂ deficiency include the elderly, individuals with human immunodeficiency virus (HIV) infection, vegans, and those who have undergone partial or total gastrectomy.

Parenteral cyanocobalamin or hydroxocobalamin is usually indicated in patients with malabsorption of vitamin B₁₂, such as those with tropical or nontropical sprue (idiopathic steatorrhea, gluten-induced enteropathy); partial or total gastrectomy; regional enteritis; gastroenterostomy; ileal resection; or malignancies, granulomas, strictures, or anastomoses involving the ileum. When secretion of intrinsic factor (IF) is decreased by lesions that destroy the gastric mucosa (e.g., following ingestion of corrosives or in patients with extensive GI neoplasia) or by gastric atrophy secondary to multiple sclerosis, certain endocrine disorders, or iron deficiency, or when antibodies to IF are present in gastric juice, absorption of vitamin B₁₂ is decreased and cyanocobalamin or hydroxocobalamin may be required. Malabsorption of vitamin B₁₂ may also be caused by competition for vitamin B₁₂ by bacteria (blind loop syndrome) or by the fish tapeworm, Diphyllobothrium latum, or by administration of certain drugs. (See Drug Interactions.) Megaloblastic anemia associated with malabsorption syndromes characteristically results from folate deficiency; however, patients may also be deficient in vitamin B₁₂ and combined therapy may be warranted.

Cyanocobalamin nasal spray is used to maintain hematologic status in patients with pernicious anemia with no nervous system involvement who have responded (i.e., are in remission) to initial parenteral therapy with a vitamin B₁₂ preparation.103 Cyanocobalamin nasal spray also is used as a supplement for vitamin B₁₂ deficiency due to any of the following conditions: dietary vitamin B₁₂ deficiency associated with a vegan diet; malabsorption of vitamin B₁₂ secondary to structural or functional damage to the stomach or ileum, as can occur in individuals with HIV infection, Crohn's disease, tropical sprue, or nontropical sprue (i.e., idiopathic steatorrhea, gluten-induced enteropathy); inadequate secretion of IF resulting from lesions that have destroyed gastric mucosa (e.g., following ingestion of corrosives or in patients with extensive GI neoplasia), conditions associated with gastric atrophy (e.g., HIV infection, multiple sclerosis, certain endocrine disorders, iron deficiency, subtotal gastrectomy), total gastrectomy, regional ileitis, or ileal resection or malignancy; competition for vitamin B₁₂ by intestinal parasites (e.g., the fish tapeworm, D. latum ) or bacteria; or inadequate utilization of vitamin B₁₂ following the use of an antimetabolite for antineoplastic therapy.103

Long-term therapy with cyanocobalamin may not be necessary when other therapeutic measures (e.g., treatment of fish tapeworm, discontinuance of concomitant therapy, use of a gluten-free diet in patients with nontropical sprue) correct the underlying cause of the deficiency.

Increased vitamin B₁₂ requirements during pregnancy or in patients with thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, hepatic impairment, or renal impairment generally can be met by oral or intranasal administration of cyanocobalamin.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.101 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).101 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).101

The NAS has established an EAR and RDA for vitamin B₁₂ for adults based on the amount needed to maintain hematologic status and normal serum vitamin B₁₂ concentrations.101 The EAR and RDA for children and adolescents 1-18 years of age were established based on data in adults, since data in children and adolescents currently are not available.101 An AI has been set for infants 6 months of age and younger based on the observed mean vitamin B₁₂ intake of infants fed principally human milk.101 An AI for infants 7-12 months of age has been set based on the AI for younger infants and data from adults.101 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)

The principal goal of maintaining an adequate intake of vitamin B₁₂ in the US and Canada is to prevent vitamin B₁₂ deficiency and the neurologic complications associated with vitamin B₁₂ deficiency.101 Adequate intake of vitamin B₁₂ usually can be accomplished through consumption of foodstuffs; however, about 10-30% of geriatric individuals are unable to absorb naturally occurring vitamin B₁₂ and should consume vitamin B₁₂-fortified food or supplements.101 In the US, vitamin B₁₂ principally is obtained from mixed foods whose main ingredient is meat, fish, or poultry; milk and milk drinks; and fortified ready-to-eat cereals.101

For specific information on currently recommended AIs and RDAs of vitamin B₁₂ for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration.

Although an adequate amount of vitamin B₁₂ is usually obtained from dietary sources in patients with normal GI absorption, dietary vitamin B₁₂ deficiency can occur in some individuals, especially in strict vegetarians and their breast-fed infants. Cyanocobalamin or hydroxocobalamin is useful in preventing vitamin B₁₂ deficiency in these individuals. Increased vitamin B₁₂ requirements may rarely be associated with pregnancy, oral contraceptive use, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and/or hepatic and renal disease; however, dietary deficiency of vitamin B₁₂ is rare and nutritional megaloblastic anemia more often results from folate deficiency. Megaloblastic anemia in association with the puerperium, infancy, or alcoholism usually results from folate deficiency; however, vitamin B₁₂ deficiency may also occur and combined therapy may be warranted. Folic acid should be administered with vitamin B₁₂ if both folic acid and vitamin B₁₂ concentrations are inadequate. Malabsorption syndromes should be corrected, if present, and an adequate, well-balanced diet should be prescribed.

Metabolic Disorders

Cyanocobalamin has been used in the management of familial selective B₁₂ malabsorption and hereditary deficiency of transcobalamin II. Large doses of cyanocobalamin have been used in the management of methylmalonic aciduria in infants and in pregnant women when amniocentesis shows methylmalonic acidemia in the fetus†.

Schilling Test

Parenteral cyanocobalamin and hydroxocobalamin are used in conjunction with cyanocobalamin Co 57 in the Schilling test to study vitamin B₁₂ absorption. Cyanocobalamin nasal spray is not used in the Shilling test.

Cyanide Poisoning

Hydroxocobalamin (Cyanokit^®) is used for the treatment of known or suspected cyanide poisoning.104,107,108,109 In an open-label study in individuals older than 15 years of age treated with hydroxocobalamin for suspected smoke inhalation-associated cyanide poisoning, 67% of those with pretreatment cyanide levels considered potentially toxic survived.104,109 Survival rates of 42 or 56% were reported in 2 additional studies in subjects exposed to cyanide from fire or smoke inhalation.104 In a retrospective review undertaken to assess safety and efficacy of hydroxocobalamin for cyanide poisoning from sources other than fire or smoke (i.e., ingestion or inhalation), 71% of patients treated with hydroxocobalamin survived.104,108 Individuals in these studied received 5-20 g of hydroxocobalamin.104,108,109

Other Uses

Vitamin B₁₂ is ineffective in the treatment of psychiatric disorders unless they can be proven to be a consequence of vitamin B₁₂ deficiency.

Administration

Cyanocobalamin is administered by IM or deep subcutaneous injection. Cyanocobalamin also is administered orally and intranasally. Hydroxocobalamin is administered by IM injection or IV infusion. Oral therapy with vitamin B₁₂ preparations is markedly inferior to parenteral therapy and should be used only for the treatment of dietary vitamin B₁₂ deficiency in patients with normal GI absorption.

Parenteral Administration

Cyanocobalamin is administered by IM or deep subcutaneous injection. If the drug is administered subcutaneously, care should be taken to avoid injection into the dermis or upper subcutaneous tissue. Because the drug is excreted more rapidly after IV injection, the IV route should be avoided.

Hydroxocobalamin is administered by IM injection (vitamin deficiency) or IV infusion (cyanide poisoning). The IV route should not be used for the treatment of vitamin B₁₂ deficiency.105

Reconstitution and Administration

Hydroxocobalamin (Cyanokit^®) is administered by IV infusion.104 Administration of hydroxocobalamin may require a dedicated IV line; the drug should not be administered through the same IV line as blood products.104

Hydroxocobalamin lyophilized powder should be reconstituted by adding 100 mL of 0.9% sodium chloride injection to a vial labeled as containing 2.5 g of hydroxocobalamin to provide a solution containing 25 mg/mL.104 Lactated Ringer's injection or 5% dextrose injection can be used if 0.9% sodium chloride injection is not available.104 Following addition of the diluent, each vial should be inverted or rocked for at least 30 seconds; the vial should not be shaken.104 The initial dose of hydroxocobalamin is 5 g (2 vials).104 The reconstituted solution should be inspected visually for particulate matter and color.104 The reconstituted solution should be dark red and should not be used if not dark red or if particulate matter is present.104

Intranasal Administration

Cyanocobalamin is administered by nasal inhalation using a metered-dose nasal spray pump.103 Patients should be instructed carefully in the use of the pump. To obtain optimum results, patients should be given a copy of the patient instructions provided by the manufacturer.

Prior to intranasal administration of cyanocobalamin nasal spray, patients should clear their nasal passages.110 Because hot foods can produce nasal secretions and interfere with absorption of the drug, cyanocobalamin nasal spray should be administered 1 hour before or 1 hour after ingestion of hot foods or liquids.103 Prior to initial use, the nasal pump must be primed.103 Priming of the pump should be repeated before each dose.103 Patients should insert the nasal adapter 1 cm into one nostril, point the tip of the adapter toward the back of the nose, hold the other nostril closed, and tilt their head slightly forward.110 The patient should pump the drug into the nostril, sniff gently during and immediately following dosing, return the head to an upright position, and remove the pump unit from the nose.110

Dosage

Vitamin B12 Deficiency

Hematocrit, reticulocyte count, vitamin B₁₂, folate, and iron levels should be obtained prior to treatment for vitamin B₁₂ deficiency;102,103 hematologic parameters should be monitored as necessary during therapy.102,103

In general, patient response to vitamin B₁₂ therapy depends on the degree and nature of the deficiency; however, once proper corrective measures are undertaken, deficient patients generally respond rapidly. Early neurologic symptoms can be completely reversed by prompt treatment with vitamin B₁₂; however, vitamin B₁₂ deficiency that is allowed to progress for longer than 3 months may result in permanent degenerative lesions of the spinal cord. During the first 24 hours of treatment, the patient experiences an improved sense of well being; within 48 hours, the bone marrow begins to become normoblastic. Reticulocytosis generally begins within 2-5 days after the start of therapy.

Parenteral Dosage

For the treatment of pernicious anemia, the usual initial IM or subcutaneous dosage of cyanocobalamin is 100 mcg daily for 6-7 days. If clinical manifestations have improved and a reticulocyte response is observed, cyanocobalamin can then be administered in a dosage of 100 mcg every other day for 7 doses and then 100 mcg every 3-4 days for 2-3 weeks. Once hematologic values have returned to normal, cyanocobalamin can be administered IM or subcutaneously in a dosage of 100 mcg once monthly for life. Folic acid should be used concomitantly if necessary.

For the treatment of vitamin B₁₂ deficiency in adults, the usual IM dosage of hydroxocobalamin is 30 mcg daily for 5-10 days. Once clinical symptoms have subsided and the blood components have returned to normal, monthly IM maintenance doses of 100-200 mcg appear to be sufficient to maintain a normoblastic bone marrow. For the treatment of vitamin B₁₂ deficiency in children, the usual total IM dose of hydroxocobalamin is 1-5 mcg over 2 or more weeks, given in single doses of 100 mcg. For maintenance, the IM or subcutaneous pediatric dosage is at least 60 mcg per month; however, smaller doses may often suffice for deficiency states not caused by pernicious anemia.

Intranasal Dosage

The commercially available cyanocobalamin metered-dose pump delivers 0.1 mL of solution containing 500 mcg of the drug per actuation. The recommended initial dosage of cyanocobalamin nasal spray is 500 mcg (one actuation) administered intranasally once weekly.103 The dosage may need to be increased in patients who experience a decline in serum vitamin B₁₂ concentrations after 1 month of therapy with this preparation.103 Therapy with a parenteral vitamin B₁₂ preparation may be necessary in patients who do not achieve a satisfactory response to intranasal cyanocobalamin.103

Parenteral and Intranasal Maintenance Therapy

Patients with pernicious anemia require maintenance injections of cyanocobalamin or hydroxocobalamin for the remainder of their lives to prevent irreversible neurologic damage. Alternatively, cyanocobalamin nasal spray can be used to maintain hematologic status in adults who have responded to initial parenteral therapy with a vitamin B₁₂ preparation. Because the liver can retain vitamin B₁₂ for long periods, it may be months or years before a patient whose pernicious anemia has been corrected with vitamin B₁₂ has a relapse after therapy is discontinued. In one study, the average interval between discontinuance of therapy and full relapse was about 69 months (range 21-123 months); macrocytosis without anemia occurred earlier than that with anemia. For this reason and because the patient receiving maintenance therapy feels no physical improvement and will experience falsely reassuring clinical well-being long after the vitamin has been discontinued, it is extremely important that the patient understand the need for lifelong, regular maintenance therapy. Although the need for monthly maintenance therapy with parenteral vitamin B₁₂ has been questioned since many months to years are required to deplete body stores of the vitamin following discontinuance of therapy, the safety and efficacy of less frequent (e.g., every 6 months) administration of parenteral vitamin B₁₂ have not been fully determined. Pending accumulation of additional data, monthly maintenance therapy is currently recommended if a parenteral product is used for such therapy.

In an open-label study in patients who had received at least 6 months of IM therapy with vitamin B₁₂ for vitamin B₁₂ malabsorption, intranasal administration of cyanocobalamin 500 mcg once weekly for 4 weeks resulted in clinically adequate serum vitamin B₁₂ concentrations over the 4-week period.

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of vitamin B₁₂ currently recommended by the National Academy of Sciences (NAS) for healthy infants through 6 months of age is 0.4 mcg of vitamin B₁₂ (0.06 mcg/kg) daily and for those 7-12 months of age is 0.5 mcg (0.06 mcg/kg) daily.101 Infants born to vegan mothers should be supplemented with the AI for vitamin B₁₂ from birth, since their vitamin B₁₂ stores at birth are low and their mother's milk may supply very small amounts of the vitamin.101 The Recommended Dietary Allowance (RDA) of vitamin B₁₂ currently recommended by NAS for healthy children 1-3, 4-8, 9-13, or 14-18 years of age is 0.9, 1.2, 1.8, or 2.4 mcg of vitamin B₁₂ daily, respectively.101 The RDA for healthy men and women 19-50 years of age is 2.4 mcg of vitamin B₁₂ daily.101 The RDA for healthy men and women 51 years of age or older is 2.4 mcg of vitamin B₁₂ daily.101 While the RDA for men and women 51 years of age and older is the same as that for younger adults, the NAS advises that most of the amount be obtained from foods fortified with vitamin B₁₂ or a vitamin B₁₂ supplement.101 These RDAs are not expected to meet the needs of individuals with malabsorption syndrome.101 HIV-infected individuals with chronic diarrhea also may require additional oral or parenteral vitamin B₁₂.101 Some individuals (i.e., those with pernicious anemia, Crohn's disease involving the terminal ileum, postgastrectomy, gastric bypass, or ileal resection) will require vitamin B₁₂ under a clinician's direction.101 Bioavailability of vitamin B₁₂ may be reduced in individuals with atrophic gastritis or pancreatic insufficiency, or those receiving long-term proton-pump inhibitor (e.g., omeprazole) therapy.101 While these individuals require usual amounts of the vitamin, intake of the vitamin should be from vitamin B₁₂-fortified food or vitamin supplements containing B₁₂.101

The RDA of vitamin B₁₂ recommended by the NAS for pregnant women is 2.6 mcg daily.101 To ensure an adequate concentration of vitamin B₁₂ in milk, the NAS recommends a RDA of 2.8 mcg of vitamin B₁₂ daily for lactating women.101

Oral cyanocobalamin dosages of 1-25 mcg daily are usually considered sufficient as a dietary supplement in patients with normal GI absorption. Although most clinicians consider oral therapy inadequate and unreliable in the treatment of vitamin B₁₂ deficiencies, oral dosages of up to 1 mg (1000 mcg) daily have been recommended by some clinicians when patients refuse parenteral therapy. Although follow-up therapy for one month with an oral multivitamin preparation containing 15 mcg of vitamin B₁₂ daily may be beneficial for patients with multiple vitamin deficiencies who have normal GI absorption, multivitamin preparations are usually unnecessary in patients who maintain a well-balanced diet.

Cyanide Poisoning

The initial dose of hydroxocobalamin (Cyanokit^®) for the treatment of known or suspected cyanide poisoning in adults is 5 g administered by IV infusion over 15 minutes.104 A second 5-g dose may be administered depending on the severity of the poisoning and response of the patient.104 If a second 5-g dose is needed, the dose is administered by IV infusion over 15 minutes (for patients in extremis) to 2 hours; the rate of administration depends on the patient's condition.104 Hydroxocobalamin is used in conjunction with airway and cardiovascular support, and management of seizure activity.104

A hydroxocobalamin dose of 70 mg/kg has been used for the treatment of cyanide poisoning in children†.104,107

Metabolic Disorders

For the management of familial selective B₁₂ malabsorption†, an IM cyanocobalamin dosage of 1 mg (1000 mcg) weekly for 3 weeks, followed by 250 mcg monthly for maintenance has been used. For the management of methylmalonic aciduria†, an IM cyanocobalamin dosage of 1 mg (1000 mcg) daily has been used. Cyanocobalamin has also been given prepartum to prevent methylmalonic aciduria in the neonate†; a prepartum IM cyanocobalamin dosage of 5 mg (5000 mcg) daily and a neonatal IM dosage of 1 mg (1000 mcg) daily for 11 days in combination with a protein-restricted diet have been used. For the management of congenital transcobalamin II deficiency†, 1-2 mg (1000-2000 mcg) of cyanocobalamin has been given weekly by IM injection.

Adverse Effects

Vitamin B₁₂ is usually nontoxic even in large doses; however, mild transient diarrhea, peripheral vascular thrombosis, itching, transitory exanthema, urticaria, feeling of swelling of the entire body, anaphylaxis, and death have been reported in patients receiving parenteral vitamin B₁₂. Although allergic reactions to vitamin B₁₂ have generally been attributed to impurities in the preparation, a few patients have reacted positively to skin testing with purified cyanocobalamin or hydroxocobalamin. Pulmonary edema and congestive heart failure have been reported during early therapy with parenteral vitamin B₁₂, possibly because of an increase in blood volume induced by the drug. Headache, infection, and paresthesia have been reported in patients receiving intranasal cyanocobalamin.103

Allergic reactions, transient chromaturia, erythema, rash (predominately acneform), increased blood pressure, nausea, headache, oxalate crystals in urine, and infusion site reaction has occurred in adults receiving hydroxocobalamin (Cyanokit^®).104

Precautions and Contraindications

A sensitivity history should be obtained from the patient prior to administration of vitamin B₁₂; an intradermal test dose is recommended before vitamin B₁₂ is administered for the management of vitamin deficiency to patients who may be sensitive to cobalamins.

Serum potassium concentrations should be monitored during early vitamin B₁₂ therapy and potassium administered if necessary, since fatal hypokalemia could occur upon conversion of megaloblastic anemia to normal erythropoiesis with vitamin B₁₂ as a result of increased erythrocyte potassium requirements. Because vitamin B₁₂ deficiency may suppress the signs of polycythemia vera, treatment with cyanocobalamin or hydroxocobalamin may unmask this condition. The increase in nucleic acid degradation produced by administering vitamin B₁₂ to vitamin B₁₂-deficient patients could result in gout in susceptible individuals. Therapeutic response to vitamin B₁₂ may be impaired by concurrent infection, uremia, folic acid or iron deficiency, or by drugs having bone marrow suppressant effects (e.g., chloramphenicol).

Folic acid should be administered with extreme caution to patients with undiagnosed anemia, since folic acid may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing neurologic complications to progress. This may result in severe nervous system damage before the correct diagnosis is made. Vitamin preparations containing folic acid should be avoided by patients with pernicious anemia because folic acid may actually potentiate neurologic complications of vitamin B₁₂ deficiency. Conversely, doses of cyanocobalamin or hydroxocobalamin exceeding 10 mcg daily may improve folate-deficient megaloblastic anemia and obscure the true diagnosis.

Efficacy of cyanocobalamin nasal spray has not been established in patients with nasal congestion, allergic rhinitis, or upper respiratory tract infection; use of the nasal spray should be deferred until clinical manifestations have subsided in patients with these conditions.103

Cyanocobalamin should not be used in patients with early Leber's disease (hereditary optic nerve atrophy), since rapid optic nerve atrophy has been reported following administration of the drug to these patients. Vitamin B₁₂ is contraindicated in patients who have experienced hypersensitivity reactions to the vitamin or to cobalt. There are no contraindications to use of hydroxocobalamin (Cyanokit^®) for the treatment of cyanide poisoning.104

Cyanocobalamin injection contains aluminum that may be toxic.102 Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired.102 Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.102 Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 g/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity.102 Tissue loading may occur at even lower rates of administration.102

Because of the potential for hydroxocobalamin to cause photosensitivity, patients who have received the drug for the treatment of cyanide poisoning should avoid direct sun exposure while their skin is discolored.104

Pediatric Precautions

Safety and efficacy of hydroxocobalamin (Cyanokit^®) has not been established in children.104 However, the drug has been administered to pediatric patients.107

Each mL of cyanocobalamin injection (e.g., generic preparation manufactured by Abraxis) contains 15 mg of benzyl alcohol as a preservative.102 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.102,111,112,113,114,115,116 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.111,112,113,114,115,116 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,111,113 the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.111

Geriatric Precautions

At least 50 individuals 65 years of age or older have received hydroxocobalamin for the treatment of known or suspected cyanide poisoning.104 No overall differences in safety or efficacy were observed between geriatric individuals and younger adults.104 Dosage of hydroxocobalamin does not need to be modified in geriatric adults.104

Mutagenicity and Carcinogenicity

Various tests have not shown hydroxocobalamin to be mutagenic.104

Pregnancy, Fertility, and Lactation

Pregnancy

Adequate and well-controlled studies have not been conducted in pregnant women.102,103,104 However, vitamin B₁₂ requirements are increased in pregnant women.101 Parenteral preparations should be used during pregnancy only when the potential benefits justify the potential risks to the fetus.102,103,104,105

Lactation

Vitamin B₁₂ is distributed into human milk.102,104 Vitamin B₁₂ requirements are increased in lactating women.101

Hydroxocobalamin may be administered to lactating women with suspected or known cyanocobalamin poisoning.104 There is no data available to determine when breastfeeding may be restarted following administration of IV hydroxocobalamin.104

Safety of concomitant administration of other cyanide antidotes with hydroxocobalamin (Cyanokit^®) has not been established.104 Caution is advised if another cyanide antidote is administered to patients receiving hydroxocobalamin.104

Absorption of vitamin B₁₂ from the GI tract may be decreased by aminoglycoside antibiotics, colchicine, extended-release potassium preparations, aminosalicylic acid and its salts, anticonvulsants (e.g., phenytoin, phenobarbital, primidone), cobalt irradiation of the small bowel, and by excessive alcohol intake lasting longer than 2 weeks. Neomycin-induced malabsorption of vitamin B₁₂ may be increased by concurrent administration of colchicine.

Ascorbic acid may destroy substantial amounts of dietary vitamin B₁₂ in vitro; this possibility should be considered when large doses of ascorbic acid are ingested within 1 hour of oral vitamin B₁₂ administration.

Prednisone has been reported to increase the absorption of vitamin B₁₂ and secretion of IF in a few patients with pernicious anemia, but not in patients with partial or total gastrectomy. The clinical importance of these findings is unknown.

Concurrent administration of chloramphenicol and vitamin B₁₂ reportedly may antagonize the hematopoietic response to vitamin B₁₂ in vitamin B₁₂-deficient patients. The hematologic response to vitamin B₁₂ in patients receiving both drugs should be carefully monitored and alternate anti-infectives should be considered.

Laboratory Test Interferences

Methotrexate, pyrimethamine, and most anti-infectives invalidate diagnostic microbiologic blood assays for vitamin B₁₂. Prior administration of cyanocobalamin may result in false-positive test results for intrinsic factor (IF) antibodies that are present in blood in approximately 50% of patients with pernicious anemia.

Hydroxocobalamin (Cyanokit^®) interferes with certain laboratory parameters that are determined using colorimetric methods (e.g., clinical chemistry, hematology, coagulation, urine parameters).104 This interference is due to the deep red color of hydroxocobalamin.104 The extent and duration of interference depends on several factors and the product labeling should be consulted for specific information.104

Pharmacology

In humans, an exogenous source of vitamin B₁₂ is required for nucleoprotein and myelin synthesis, cell reproduction, normal growth, and the maintenance of normal erythropoiesis. Cells characterized by rapid division (e.g., epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for vitamin B₁₂. Vitamin B₁₂ can be converted to coenzyme B₁₂ in tissues, and as such 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, and a functional folate deficiency occurs. 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 that begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head. Parenteral administration of vitamin B₁₂ completely reverses the megaloblastic anemia and GI symptoms of vitamin B₁₂ deficiency; the degree of improvement in neurologic symptoms depends on the duration and severity of the lesions, although progression of the lesions is immediately arrested.

Hydroxocobalamin detoxifies cyanide by binding to it to form cyanocobalamin which is excreted in the urine.104,107

Pharmacokinetics

Absorption

Vitamin B₁₂ is irregularly absorbed from the distal small intestine following oral administration. Dietary vitamin B₁₂ is protein bound and this bond must be split by proteolysis and gastric acid before absorption. In the stomach, free vitamin B₁₂ is attached to intrinsic factor (IF); IF, a glycoprotein secreted by the gastric mucosa, is necessary for active absorption of the vitamin from the GI tract. The vitamin B₁₂-IF complex passes into the intestine, where much of the complex is transiently retained at specific receptor sites in the wall of the lower ileum before the vitamin B₁₂ portion is absorbed into systemic circulation. Calcium and a pH greater than approximately 6 (range 5.4-8) are required for attachment to the receptor sites. The IF transport mechanism is saturated by 1.5-3 mcg of vitamin B₁₂; however, additional amounts of the vitamin may be absorbed independent of IF by passive diffusion through the intestinal wall. This mechanism of passive diffusion becomes important only in the presence of quantities of vitamin B₁₂ much larger (approximating at least 1 mg) than the usual dietary intake (5-15 mcg). Absorption of vitamin B₁₂ following oral administration is decreased by structural or functional damage to the stomach or ileum. In patients with pernicious anemia, the extent of absorption of vitamin B₁₂ is initially increased by concurrent oral administration of intrinsic factor; however, approximately 50% of patients treated with this combination develop an intestinal antibody to some fraction of the IF concentrate and become refractory to the mixture.

Following oral administration of vitamin B₁₂ doses less than 3 mcg, peak plasma concentrations are not reached for 8-12 hours because the vitamin is transiently retained in the wall of the lower ileum. Normal serum vitamin B₁₂ concentrations have been reported to range from 200-900 pg/mL, with a mean normal plasma concentration of 450 pg/mL. In general, serum vitamin B₁₂ concentrations less than 200 pg/mL indicate vitamin B₁₂ deficiency and concentrations less than 100 pg/mL usually result in megaloblastic anemia and/or neurologic damage.

In healthy individuals and in vitamin B₁₂-deficient patients, IM administration of hydroxocobalamin produces a more sustained rise in serum cobalamin concentration and less short-term urinary excretion of cobalamin than does a similar dose of cyanocobalamin. Hydroxocobalamin is absorbed more slowly from the site of injection than is cyanocobalamin and there is some evidence that liver uptake of hydroxocobalamin may be greater than that of cyanocobalamin. It is believed that the increased retention of hydroxocobalamin compared with that of cyanocobalamin results from the greater affinity of hydroxocobalamin for both specific and nonspecific binding proteins in blood and tissues, as well as to its slower absorption from the injection site.

Following intranasal administration of cyanocobalamin, peak serum concentrations of vitamin B₁₂ are attained within 1.25-1.9 hours and average 758 pg/mL.103 Systemic bioavailability of cyanocobalamin nasal spray reportedly is about 6.1% of that attained with IM administration of the vitamin.103

Distribution

In the intestinal mucosal cell, vitamin B₁₂ is released from the vitamin B₁₂-IF complex and becomes rapidly bound to plasma proteins in the blood, mainly to a specific β-globulin transport protein, transcobalamin II. Lesser amounts are bound to the storage protein transcobalamin I (an α-glycoprotein) and to transcobalamin III (an inter-α-glycoprotein); a small amount (1-10%) may be free or very loosely bound. Blood concentrations of transcobalamin II recede after vitamin B₁₂ is absorbed. In the fasting state, the majority of circulating vitamin B₁₂ is bound to transcobalamin I.

Vitamin B₁₂ is distributed into the liver, bone marrow, and other tissues, including the placenta. At birth, the blood concentration of vitamin B₁₂ in neonates is 3-5 times that in the mother. Vitamin B₁₂ is distributed into the milk of nursing women in concentrations that approximate the maternal blood vitamin B₁₂ concentration. Total body stores of vitamin B₁₂ in healthy individuals are estimated to range from 1-11 mg, with an average of 5 mg; 50-90% is stored in the liver. Vitamin B₁₂ is believed to be converted to coenzyme form in the liver and is probably stored in tissues in this form.

Elimination

The daily turnover rate of vitamin B₁₂ is 0.05-0.2% of total body stores, and may range from 0.4-8 mcg, depending on the size of the storage pool. In healthy individuals receiving only dietary vitamin B₁₂, about 3-8 mcg of the vitamin is secreted into the GI tract daily, mainly via bile, with all but about 1 mcg being reabsorbed; less than 0.25 mcg of the vitamin is usually excreted in urine daily. When vitamin B₁₂ is administered in amounts which exceed the binding capacity of plasma, liver, and other tissues, it is free in the blood and available for urinary excretion. Although about 80-90% of an initial injected dose up to 50 mcg is retained by the body, with higher doses, the percent retained decreases rapidly and is subject to individual variation. Following IV or IM administration of 0.1-1 mg of cyanocobalamin, 50-90% of the dose may be excreted in urine by glomerular filtration within 48 hours, with the major portion being excreted in the first 8 hours. Cyanocobalamin is excreted much more rapidly after IV than after IM injection. Within 72 hours after IM injection of 0.5-1 mg of hydroxocobalamin, 16-66% of the dose may be excreted in urine. The major portion is excreted within the first 24 hours. Approximately 10-15 mcg of vitamin B₁₂ is synthesized daily by bacteria in the large intestine but is excreted in feces without being absorbed.

Chemistry and Stability

Chemistry

Vitamin B₁₂ is a cobalt-containing B complex vitamin synthesized by microorganisms. Vitamin B₁₂ is a group of cobalt-containing corroids, known as cobalamins, having biologic activity in humans. Vitamin B₁₂ is present in coenzyme form (mainly as adenosylcobalamin and methylcobalamin) in many foods of animal origin, particularly liver, kidney, fish and shellfish, meat, and dairy foods; plants contain minimal amounts of the vitamin.

Cyanocobalamin and Hydroxocobalamin

Cyanocobalamin and hydroxocobalamin are synthetic forms of vitamin B₁₂. These drugs share the cobalamin molecular structure but differ in the group attached to the cobalt atom. Cyanocobalamin and hydroxocobalamin have equivalent vitamin B₁₂ activity. Cyanocobalamin, which contains an anionic cyanide group attached to the cobalt atom, occurs as dark red crystals or an amorphous or crystalline red powder and is sparingly soluble in water and soluble in alcohol.

Commercially available cyanocobalamin injections are clear, pink to red solutions and have a pH of 4.5-7. Hydroxocobalamin, which contains a hydroxyl group attached to the cobalt atom, occurs as dark red crystals or as a red crystalline powder and is sparingly soluble in water and in alcohol. Commercially available hydroxocobalamin injections are clear, deep red solutions and have a pH of 3.5-5. As an injection, hydroxocobalamin is also available as a sterile, dark red, lyophilized powder (Cyanokit^®) for IV infusion.104 Following reconstitution, hydroxocobalamin solutions are dark red and have a pH of 3.5-6.104

Commercially available cyanocobalamin nasal spraynhas a pH of 4.5-5.5 and also contains sodium citrate, citric acid, glycerin, benzalkonium chloride, and purified water.103

Stability

Cyanocobalamin and hydroxocobalamin are very hygroscopic; both drugs should be protected from light. Solutions of cyanocobalamin in water or 0.9% sodium chloride are stable and can be autoclaved for short periods of time (15-20 minutes) at 121°C.

Hydroxocobalamin for injection (Cyanokit^®) should be stored at 25°C.104 Hydroxocobalamin for injection (Cyanokit^®) may be stored for short periods at temperatures that occur with usual transport (15 days at 5-40°C), transport in the desert (4 days at 5-60°C), and freezing/defrost cycles (15 days in a range from -20 to 40°C).104 Reconstituted solutions may be stored at a temperature not exceeding 40°C for up to 6 hours; the solution should not be frozen.104

Vitamin B₁₂ injection has been reported to be incompatible with chlorpromazine hydrochloride, phytonadione, prochlorperazine edisylate, warfarin sodium, ascorbic acid, dextrose, heavy metals, oxidizing or reducing agents, and alkaline or strongly acidic solutions. Specialized references should be consulted for more specific compatibility information.

Hydroxocobalamin injection (Cyanokit^®) is incompatible with ascorbic acid, diazepam, dobutamine, fentanyl, nitroglycerin, pentobarbital, propofol, sodium nitrite, sodium thiosulfate, thiopental.104

Cyanocobalamin nasal spray should be stored upright at a controlled room temperature of 15-30°C.103 Freezing should be avoided.103

Only references cited for selected revisions after 1984 are available electronically.

100. National Research Council Food and Nutrition Board Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press; 1989:158-65.

101. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. (Prepublication copy uncorrected proofs.)

102. Abraxis Pharmaceuticals. Cyanocobalamin injection prescribing information. Schaumburg, IL; 2005 Jun.

103. QOL Medical Company. Nascobal^® (cyanocobalamin nasal spray) prescribing information. Kirkland, WA; 2006 Aug.

104. Dey. Cyanokit^® (hydroxocobalamin for injection) prescribing information. Napa, CA; 2006 Dec. (

105. Watson Laboratories. Hydroxocobalamin injection prescribing information. Corona, CA; 2006 Feb.

106. Nature's bounty vitamin B₁₂ 1000 mcg tablets package information. From ([Web]). Accessed 31 May 2007.

107. Geller RJ, Barthold C, Salers JA, Hall AH. Pediatric cyanide poisoning: causes, manifestations, management, and unmet needs. Pediatrics . 2006; 118:2146-58. [PubMed 17079589]

108. Borron SW, Baud FJ, Mégarbane B, Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by injestion or inhalation. Am J Emerg Med . 2007; 25:551-8. [PubMed 17543660]

109. Borron SW, Baud FJ, Barriot P et al. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med . 2007; 49:794-801. [PubMed 17481777]

110. QOL Medical Company. Nascobal^® (cyanocobalamin nasal spray) patient information. Kirkland, WA; 2006.

111. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics . 1983; 72:356-8. [PubMed 6889041]

112. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull . 1982; 12:10-11. [PubMed 7188569]

113. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep . 1982; 31:290-91. [PubMed 6810084]

114. Gershanik J. Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med . 1982; 307:1384-8. [PubMed 7133084]

115. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol . 1984; 1:288-92. [PubMed 6440575]

116. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol . 1984; 148:344-6. [PubMed 6695984]