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cyanocobalamin 1,000 mcg/ml vial (generic vitamin b-12)

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Uses

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. 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.

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. 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). 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).

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. 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. 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. An AI for infants 7-12 months of age has been set based on the AI for younger infants and data from adults.

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. 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. 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.

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. 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. Survival rates of 42 or 56% were reported in 2 additional studies in subjects exposed to cyanide from fire or smoke inhalation. 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. Individuals in these studied received 5-20 g of hydroxocobalamin.

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.

Dosage and Administration

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.

Reconstitution and Administration

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

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. Lactated Ringer's injection or 5% dextrose injection can be used if 0.9% sodium chloride injection is not available. Following addition of the diluent, each vial should be inverted or rocked for at least 30 seconds; the vial should not be shaken. The initial dose of hydroxocobalamin is 5 g (2 vials). The reconstituted solution should be inspected visually for particulate matter and color. The reconstituted solution should be dark red and should not be used if not dark red or if particulate matter is present.

Intranasal Administration

Cyanocobalamin is administered by nasal inhalation using a metered-dose nasal spray pump. 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. 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. Prior to initial use, the nasal pump must be primed. Priming of the pump should be repeated before each dose. 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. 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.

Dosage

Vitamin B12 Deficiency

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

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. 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. Therapy with a parenteral vitamin B12 preparation may be necessary in patients who do not achieve a satisfactory response to intranasal cyanocobalamin.

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. 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. 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. The RDA for healthy men and women 19-50 years of age is 2.4 mcg of vitamin B12 daily. The RDA for healthy men and women 51 years of age or older is 2.4 mcg of vitamin B12 daily. 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. These RDAs are not expected to meet the needs of individuals with malabsorption syndrome. HIV-infected individuals with chronic diarrhea also may require additional oral or parenteral vitamin B12. 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. 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. 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.

The RDA of vitamin B12 recommended by the NAS for pregnant women is 2.6 mcg daily. 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.

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. A second 5-g dose may be administered depending on the severity of the poisoning and response of the patient. 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. Hydroxocobalamin is used in conjunction with airway and cardiovascular support, and management of seizure activity.

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

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.

Cautions

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.

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).

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.

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.

Cyanocobalamin injection contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. 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. Tissue loading may occur at even lower rates of administration.

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.

Pediatric Precautions

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

Each mL of cyanocobalamin injection (e.g., generic preparation manufactured by Abraxis) contains 15 mg of benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates. Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, 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.

Geriatric Precautions

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

Mutagenicity and Carcinogenicity

Various tests have not shown hydroxocobalamin to be mutagenic.

Pregnancy, Fertility, and Lactation

Pregnancy

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

Lactation

Vitamin B12 is distributed into human milk. Vitamin B12 requirements are increased in lactating women.

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

Drug Interactions

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

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.

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. Systemic bioavailability of cyanocobalamin nasal spray reportedly is about 6.1% of that attained with IM administration of the vitamin.

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.

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