Pharmacologic Classifications: Water-Soluble Vitamins, Hematinics
General Information: 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 (see Hydroxocobalamin monograph). Cyanocobalamin is available nasally, orally, and parenterally, and is equal in biologic activity to hydroxocobalamin. Cyanocobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the 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. Vitamin B12 is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Cyanocobalamin was approved by the FDA in 1949. The intranasal metered gel solution form (Nascobal®) was approved in November 1996 for vitamin B12 deficiency resulting from various conditions; in 2002, such conditions were expanded to include use in vitamin B12-deficient patients with HIV infection, AIDS, or Crohn's disease. An intranasal spray solution of B12, also called Nascobal®, with the same indications, was FDA approved in January 2005. Another intranasal spray, CaloMist™, was approved July 2007 for maintenance therapy after normalization with IM vitamin B12.
Mechanism of Action: 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.
Pharmacokinetics: 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. This vitamin crosses the placenta and is distributed into breast milk. Enterohepatic recirculation conserves systemic stores. The half-life is about 6 days (400 days in the liver). Elimination is primarily through the bile; however, excess cyanocobalamin is excreted unchanged in the urine.
Route-Specific Pharmacokinetics: Oral Route: 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.1 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. Peak plasma levels are attained for oral in 8—12 hours.
Intravenous Route: Peak plasma levels of cyanocobalamin are attained within 1 hour for parenteral doses.
Intramuscular Route: Bioavailability of the nasal gel and spray forms relative to an IM injection are about 9% and 6%, respectively. Because the intranasal forms have lower absorption than the IM dosage form, intranasal B12 forms are administered once weekly. After 1 month of treatment in pernicious anemia patients, the once weekly dosing of 500 mcg B12 intranasal gel resulted in a statistically significant increase in B12 levels when compared to a once monthly 100 mcg IM dose.
Contraindications/Precautions: Who should not take this medication? Patients with early hereditary optic nerve atrophy, cyanocobalmin hypersensitivity, and those who are pregnant. Your health care provider needs to know if you have any of these conditions: kidney disease; Leber's disease; megaloblastic anemia; an unusual or allergic reaction to cyanocobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding.
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 (see separate monograph in Less Common Drugs).
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, vitamin B12 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 or hydroxocobalamin may unmask this condition.
Folic Acid, vitamin B9 is not a substitute for cyanocobalamin, 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. 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 folic acid deficiency may result in a blunted or impeded response to cyanocobalamin therapy.2
Certain conditions may blunt or impede therapeutic response to cyanocobalamin therapy. These include serious infection, uremia or renal failure, drugs with bone marrow suppression properties (e.g., chloramphenicol), or concurrent undiagnosed folic acid or iron deficiency anemia. The mechanism appears to be interference with erythropoiesis. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of cyanocobalamin.
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.
Parenteral and intranasal cyanocobalamin, vitamin B12 are classified as pregnancy category C. 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.3 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 (see Dosage).4
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 (see Dosage).4 The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding.5 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.
This list may not include all contraindications.
Pregnancy: Parenteral and intranasal cyanocobalamin, vitamin B12 are classified as pregnancy category C. 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.3 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 (see Dosage).4
Breast-feeding: 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 (see Dosage).4 The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding.5 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.
Interactions: Several drugs, including para-aminosalicylic acid, have been reported to reduce the absorption of cyanocobalamin, vitamin B12. Monitor for the desired therapeutic response to vitamin B12.6
The heavy consumption of ethanol for greater than 2 weeks has been reported to reduce the absorption of cyanocobalamin, vitamin B12.6 Patients should be aware that heavy, chronic ethanol use may counteract the therapeutic effects of vitamin B12; such patients with regular and chronic ethanol consumption be monitored for the desired therapeutic response to vitamin B12.6
Several drugs, including colchicine, have been reported to reduce the absorption of cyanocobalamin, vitamin B12.6 Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa.7 Although further study of these interactions is necessary, patients receiving these agents concurrently should be monitored for the desired therapeutic response to vitamin B12.67
In a study of 10 healthy male volunteers, omeprazole, in doses of 20 mg—40 mg per day, caused a significant decrease in the oral absorption of cyanocobalamin, vitamin B12.8Theoretically this interaction is possible with other proton pump inhibitors (PPIs), although specific clinical data are lacking. Patients receiving long-term therapy with omeprazole or other proton pump inhibitors (PPIs) should be monitored for signs of B12 deficiency.
Chloramphenicol can antagonize the hematopoietic response to cyanocobalamin, vitamin B12 through interference with erythrocyte maturation. Chloramphenicol is known to cause bone marrow suppression, especially when serum concentrations exceed 25 mcg/ml.910 Chloramphenicol should be discontinued if anemia attributable to chloramphenicol is noted during periodic blood studies, which should be done approximately every 2 days during chloramphenicol receipt. Aplastic anemia and hypoplastic anemia are known to occur after chloramphenicol administration. Peripherally, pancytopenia is most often observed, but only 1—2 of the major cell types (erythrocytes, leukocytes, platelets) may be depressed in some cases.10
Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor.11 The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin, vitamin B12 supplementation. Certain individuals may be predisposed to this interaction. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
Medications know to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to cyanocobalamin, vitamin B12therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12.6 However, cancer patients usually benefit from vitamin B12supplementation. The use of methotrexate may additionally invalidate diagnostic assays for folic acid and vitamin B12; however, this is a diagnostic laboratory test interference and not a drug interaction.6
The intranasal forms of cyanocobalamin, vitamin B12, should be administered at least 1 hour before or 1 hour after ingestion of hot food or liquids.6 Hot foods may cause nasal secretions and a resulting loss of medication or medication efficacy.6 Interactions between foods and oral or injectable forms of cyanocobalamin are not expected.
Depressed levels of cyanocobalamin, vitamin B12, and abnormal Schilling's test have been reported in patients receiving octreotide.12
The use of antiinfective agents or pyrimethamine may invalidate diagnostic assays for folic acid and vitamin B12; however, these are diagnostic laboratory test interferences and not true drug interactions.6
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
Adverse Reactions & Side Effects: Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg
In most cases, cyanocobalamin is nontoxic, even in large doses. Adverse reactions reported following cyanocobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.
During the initial treatment period with cyanocobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral cyanocobalamin. This is believed to result from the increased blood volume induced by cyanocobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral cyanocobalamin.4
Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with cyanocobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral cyanocobalamin.4
Adverse reactions associated with the intranasal cyanocobalamin nasal spray CaloMist are based on an uncontrolled clinical trial in 25 patients. The most common adverse reactions reported in at least 3 (12%) of patients were arthralgia, dizziness, headache, nasopharyngitis, and rhinorrhea. Those occurring in at least 2 (8%) of patients were bronchitis, nasal discomfort, nasal pain, and rash (unspecified). Adverse reactions reported in at least 1 (4%) patient included asthma, back pain, cough, epistaxis, hypersomnia, flu-like symptoms, malaise, pharyngolaryngeal pain, postnasal drip, procedural pain, pyrexia (fever), scab, sinus headache, sinusitis, and tooth abscess. Another intranasal cyanocobalamin product, Nascobal gel, reported adverse reactions based on a short-term clinical trial in vitamin B12 deficient patients in hematologic remission receiving Nascobal (n = 24) and IM vitamin B12 (n = 25). Adverse reactions thought to be possibly related to Nascobal include headache, nausea, and rhinitis; these adverse reactions were also possibly related to the patient's clinical state or other concomitant drug therapy. The incidence of adverse reactions between Nascobal gel and Nascobal nasal spray were similar in a pharmacokinetic study by the manufacturer.2
How is this medication best taken? This medicine is injected into a muscle or deeply under the skin. It is usually given by a health care professional in a clinic or doctor's office. However, your doctor may teach you how to inject yourself. Follow all instructions. Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.
What do I do if I miss a dose? If you are given your dose at a clinic or doctor's office, call to reschedule your appointment. If you give your own injections and you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
Storage: Store this medication at 59°F to 86°F (15°C to 30°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the expiration date. Do not flush unused medications or pour down a sink or drain.
- 1. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994;120:211-5.
- 2. a. b. Nascobal (cyanocobalamin, vitamin B-12) package insert. Union City, CA: Nastech Pharmaceutical Company Inc.; 2005 Feb.
- 3. a. b. Briggs GG, Freeman RK, Yaffee SJ. Vitamin B12. In: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed. Philadelphia: Lippincott Williams & Wilkins: 2008;1969-21.
- 4. a. b. c. d. e. f. Cyanocobalamin inj package insert. Shirley, NY: American Regent, Inc.; 2005 Nov.
- 5. a. b. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
- 6. a. b. c. d. e. f. g. h. i. j. Nascobal® (cyanocobalamin, vitamin B-12) package insert. Union City, CA: Nastech Pharmaceutical Company Inc.; 2005 Feb.
- 7. a. b. Colchicine Injection, USP package insert. Bedford, OH: Bedford Laboratories; 1999 Apr.
- 8. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994;120:211—5.
- 9. Yunis AA. Chloramphenicol-induced bone marrow suppression. Sem Hematol 1973;10:225—234.
- 10. a. b. Chloromycetin® (chloramphenicol) package insert. Rochester, MI: Parkedale Pharmaceuticals, Inc.; 1999 May.
- 11. Glucophage®/Glucophage® XR (metformin) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2003 Apr.
- 12. Plockinger U, Dienemann D, Quabbe HJ. Gastrointestinal side-effects of octreotide during long-term treatment of acromegaly. J Clin Endocrin Metab 1990;71:1658—62.