Methylcobalamin (Vitamin B12)
Methylcobalamin, or vitamin B12, is found in fish, shellfish, meats, and dairy products. Although the two terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption using the Schilling test. B12 deficiency in healthy individuals is rare; the elderly, those with vegan diets, and patients with malabsorption problems are more likely to experience this problem. If vitamin B12 deficiency is not treated with supplementation, then anemia, intestinal problems, and nerve damage may occur.
Methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring. The central metal ion is Co (cobalt). Plants and animals do not have the enzymes to synthesize methylcobalamin; only bacteria and archaea can do this. Higher plants do not concentrate methylcobalamin from the soil, human dietary B12 needs are better met with animal then plant tissues.
Vitamin B12 is used in the body in two forms, methylcobalamin and 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine which is, in turn, required for DNA methylation.
5-deoxyadenosylcobalamin is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA, an extraction that allows an organism to gain energy from proteins and fats. Furthermore, succinyl CoA is required for the production of hemoglobin, the substance that allows oxygen to be carried by red blood cells.
Methylcobalamin is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division appear to require methylcobalamin the most. Vitamin B12 can be converted to coenzyme B12 in tissues; 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; A lack of or inhibition of intrinsic factor leads to pernicious anemia.
Methylcobalamin is administered intranasally, orally, and parenterally. Once absorbed, vitamin B12 is highly bound to a transcobalamin II protein and is stored primarily in the liver as coenzyme B12, and also in the bone marrow. B12 crosses the placenta and is distributed into breast milk. Systemic stores are conserved by enterohepatic recirculation. The half-life of B12 is about 6 days (400 days in the liver). Elimination takes place through the bile; however, excess methylcobalamin is excreted unchanged in the urine.
Intramuscular Injection Route: Bioavailability of the nasal gel and spray forms relative to an IM injection are low: 9% and 6%, respectively. Because of their lower absorption rate, 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 significantly increased B12 levels when compared to a monthly 100 mcg IM dose.
Intravenous Route: Peak plasma levels of cyanocobalamin are attained within 1 hour for parenteral doses.
B12 should be avoided for patients with early hereditary optic nerve atrophy, cyanocobalmin hypersensitivity, and those who are pregnant. Healthcare providers should be made aware of any of these conditions: kidney disease; Leber's disease; megaloblastic anemia; an unusual or allergic reaction to methylcobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding.
Methylcobalamin is contraindicated in patients with methylcobalamin hypersensitivity or sensitivity to any medication components, including cobalt. In cases of cobalt hypersensitivity, anaphylactic shock and death have followed parenteral administration of methylcobalamin.
Optic nerve atrophy can worsen in patients whose methylcobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population.
Benzyl alcohol is used as a preservative in most formulations of methylcobalamin. Methylcobalamin injections should be used cautiously in those patients with benzyl alcohol allergy or hypersensitivity. 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 methylcobalamin or hydroxocobalamin may unmask this condition.
Folic Acid, vitamin B9 does not counter vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. Exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in neurologic damage. Before receiving folic acid or methylcobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. All hematologic parameters should be normal before beginning the methylcobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may blunt a patient’s response to methylcobalamin therapy.
Due to interference with erythropoiesis, certain conditions may impede therapeutic response to methylcobalamin therapy, including serious infection, uremia or renal failure, drugs with bone marrow suppression properties, or concurrent folic acid or iron deficiency anemia. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration.
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 at the lower end of the dosing range.
Parenteral methylcobalamin is classified as pregnancy category C. Adequate research is not available, however, no maternal or fetal complications have been associated with recommended doses during pregnancy, and treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Pernicious anemia resulting from vitamin B12 deficiency may in fact cause infertility and poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of 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 either through dietary intake or supplementation should be taken during pregnancy.
Methylcobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk provides adequate methylcobalamin intake by breast-feeding infants. Adequate maternal intake benefits both the mother and infant during nursing, and maternal requirements increase during lactation. Daily recommended amounts for lactating women should be taken maternally during breast-feeding. The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers should report the effect to the FDA.
Patients should give their health care provider a list of all current medicines, herbs, non-prescription drugs, or dietary supplements, and should describe any use of tobacco, alcohol or illegal drugs.
Several drugs, including para-aminosalicylic acid, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Monitor for the desired therapeutic response to vitamin B12.
The heavy consumption of alcohol for greater than 2 weeks has been reported to reduce the absorption of vitamin B12, and heavy chronic drinking can blunt the effects of therapy.
Choline may reduce the absorption of methylcobalamin, vitamin B12. Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Patients receiving these agents concurrently should be monitored for the desired therapeutic response to vitamin B12.
Patients receiving long-term therapy with omeprazole or other proton pump inhibitors (PPIs) should be monitored for signs of B12deficiency.
Chloramphenicol can antagonize the hematopoietic response to vitamin B12 through interference with erythrocyte maturation. Chloramphenicol is known to cause bone marrow suppression, especially when serum concentrations exceed 25 mcg/ml. 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 may occur after chloramphenicol administration.
Metformin may prevent oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or B12 supplementation. Regular measurement of hematologic parameters is recommended during 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 methylcobalamin, vitamin B12 therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12. However, cancer patients usually benefit from vitamin B12 supplementation. 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.
The intranasal forms of methylcobalamin, vitamin B12, should be administered at least 1 hour before or 1 hour after ingestion of hot food or liquids. Hot foods may cause nasal secretions and a resulting loss of medication efficacy.
Depressed levels of vitamin B12 and abnormal Schilling's test have been reported in patients receiving octreotide.
The use of antiinfective agents or pyrimethamine may invalidate diagnostic assays for folic acid and vitamin B12.
Methylcobalamin is generally nontoxic, even in large doses. Adverse reactions include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular injection have included anxiety, mild diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of overall body swelling. Some patients have experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. If cobalt hypersensitivity is suspected, an intradermal test dose should be administered.
During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have been reported in early parenteral treatment. This is believed to result from increased blood volume. Peripheral vascular thrombosis has also occurred. Angioedema and angioedema-like reactions have been reported with parenteral methylcobalamin.
Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, platelet count and serum potassium concentrations should be monitored during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin.
Diarrhea and headache may occur.
Call your health care provider if you experience 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.