B12 Methylcobalamin

Methylcobalamin is a naturally occurring form of vitamin B12 (cobalamin) in which a methyl group is bound to the cobalt atom. No FDA-approved drug product contains methylcobalamin; it is used as a bulk drug substance in compounded injections and oral preparations and is sold as a dietary supplement. The FDA-approved cobalamin drugs are cyanocobalamin (injection and nasal spray) and hydroxocobalamin (injection), and their labeling is the basis for the class safety information here.

No FDA-labeled indication or dose exists for methylcobalamin. FDA-approved injectable cobalamins are labeled for vitamin B12 deficiency due to malabsorption, including pernicious anemia, gastrointestinal pathology, dysfunction or surgery, fish tapeworm infestation, and malignancy of the pancreas or bowel.

Prescribers use compounded methylcobalamin injection for patients they determine need parenteral vitamin B12. Dosing is individualized by the prescriber.

Cobalamins taken into cells are processed to a common intermediate, which is converted to the two active coenzymes. Methylcobalamin is the cofactor for methionine synthase, which transfers a methyl group from 5-methyltetrahydrofolate to homocysteine to form methionine. This regenerates tetrahydrofolate for DNA synthesis and supplies methionine for S-adenosylmethionine-dependent methylation.

Adenosylcobalamin, not methylcobalamin, is the cofactor for methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. Deficiency causes megaloblastic anemia, raised homocysteine and methylmalonic acid, and neurologic damage including demyelination.

After intramuscular or subcutaneous injection, cobalamin enters the circulation and binds plasma proteins: transcobalamin II, which delivers it to tissues, and haptocorrin. It is stored mainly in the liver, where body stores of a few milligrams can last years, and undergoes enterohepatic circulation. When binding capacity is exceeded after a large parenteral dose, much of the dose is excreted unchanged in urine, mostly within 48 hours.

Oral absorption normally depends on intrinsic factor; about 1% of a large oral dose is absorbed by passive diffusion. Pharmacokinetic data specific to methylcobalamin injection are limited.

• Hypersensitivity to cobalamins, cobalt or any component of the preparation.

• Hypersensitivity: anaphylactic shock and death have been reported with parenteral cobalamin. Cyanocobalamin labeling recommends an intradermal test dose in patients suspected of sensitivity.
• Leber's disease: this caution comes from cyanocobalamin labeling, which reports severe and swift optic atrophy in patients with early Leber's disease (hereditary optic nerve atrophy) treated with cyanocobalamin. It is applied to methylcobalamin by caution; relevance to methylcobalamin is not established.
• Hypokalemia: hypokalemia and sudden death can occur when severe megaloblastic anemia is treated intensively, as new red cells take up potassium. Monitor serum potassium closely early in therapy.
• Polycythemia vera may be unmasked when B12 deficiency is corrected. Pulmonary edema and heart failure have occurred early in treatment of severe anemia.
• Diagnosis: folic acid above 0.1 mg/day can produce a hematologic response in B12 deficiency while neurologic damage progresses, and B12 above 10 mcg/day can produce a hematologic response in folate deficiency; confirm the diagnosis before treatment. Deficiency allowed to progress for more than 3 months can cause permanent spinal cord degeneration.
• Uremia, infection, bone marrow suppression and iron or folate deficiency can blunt the response. Preparations containing benzyl alcohol should not be used in neonates (gasping syndrome).

• Chloramphenicol may antagonize the hematologic response to vitamin B12; monitor blood counts.
• Nitrous oxide inactivates cobalamin and can precipitate or worsen deficiency, including neurologic injury.
• Metformin, proton pump inhibitors, H2 blockers and colchicine reduce absorption of oral and dietary B12 and can contribute to deficiency; they do not affect injected B12.
• Most antibiotics, methotrexate and pyrimethamine invalidate microbiological assays for B12 and folate.

Parenteral cobalamin is usually well tolerated. Reactions reported in cyanocobalamin labeling include injection-site pain, mild transient diarrhea, itching, transient rash, a feeling of whole-body swelling, pulmonary edema and heart failure early in therapy, peripheral vascular thrombosis, polycythemia vera, and anaphylaxis, including fatal cases. Hypokalemia can occur during treatment of severe megaloblastic anemia. Acneiform eruptions have been reported with high doses.

Vitamin B12 is an essential nutrient, and requirements increase in pregnancy and lactation (recommended intakes of 2.6 mcg/day in pregnancy and 2.8 mcg/day in lactation). Cobalamin crosses the placenta and is present in human milk. Correcting deficiency is not expected to harm the fetus or infant, and maternal deficiency can cause deficiency and developmental problems in breastfed infants. Data on high-dose methylcobalamin injection in pregnancy are limited.

• Before treatment: hematocrit, reticulocyte count, and serum B12, folate and iron, per cyanocobalamin labeling. Methylmalonic acid and homocysteine can help confirm deficiency.
• Megaloblastic anemia: serum potassium during the first 48 hours, and reticulocytes and hematocrit early in treatment, as the prescriber directs.
• Long-term therapy: periodic serum B12 and blood counts, and neurologic status where deficiency affected it.

• Cyanocobalamin Injection, USP Prescribing Information (FDA-approved labeling).
• Hydroxocobalamin Injection, USP Prescribing Information (FDA-approved labeling).
• National Institutes of Health, Office of Dietary Supplements. Vitamin B12: Fact Sheet for Health Professionals.