Pharmacologic Classifications: Water-Soluble Vitamins, Hematinics
Methylcobalamin, or vitamin B12, is a
B-vitamin. It is found in a variety of foods such as fish, shellfish,
meats, and dairy products. Although methylcobalamin and vitamin B12 are
terms used interchangeably, vitamin B12 is also available as
hydroxocobalamin, a less commonly prescribed drug product (see
Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin 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.
The most chemically complex of all the vitamins, methylcobalamin is a
water-soluble, organometallic compound with a trivalent cobalt ion
bound inside a corrin ring which, although similar to the porphyrin ring
found in heme, chlorophyll, and cytochrome, has two of the pyrrole
rings directly bonded. The central metal ion is Co (cobalt).
Methylcobalamin cannot be made by plants or by animals; the only type of
organisms that have the enzymes required for the synthesis of
methylcobalamin are bacteria and archaea. Higher plants do not
concentrate methylcobalamin from the soil, making them a poor source of
the substance as compared with animal tissues.
Mechanism of Action
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. The other
form, 5-deoxyadenosylcobalamin, is a cofactor needed by the enzyme that
converts L-methylmalonyl-CoA to succinyl-CoA. This conversion is an
important step in the extraction of energy from proteins and fats.
Furthermore, succinyl CoA is necessary for the production of hemoglobin,
the substance that carries oxygen in red blood cells.
Vitamin B12, or methylcobalamin, 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
methylcobalamin. 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.
Methylcobalamin 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 methylcobalamin is excreted unchanged in the
Intramuscular Route Specific Pharmacokinetics: 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.
Intravenous Route: Peak plasma levels of cyanocobalamin are attained within 1 hour for parenteral doses.
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 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 hypersensitivity to any of the medication
components. Methylcobalamin is also contraindicated in patients with
cobalt hypersensitivity because methylcobalamin 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 methylcobalamin.
Methylcobalamin should not be used in patients with early hereditary
optic nerve atrophy (Leber's disease). Optic nerve atrophy can worsen in
patients whose methylcobalamin levels are already elevated.
Hydroxocobalamin is the preferred agent in this patient population (see
separate monograph in Less Common Drugs).
Most formulations of methylcobalamin injection contain benzyl alcohol
as a preservative. Benzyl alcohol may cause allergic reactions.
Methylcobalamin injections should be used cautiously in those patients
with benzyl alcohol hypersensitivity. Methylcobalamin, 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 methylcobalamin or hydroxocobalamin may unmask this
Folic Acid, vitamin B9 is not a substitute for methylcobalamin,
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
methylcobalamin, 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 methylcobalamin
intranasal formulations. Concurrent iron-deficiency anemia and folic
acid deficiency may result in a blunted or impeded response to
Certain conditions may blunt or impede therapeutic response to
methylcobalamin 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 methylcobalamin.
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.
Parenteral methylcobalamin is 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. 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 methylcobalamin, vitamin B12
either through dietary intake or supplementation should be taken during
pregnancy (see Dosage).
Methylcobalamin is distributed into breast
milk in amounts similar to those in maternal plasma, and distribution in
breast milk allows for adequate intakes of methylcobalamin 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 methylcobalamin, vitamin B12 for
lactating women should be taken maternally during breast-feeding (see
Dosage). 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 are encouraged to report the adverse effect to the
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.
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 ethanol for greater than 2 weeks has been
reported to reduce the absorption of Methylcobalamin, vitamin B12.
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.
Several drugs, including colchicine, have been reported to 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. Although further study of these
interactions is necessary, patients receiving these agents concurrently
should be monitored for the desired therapeutic response to vitamin B12.
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 methylcobalamin, vitamin B12. Theoretically 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 B12deficiency.
Chloramphenicol can antagonize the hematopoietic response to
Methylcobalamin, 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 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.
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. The interaction very rarely
results in a pernicious anemia that appears reversible with
discontinuation of metformin or with Methylcobalamin, 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 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
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 or medication efficacy. Interactions between foods
and oral or injectable forms of methylcobalamin are not expected.
Depressed levels of methylcobalamin, 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; however, these are
diagnostic laboratory test interferences and not true drug interactions.
Adverse Reactions/Side Effects
In most cases,
methylcobalamin is nontoxic, even in large doses. Adverse reactions
reported following methylcobalamin 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 methylcobalamin, pulmonary
edema and congestive heart failure have reportedly occurred early in
treatment with parenteral methylcobalamin. This is believed to result
from the increased blood volume induced by methylcobalamin. Peripheral
vascular thrombosis has also occurred. In post-marketing experience,
angioedema and angioedema-like reactions were reported with parenteral
Hypokalemia and thrombocytosis could occur upon conversion of severe
megaloblastic anemia to normal erythropoiesis with methylcobalamin
therapy. Therefore, monitoring of the platelet count and serum potassium
concentrations are recommended during therapy. Polycythemia vera has
also been reported with parenteral methylcobalamin.
Diarrhea and headache.
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
How is this medication best taken?
This medicine is
injected into 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.
Keep this medicine in a refrigerator below 41°F
(5°C) and away from 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.
Do not share or take any one else's
medicine. Talk with your healthcare provider before starting any new
medicine, including over-the-counter, natural products, or vitamins.
This patient information summarizes the most important information about
your medication; if you would like more information, talk with your