Cyanocobalamin (Vitamin B12) Injection
Cyanocobalamin, also known as vitamin B-12, is found in 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). Cyanocobalamin and hydrocobalamin offer equal biological activity and can be administered nasally, orally, and parenterally. Cyanocobalamin is used to treat pernicious anemia and vitamin B12 deficiency, and is also used to determine vitamin B12 absorption via 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 become deficient. If vitamin B12 deficiency is not treated, anemia, intestinal problems, and irreversible nerve damage may occur. Oral therapy is not always effective, as some patients lack an endogenous substance produced by the stomach that is necessary for oral B12 absorption. Other patients may not be able to absorb oral vitamin B12 due to compromised intestines in the area where vitamin B12 absorption occurs. Parenteral or nasal therapy may be needed in such cases; however, intranasal therapy should only be applied for maintenance after the condition has been controlled parenterally. Cyanocobalamin was approved by the FDA in 1949.
Vitamin B12, or cyanocolbalamin, is essential for cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Rapidly dividing cells (epithelial cells, bone marrow, myeloid cells) appear to require cyanocobalamin more than others. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for the conversion of methylmalonate to succinate and it is also required for the synthesis of methionine from homocysteine. In the absence of B12, tetrahydrofolate cannot regenerate from its inactive storage form, 5-methyl tetrahydrofolate, which results in a folate deficiency. Vitamin B12 also may maintain sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 participates in fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage. Vitamin B12 requires factor-mediated active transport for absorption; insufficient intrinsic factor results in pernicious anemia.
Cyanocobalamin is administered intranasally, orally, and parenterally; hydroxocobalamin is administered only parenterally. Once absorbed, vitamin B12 is bound to transcobalamin II, a specific B-globulin carrier protein, and is stored in the liver as coenzyme B12. Significant B12 is also stored in the bone marrow. B12 crosses the placenta and enters breast milk. Its half-life is about 6 days (400 days in the liver), and elimination takes place through the bile; excess cyanocobalamin is excreted unchanged with the urine.
- Intravenous: After administration of a parenteral dose, peak plasma levels of cyanocobalamin are attained within one hour.
- Intramuscular: Relative to an IM injection, the bioavailability of the nasal gel and spray forms are about 9% and 6%, respectively. Intranasal forms have lower absorption than IM administration, so intranasal B12 forms are administered once weekly. After one month of pernicious anemia treatment, weekly dosing of 500 mcg B12 intranasal gel resulted in a significant increase in B12 levels when compared to a once monthly 100 mcg IM dose.
Pregnant patients, patients with early hereditary optic nerve atrophy, and those with cyanocobalmin hypersensitivity should not take this medication. Any of the following conditions should require patients to consult a health care provider before pursuing this treatment: kidney disease; Leber's disease; megaloblastic anemia; an allergy to cyanocobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnancy or potential pregnancy; breast-feeding.
In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered before treatment. Anaphylactic shock and death have followed parenteral administration of cyanocobalamin for patients with this condition.
Intranasal formulations of cyanocobalamin cannot be used for the vitamin B12 absorption test.
Cyanocobalamin can accelerate optic nerve atrophy in patients who have this condition.
Benzyl alcohol, a common preservative in most formulations of cyanocobalamin injection, may cause allergic reactions. Injections should be used cautiously in patients with benzyl alcohol sensitivity. Preparations containing benzyl alcohol should also be avoided in premature neonates because benzyl alcohol has been associated with 'gasping syndrome,' a potentially fatal condition.
Vitamin B12 deficiency can suppress the symptoms of polycythemia vera, a condition that may be unmasked by treatment with cyanocobalamin or hydroxocobalamin.
Folic Acid, or vitamin B9, should not be used to treat vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. Exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could lead to progressive, irreversible neurologic damage. Before receiving folic acid or cyanocobalamin, patients should be assessed for deficiency. All hematologic parameters should be normal before beginning treatment with cyanocobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may blunt or impede the response to cyanocobalamin therapy.
Certain conditions may also blunt or impede the response to therapy, including infection, uremia or renal failure, drugs that suppress bone marrow, and concurrent undiagnosed folic acid or iron deficiency anemia. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses of cyanocobalamin or more frequent administration.
Patients with rhinorrhea who receive intranasal formulations of cyanocobalamin may experience decreased medication absorption as a result of nasal discharge. Intranasal cyanocobalamin administration should be delayed until patients no longer experience nasal congestion, allergic rhinitis, and upper respiratory infection. For patients with chronic nasal symptoms, more frequent monitoring is required because of the potential for blunted absorption.
Cyanocobalamin/ vitamin B12 is classified as pregnancy category C. No maternal or fetal complications have been associated with doses during pregnancy, and appropriate treatment should not be withheld from pregnant women with anemias that respond to vitamin B12, and it should be noted that pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of mothers who consume no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Pregnancy can increase maternal requirements for vitamin B12. The usual daily recommended amounts should be taken during pregnancy.
Cyanocobalamin is distributed into breast milk and the distribution allows for adequate intake 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. The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. If a breast-feeding infant experiences an adverse effect related to any maternally ingested drug, healthcare providers should report the effect to the FDA.
Studies of intranasal cyanocobalamin did not include sufficient numbers of geriatric patients over age 65 to determine if age plays a role in outcomes. Clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution, because elderly patients have a greater frequency of decreased hepatic, renal, or cardiac function, and may also have comorbidities or may be experience other drug therapies. Doses should start at the low end.
- No maternal or fetal complications have been associated with cyanocobalamin doses that are recommended during pregnancy, and treatment should not be withheld from pregnant women with vitamin B12 responsive anemias; these anemias if left untreated can lead to infertility and poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of mothers whose diets contain no animal products, even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy, and the usual daily recommended amounts should be taken.
- Cyanocobalamin is distributed into breast milk which allows for adequate intakes of cyanocobalamin by breast-feeding infants. Maternal requirements for vitamin B12 increase during lactation and the usual daily recommended amounts of cyanocobalamin, vitamin B12 for lactating women should be taken 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 any maternally ingested drug, healthcare providers should report the effect to the FDA.
Several drugs, including para-aminosalicylic acid, area shown to reduce the absorption of cyanocobalamin, vitamin B12. Monitor for the desired therapeutic effects.
Heavy alcohol consumption for more than two weeks can reduce the absorption of cyanocobalamin; Patients should be aware that heavy drinking may counteract the effects of vitamin B12.
Several drugs, including colchicine, reduce the absorption of cyanocobalamin. Colchicine can induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Further study is needed, but patients receiving these agents concurrently should be monitored.
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. 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 by interfering with erythrocyte maturation. Chloramphenicol is known to cause bone marrow suppression, especially at high serum concentrations, and should be discontinued if anemia attributable to chloramphenicol is noted during periodic blood studies conducted every two days. Aplastic anemia and hypoplastic anemia are known to occur after chloramphenicol administration.
Metformin may impede oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. In rare cases, the interaction may result in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Hematologic parameters should be measured regularly in all patients on chronic metformin treatment and abnormalities should be investigated.
Medications that cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) can blunt or impede the response to cyanocobalamin therapy. Antineoplastics that are antimetabolites for the vitamin may prevent adequate 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; this is a diagnostic test interference and not a drug interaction.
Intranasal forms of vitamin B12 should be administered at least one hour before or one hour after ingestion of hot food or liquids, because hot foods may cause nasal secretions and a resulting loss of medication efficacy.
In patients receiving octreotide, depressed levels of cyanocobalamin, vitamin B12, and abnormal Schilling's test results have been reported.
Antiinfective agents or pyrimethamine may invalidate diagnostic assays for folic acid and vitamin B12; these are test interferences and not true drug interactions.
Before self-administering vitamin B12, share a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use with your doctor. Also tell your provider if you smoke, drink alcohol, or use illegal drugs, since they may interact with your medicine.
In most cases, cyanocobalamin is nontoxic, even in large doses. Allergic reaction may occur, which could include skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, or a red, swollen painful area on the leg.
Other rare adverse reactions may include headache, infection, nausea/vomiting, paresthesias, and rhinitis.
Adverse reactions following IM injection may include anxiety, mild diarrhea, ataxia, nervousness, pruritus, exanthema, and a swelling feeling in the entire body. Some patients have experienced a hypersensitivity reaction that has resulted in anaphylactic shock and death. If cobalt hypersensitivity is suspected, begin with an intradermal test dose.
During the initial treatment period with cyanocobalamin, pulmonary edema and congestive heart failure have reportedly occurred. This may result from increased blood volume. Peripheral vascular thrombosis has also occurred as well as angioedema and angioedema-like reactions.
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.
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.