Continuing Education Activity

Cyanocobalamin is a medication used in the management and treatment of vitamin B12 deficiencies. This activity reviews the indications, action, and contraindications for cyanocobalamin as a valuable agent in the management of vitamin B12 deficiencies and other off label uses (and other disorders when applicable). This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the care of patients with such conditions.

Objectives:

• Identify the indications of cyanocobalamin.
• Describe the mechanism of action of cyanocobalamin.
• Outline adverse effects of cyanocobalamin therapy.
• Summarize the importance of collaboration amongst physicians, nurse practitioners, nutritionists, and specialists like hematologists, gastroenterologists, geriatricians, and others in evaluating cyanocobalamin therapy.

Indications

Cyanocobalamin is a synthetic solution of vitamin B12 used mainly to treat deficiencies of the vitamin.[1] Chemically it belongs to "corrinoids," and it is a crystallizable cobalt-complex. The name cyanocobalamin is owing to the fact it has a cyanide group attached to the molecule.[2] It has a role in several methylation reactions in the body.[3] In the body, in the form of methylcobalamin, it acts as a cofactor in the conversion of homocysteine to methionine and the form of adenosylcobalamin for the conversion of methylmalonyl-CoA to succinyl-CoA. Both these reactions are vital for cell division and growth.

FDA approved indications:

• Pernicious anemia: this condition is an autoimmune disorder against parietal cells. These cells are responsible for the production of the intrinsic factor. As the parietal cells are destroyed, there is no intrinsic factor to which the dietary B12 can bind; this leads to a deficiency of vitamin B12.
• Malabsorption- Impairment of B12 absorption
• Atrophic gastritis- Impairment of intrinsic factor production, causing impaired vitamin B12 absorption.
• Long term metformin use[4]
• Chronic acid-reducing medication use[5]
• Small bowel bacteria overgrowth- competition for vitamin B12 leads to vitamin deficiency
• Total or partial gastrectomy- eliminates site of intrinsic factor production
• Diphyllobothrium latum infection- parasite utilizes luminal B12
• Helicobacter pylori infection
• Pancreatic insufficiency- causes failure to inactivate cobalamin-binding proteins.
• Malignancy of pancreas or bowel
• Dietary deficiency of vitamin B12- eating strictly vegan foods without animal origin can lead to such deficiency[6]
• Transcobalamin II deficiency- causes impairment in transmembrane transport of B12

Non-FDA approved indications:

• Smoke inhalation
• Cyanide poisoning[7]
• Surgery-associated vasoplegia[8]
• Vasodilatory shock
• Folic acid deficiency

Mechanism of Action

Oral cyanocobalamin absorption occurs through the small intestine after binding to intrinsic factor and other cobalamin binding proteins.[9] When given by the parenteral route, it reaches the blood quite immediately.[10]

In the blood, it attaches itself to plasma proteins. Tissues absorb vitamin B12 by specific B12 binding proteins, transcobalamin I and II, to enter the cells. Most of the vitamin is stored in the liver. Vitamin B12 is essential for DNA synthesis and energy production, particularly in erythroid progenitor cells.

Vitamin B12 serves as a cofactor for two vital enzymes in the body: methylmalonyl-CoA mutase and methionine synthase. These methylation reactions are responsible for annealing Okazaki fragments during DNA synthesis.[2]

The replenishment causes total improvement of megaloblastic anemia and the gastrointestinal manifestations of vitamin B12 deficiency. The neurological symptoms in vitamin B12 deficiency improve upon cyanocobalamin administration, but the level of improvement depends on the duration and severity of deficiency.[11]

The reported but unconfirmed mechanism of action of hydroxocobalamin in vasoplegic shock is direct inhibition of nitric oxide and inhibition of guanylate cyclase.

Administration

Cyanocobalamin administration is by the oral, sublingual, intramuscular, subcutaneous, and intranasal routes. The choice of oral and other parenteral routes depends on the cause as well as the presentation of the patient.[12] A severe deficiency requires treatment with parenteral therapy (IM/SC). A patient with malabsorption cannot benefit from treatment with the oral formulation due to impaired absorption.[13] 

The initial replacement of overt deficiency is usually through parenteral therapy. Typically, 100 mcg cyanocobalamin is given daily for one week, weekly for a month, and then monthly for life. Oral/sublingual treatment is given after the initial correction of vitamin deficiency.

An intradermal test dose is an option for patients suspected of cyanocobalamin sensitivity before any parenteral treatment. Due to the possibility of anaphylaxis, cyanocobalamin should never be given intravenously (I.V.).[14]

As the vitamin is light-sensitive, the vials should be protected from light and stored at room temperature.

There are several case reports of hydroxycobalamin therapy for vasoplegic shock. The dose used in these case reports was 5 g over 15 min intravenously, with some instances of it being repeated in six hours.[15]

Adverse Effects

Cyanocobalamin, though only a vitamin, can cause several adverse effects. The patients with sensitivity can even experience life-threatening anaphylactic reactions. Apart from that, allergic reactions like itching, erythema, wheals may appear. 

Other common adverse effects include:

• Shortness of breath (even with mild exertion), swelling, rapid weight gain
• Pulmonary edema, congestive heart failure; peripheral vascular thrombosis
• Hypokalemia--leg cramps, irregular heartbeats, tingling/numbness, muscle weakness or limp feeling
• Numbness or tingling and joint pain
• Fever
• Swollen tongue
• Itching or rash
• Polycythemia (cyanocobalamin can unmask the underlying polycythemia)

Contraindications

Sensitivity to cobalt and/or vitamin B12 due to the risk of anaphylaxis.[16]

Patients with early Leber disease suffered severe and rapid optic atrophy when they received treatment with cyanocobalamin.[17]

Aluminum is present in the preparation of cyanocobalamin. CNS and bone toxicity secondary to aluminum accumulation is possible in patients with renal impairment. Thus, it is a relative contraindication to cyanocobalamin.

Monitoring

The clinician should obtain vitamin B12, folate, and iron levels along with hematocrit and reticulocyte count before treatment. 

When giving cyanocobalamin to treat vitamin B12 deficiency, there is an increase in erythrocyte metabolism, which leads to hypokalemia. As the anemia is corrected, thrombocytosis could also occur. Therefore, serum potassium levels and the platelet count should be monitored carefully during therapy.  Recommendations are to monitor vitamin B12 blood levels and peripheral blood counts in one month.

The clinicians should always ask about a history of allergies as there is a risk of anaphylaxis if a patient is allergic to cobalt or other components of the medication. Decreased therapeutic response to vitamin B12 may be due to uremia, infection, marrow suppressants like chloramphenicol, and concomitant iron or folic acid deficiency.

Folic acid supplementation is also necessary if folate levels are low. Folic acid may improve vitamin B12-deficient megaloblastic anemia, but it is not a substitute. If the clinician only uses only folic acid to treat vitamin B12 ­deficient megaloblastic anemia, progressive and irreversible neurologic damage could result; this is because it can aggravate vitamin B12 deficiency by increasing demand for the vitamin.

Toxicity

Cyanocobalamin secretion is usually in bile. With higher doses of cyanocobalamin, it undergoes rapid elimination in the urine. No overdosage occurs with cyanocobalamin. There is no antidote to vitamin B12. 

Enhancing Healthcare Team Outcomes

Cyanocobalamin treats a variety of different conditions related to vitamin B12 deficiency. Healthcare professionals, including physicians, nurse practitioners, pharmacists, and nutritionists, have to work together to manage the condition.  Early detection will prevent severe and permanent complications as prolonged Vitamin B12 deficiency may lead to permanent degenerative lesions of the spinal cord.[18] Due to the risk of hypokalemia early in treatment, electrolytes should be tested in the followup visit, which requires rigorous lab review after the office visit. This surveillance can be done by any clinician so as not to miss any abnormality.

As there are several completely unrelated causes of this deficiency, a physician is responsible for not only the identification of the probable cause but also tailor therapy and further management for different individuals depending on case to case basis.[19]

The involvement of specialists may prove necessary in several instances. For example,

• A patient with D. latum infection may need followup with an infectious disease specialist. 
• A patient with a dietary deficiency may need to see a dietician or a nutritionist.
• A patient with H.pylori infection, atrophic gastritis, malabsorption, pancreatic insufficiency, Crohn disease may need to see a gastroenterologist or a GI surgeon.
• A patient with malignancy of bowel/pancreas may need oncology followup.
• Due to the correlation of pernicious anemia with carcinoma of the stomach, an appropriate gastroenterology workup may be recommended.
• Vitamin B12 deficiency suppresses the signs of polycythemia vera, which may unmask after treatment. It is also possible to have vitamin B12 deficiency in the case of a normal MCV due to co-existent thalassemia/iron deficiency anemia. Hence, a hematologist may guide further treatment for such patients. 

Due to the possibility of hypersensitivity to the drug, it is essential that the provider administers it with necessary precautions and carry out an intradermal test if an allergy is suspected. Education about the allergic reactions and other side effects is essential for optimal outcome and prevention of anaphylactic shock. [Level 5]