Continuing Education Activity

Cyanocobalamin is a medication used to manage and treat vitamin B12 deficiencies. Chemically it belongs to a class called "corrinoids," and it is a crystallizable cobalt complex. The name cyanocobalamin derives from the cyanide group attached to the molecule. This activity reviews the indications, action, and contraindications for cyanocobalamin as a valuable agent in managing vitamin B12 deficiencies and other off-label uses (and other applicable disorders). In addition, 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 the potential 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 compound of vitamin B12 used mainly to treat vitamin deficiencies.[1] Chemically it belongs to a class called "corrinoids," and it is a crystallizable cobalt complex. The name cyanocobalamin derives from the cyanide group attached to the molecule.[2] It has a role in several methylation reactions in the body.[3] In the body, the form of methylcobalamin acts as a cofactor in the conversion of homocysteine to methionine. In the form of adenosylcobalamin, it plays a role in converting 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 gastric 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 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
• A potentially reversible cause of cognitive impairment and dementia. However, more research is required.[9]
• Nitrous oxide myelopathy[10]

Mechanism of Action

The synthetic form of supplemental vitamin B12 has long been available as cyanocobalamin for oral and injectable use.[11] Cyanocobalamin absorption occurs through the small intestine after binding to intrinsic factors and other cobalamin binding proteins.[12] When given via the parenteral route, it reaches the blood immediately.[13] In the blood, it attaches itself to plasma proteins. Tissues absorb vitamin B12 by specific B12 binding proteins, transcobalamin I and II, allowing it 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 is 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 reported but unconfirmed mechanism of action of hydroxocobalamin in vasoplegic shock is direct inhibition of nitric oxide and inhibition of guanylate cyclase.[14]

Pharmacokinetics 

Absorption: According to the manufacturer's product labeling, cyanocobalamin is rapidly absorbed from injection sites; and reaches its peak within 1 hour after intramuscular injection.

Distribution: Absorbed vitamin B12 is transported via B12 binding proteins, transcobalamin I and II. 

Metabolism: As described above, cyanocobalamin is converted in tissues into a cofactor for various metabolic processes. 

Excretion: Cynocobaline is primarily excreted through the kidney. Approximately 50 to 98% of the injected cyanocobalamin is present in the urine. A significant portion is excreted within the first eight hours. About 3-8 mcg of cyanocobalamin is secreted into the GI tract daily via the bile, and a majority is absorbed back.

Administration

Cyanocobalamin administration can be through 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.[15] 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.[16] 

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 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.).[17] The vitamin is light-sensitive, so the vials should be protected from light and stored at room temperature. There are several case reports of hydroxocobalamin 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.[18]

Use in Specific Patient Population

Patients with Hepatic Impairment: No information regarding the use of cyanocobalamin in patients with hepatic impairment has been provided in the manufacturer's product labeling. Vitamin B12 therapy has not been linked to transaminase elevations or clinically apparent acute liver injury.[19]

Patients with Renal Impairment:  No information regarding the use of cyanocobalamin in patients with renal impairment has been provided in the manufacturer's product labeling. However, according to kidney disease improving global outcomes (KDIGO) guidelines, vitamin b12 supplementation may be helpful in patients with anemia in chronic kidney disease.[20]

Pregnancy Considerations: Vitamin B12 deficiency increases the risk of adverse pregnancy outcomes.[21] Prophylactic vitamin B12 supplementation, especially in vegetarian mothers, is required.[22][23]

Breastfeeding Considerations: Vitamin B12 is present in human milk. However, risk factors for vitamin b12 deficiency in infants are exclusively breastfeeding by nursing mothers having vitamin B12 deficiency due to minimal intake of animal products or malabsorption. Adverse health outcomes in infants with vitamin B12 deficiency include anemia, failure to thrive, and neurological complications. Hence it is important to improve vitamin B12 status in infants through maternal supplementation during lactation.[24]

Adverse Effects

Though only a vitamin, cyanocobalamin can cause several adverse drug reactions, including allergic reactions like itching, erythema, and wheals.[25] Cyanocobalamin therapy's cutaneous adverse drug reactions include acne, rosacea, and anaphylaxis with cyanocobalamin injections. Cobalt is a component of cobalamin; consequently, patients with cobalt sensitivity have been reported to have allergic manifestations when receiving cobalamin replacement therapy.[26]

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. Patients with myeloproliferative disorders like polycythemia vera have an increased prevalence of vitamin B12 deficiency, despite high serum vitamin B12 levels.

Contraindications

Sensitivity to cobalt and/or vitamin B12 due to the risk of anaphylaxis.[27]

Patients with early Leber disease suffered severe and rapid optic atrophy when they received treatment with cyanocobalamin.[28]

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.

According to the manufacturer's product labeling, cyanocobalamin formulation contains benzyl alcohol. Benzyl Alcohol is associated with fatal "Gasping Syndrome" in premature infants.[29]

Monitoring

The clinician should obtain CBC, vitamin B12, folate, iron levels, hematocrit, and reticulocyte count before treatment. CBC usually reveals a macrocytic pattern (MCV > 100 fL) and hypersegmented neutrophils.[30] 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 folic acid to treat vitamin B12 ­deficient megaloblastic anemia, progressive and irreversible neurologic damage could result because it can aggravate vitamin B12 deficiency by increasing demand for the vitamin.

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, clinicians should carefully monitor serum potassium levels and platelet count during therapy. Recommendations are to monitor vitamin B12 blood levels and peripheral blood counts for one month. Methylmalonic acid levels and Serum Transcobalamin II are the most specific laboratory markers of vitamin b12 deficiency. However, hypersegmented neutrophils have a sensitivity of 98% compared to serum cyanocobalamin, with a sensitivity of 90–95%. Thus,  peripheral blood smear analysis is a cost-effective tool for diagnosing and monitoring response to vitamin B12 deficiency.[31]

The neurological symptoms of vitamin B12 deficiency can range from paraesthesia and numbness to subacute combined degeneration(dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts), which improves upon cyanocobalamin administration.[32][31] Still, the improvement level depends on the deficiency's duration and severity, and clinicians should monitor the improvement.[33]

Clinicians should also monitor for dermatological manifestations of vitamin b12 deficiency, such as hyperpigmentation, hair and nail changes, and glossitis and improvement with therapy.[26] 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 medication components. In addition, decreased therapeutic response to vitamin B12 may be due to uremia, infection, marrow suppressants like chloramphenicol, methotrexate, and concomitant iron or folic acid deficiency.[34] Monitor the patients diagnosed with vitamin b12 deficiency due to pernicious anemia, as pernicious anemia increases the risk of gastric carcinoid tumors and gastric adenocarcinoma.[35]

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. The interprofessional healthcare team must coordinate activities to manage the condition, including clinicians (MDs, DOs, NPs, PAs), nurses, pharmacists, and nutritionists. Early detection will prevent severe and permanent complications, as prolonged vitamin B12 deficiency may lead to permanent degenerative spinal cord lesions.[36] Due to the risk of hypokalemia early in treatment, electrolytes should be tested during follow-up visits, which requires rigorous lab review after the office visit. Clinicians can do this surveillance so as not to miss any abnormality. This is where all interprofessional team members can engage in coordinated activity and open communication regarding the patient's condition and response to treatment so that everyone involved in the case operates from the same information base, driving better patient outcomes. [Level 5]

As there are several completely unrelated causes of this deficiency, a physician is responsible for not only identifying the probable cause but also for tailoring therapy and further management for different individuals depending on case to case basis.[37]

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

• A patient with D. latum infection may need follow-up 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, or Crohn disease may need to see a gastroenterologist or a GI surgeon.
• A patient with malignancy of bowel/pancreas may need oncology follow-up.
• Due to the correlation of pernicious anemia with carcinoma of the stomach, an appropriate gastroenterology workup may be recommended.[35]
• Vitamin B12 deficiency suppresses the signs of polycythemia vera, which may be unmasked after treatment. It is also possible to have vitamin B12 deficiency with 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 performs an intradermal test if an allergy is suspected. Education about allergic reactions and other side effects is necessary for optimal outcomes and the prevention of anaphylactic shock. [Level 5]