Continuing Education Activity

Cyanocobalamin is a synthetic compound of vitamin B12 used to treat vitamin deficiencies. Chemically, cyanocobalamin is classified as a "corrinoid," representing a crystallizable cobalt complex. The name "cyanocobalamin" is derived from including a cyanide group within the molecule. Cyanocobalamin is approved by the United States Food and Drug Administration (FDA) for pernicious anemia, malabsorption, atrophic gastritis, gastrectomy, Helicobacter pylori infection, and other conditions.

Vitamin B12 facilitates several methylation reactions within the body. Methylcobalamin serves as a cofactor in the conversion of homocysteine to methionine in the body. Furthermore, in the form of adenosylcobalamin, the vitamin is crucial in converting methylmalonyl-coenzyme A (CoA) to succinyl-CoA. Both of these reactions are essential for cell division and growth. This activity provides a comprehensive review of cyanocobalamin, covering the indications, mechanism of action, adverse event profile, contraindications, and relevant interactions, as a valuable agent managing vitamin B12 deficiencies. This review is particularly relevant for interprofessional healthcare teams who care for patients with indicated conditions to enhance long-term outcomes.

Objectives:

• Identify patients with vitamin B12 deficiencies who may benefit from cyanocobalamin therapy based on clinical presentations, medical history, and diagnostic findings.

• Implement evidence-based guidelines into clinical practice to effectively prescribe and administer cyanocobalamin for different vitamin B12 deficiency disorders, considering optimal routes of administration.

• Select appropriate cyanocobalamin formulations and dosages based on patient characteristics, response to therapy, and the specific indications for vitamin B12 supplementation.

• Collaborate with other healthcare professionals to ensure a multidisciplinary approach in managing complex cases of vitamin B12 deficiencies, incorporating diverse perspectives for comprehensive care.

Indications

Cyanocobalamin is a synthetic compound of vitamin B12 approved by the United States Food and Drug Administration (FDA) to treat vitamin deficiencies.[1] Chemically, cyanocobalamin is classified as a "corrinoid," representing a crystallizable cobalt complex. The name "cyanocobalamin" is derived from including a cyanide group within the molecule.[2]

Vitamin B12 facilitates several methylation reactions within the body.[3] Methylcobalamin is a cofactor that helps in the conversion of homocysteine to methionine in the body. Furthermore, in the form of adenosylcobalamin, the vitamin is crucial in converting methylmalonyl-coenzyme A (CoA) to succinyl-CoA. Both of these reactions are essential 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, no intrinsic factor is present for dietary B12 to 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 the 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 vitamin B12

Off-Label Uses

• 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 administered via the parenteral route, the vitamin reaches the blood immediately.[13] In the blood, vitamin B12 attaches to plasma proteins. Tissues absorb vitamin B12 by specific B12 binding proteins, transcobalamin I and II, facilitating transport into 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 2 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 directly inhibits nitric oxide and guanylate cyclase.[14]

Pharmacokinetics 

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

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

Administration

Cyanocobalamin administration uses oral, sublingual, IM, subcutaneous (SC), 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 or 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 of cyanocobalamin is given daily for 1 week, weekly for a month, and monthly for life. Oral or 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 (IV).[17] The vitamin is light-sensitive, so the vials should be protected from light and stored at room temperature. Several case reports of hydroxocobalamin therapy for paraplegic shock have been published. The dose used in these case reports was 5 g over 15 min IV, with some instances of it being repeated in 6 hours.[18]

Specific Patient Population

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]

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 and 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 who have 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, improving vitamin B12 status in infants through maternal supplementation during lactation is essential.[24]

Adverse Effects

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

Few reports with early Leber disease suffered adverse outcomes with regards to optic atrophy when they received treatment with cyanocobalamin; use with caution is advised in such cases due to limited data.[28][29]

Aluminum is present in the preparation of cyanocobalamin. Central nervous system and bone toxicity secondary to aluminum accumulation are possible in patients with renal impairment. Thus, renal impairment 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.[30]

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.[31] Folic acid supplementation is also necessary if folate levels are low. Folic acid may improve vitamin B12-deficient megaloblastic anemia but 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 from aggravated vitamin B12 deficiency.

When delivering cyanocobalamin to treat vitamin B12 deficiency, erythrocyte metabolism increases, leading to hypokalemia. As the anemia is corrected, thrombocytosis could also occur. 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 1 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, which has a 90% to 95% sensitivity. Thus, peripheral blood smear analysis is a cost-effective tool for diagnosing and monitoring responses to vitamin B12 deficiency.[32]

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.[33][32] Additionally, the improvement level depends on the deficiency's duration and severity, and clinicians should monitor the improvement.[34]

Clinicians should also monitor dermatological manifestations of vitamin B12 deficiency, such as hyperpigmentation, hair and nail changes, glossitis, and improvement with therapy.[26] The clinicians should always ask about a history of allergies to account for the 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.[35] 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.[36]

Toxicity

Cyanocobalamin secretion is usually in bile. With higher doses of cyanocobalamin, secretion 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 conditions related to vitamin B12 deficiency. The interprofessional team, including clinicians, nurses, pharmacists, and nutritionists, must coordinate activities to manage the condition. Early detection will prevent severe and permanent complications, as prolonged vitamin B12 deficiency may lead to permanent degenerative spinal cord lesions.[37] 

Due to the risk of hypokalemia early in treatment, electrolytes should be measured during follow-up visits, which require rigorous lab review after the office visit. Clinicians manage 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 operates from the same information base, driving better patient outcomes.

With several completely unrelated causes of this deficiency, a clinician is responsible for identifying the probable cause and tailoring therapy and further management of various conditions for different individuals depending on a case-to-case basis.[38]

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 surgeon.
• A patient with malignancy of the bowel/pancreas may need oncology follow-up.
• Due to the correlation of pernicious anemia with carcinoma of the stomach, a gastroenterology workup may be recommended.[36]
• Vitamin B12 deficiency suppresses the signs of polycythemia vera, which may be unmasked after treatment—vitamin B12 deficiency with a normal MCV due to co-existent thalassemia/iron deficiency anemia. Hence, a hematologist may guide further therapy. 

Due to the possibility of hypersensitivity to the drug, the clinician administers it with necessary precautions and performs an intradermal test if an allergy is suspected. Education about allergic reactions and other adverse effects is necessary for optimal outcomes and the prevention of anaphylactic shock.