Cobalamin consists of four compounds with different biological functions, although these molecules are chemically similar. Cobalamine is a tetrapyrrolic corrin ring with central cobalt moiety. Cyanocobalamin and hydroxocobalamin are synthetic forms of cobalamin, whereas adenosylcobalamin (AdoCbl) and methylcobalamin have a biological activity to act as cofactors in enzymatic reactions that play a role in the synthesis of DNA, myelin and fatty acids which are vital for cell division and growth. Bioavailability of cyanocobalamin and hydroxocobalamin is different, has distinct pharmacologic properties, and can be used according to the approval in a particular country.[1][2][3][4][5]

FDA approved indications:

• Pernicious anemia: Intrinsic factor of Castle deficiency due to autoantibody formation against parietal cells of the stomach, which results in decreased absorption of vitamin B12 through ileum. 
• Malabsorption: Impairment of vitamin B12 absorption.
• Atrophic gastritis: Intrinsic factor level decreases and leads to reduced absorption of vitamin B12.
• Chronic acid-reducing medication use: Chronic reduction of acid secretion decreases the release of bound vitamin B12 from the protein of food particles, so R factor can't bind, and ultimately vitamin B12 absorption is reduced. 
• Long term metformin use: It may relate to reducing intestinal mobility or to intestinal bacterial overgrowth that competes with vitamin B12 and decreases its absorption. 
• Total or partial gastrectomy: It reduces the level of the intrinsic factor of Castle that needed for vitamin B12 absorption, so decreased intrinsic factor leads to decreased vitamin B12 absorption.[6]
• Small bowel bacteria overgrowth: Vitamin B12 is overused by bacteria leading to B12 deficiency.
• Diphyllobothrium latum infection: Competes with vitamin B12 for absorption through the intestine.
• Pancreatic insufficiency
• Helicobacter pylori infection
• Dietary deficiency of vitamin B12[2]

Non-FDA approved indications:

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

The oral formulation of cobalamin is absorbable through the intestine despite the absence of intrinsic factor of Castle. Approximately 1.2% vitamin B12 is absorbed passively without the help of intrinsic factor. If a patient receives the oral formulation at high doses, this passive absorption is sufficient to replenish vitamin B12 deficiency. If intrinsic factor is present in an adequate amount, then oral cobalamin is absorbed with the help of intrinsic factor. When administering cobalamin parenterally, it bypasses the intestinal barrier and absorbs quickly by diffusion and enters into the systemic circulation.[9]

In the systemic circulation, cobalamin binds with transporter protein termed transcobalamin II (TCII) and enters into the tissue with the receptor of transcobalamin II. Cobalamin has many cellular effects with the greatest impact on new blood cell generation and neurological function. At the cellular level, cobalamin act as a cofactor of two enzymatic reactions that involve methionine synthase and methyl- malonyl-co A mutase.

Methionine synthase helps to convert homocysteine to methionine with the help of cobalamin where methyl-THF converts to THF as a byproduct of this reaction, which helps DNA synthesis. Methionine is an amino acid that converts into S-adenosylmethionine and participates in numerous methylation processes of cells. This methylation reaction is necessary for the synthesis of many molecules such as phospholipids, neurotransmitters, and regulation of gene expression. If cobalamin is not present in sufficient amount, megaloblastic anemia occurs by inhibition of DNA synthesis due to the folate trap. Cobalamin (vitamin B12) in the form of adenosylcobalamin acts as a cofactor for enzyme methyl- malonyl-co A mutase, which converts methyl malonyl CoA to succinyl CoA. Through this reaction, it helps to metabolize odd chain fatty acids and branch chain amino acids.[4][5][6]

Cobalamin can be administered orally or intramuscularly that depends on the cause, presentation, and demands of the patients. A patient with severe cobalamin deficiency is treated initially by the intramuscular route. If the deficiency is less severe, then oral formulation is also helpful in replenishing the B12 level. Intramuscular cobalamin remains as two forms, cyanocobalamin and hydroxocobalamin. Cyanocobalamin requires conversion to metabolically active cobalamin, which is available in the United States, whereas hydroxocobalamin is the preferred agent in parts of Europe. In the United States, cobalamin injections are usually given 1mg daily for 1st week of treatment, then once weekly in the following month and then monthly.[9][10][11][12]

Sublingual or nasal routes are expensive and inadequately studied; hence these routes cannot be recommended.[10]

If cobalamin deficiency develops due to a strict vegan diet, oral formulation is enough in this case. High dose oral cobalamin is also sufficient to replenish the B12 level absorbed through passive absorption or if the patient refuses to take injections. Oral daily 1-2mg of cobalamin seems to be suitable in these scenarios. The benefits of oral therapy include patient compliance, cost-effectiveness, as well as to reduce the bleeding risk in a patient taking anticoagulation.[5][9][13][14]

If a patient receives a diagnosis of pernicious anemia, then treatment should be for life. If there are other causes rather than pernicious anemia, treatment should continue until hematological indices improve.[14]

Due to cobalamin sensitivity, an intradermal test is necessary before any kind of parenteral treatment. Because of the tendency to develop anaphylaxis, cobalamin administration is never via the intravenous route.[15]

Significant pain is the common adverse effects of intramuscular vitamin B12, especially in thin people. Injectable cobalamin may also cause bleeding if the patient is taking anticoagulants. Although allergic reactions rarely happen, it can cause life-threatening anaphylaxis. Injections are more allergenic than pills, and hydroxocobalamin seems to be more allergenic than cyanocobalamin, although reactions can occur with all cobalamin forms. Management options for allergic reactions include desensitization, antihistamines, and steroids.[9][10]

Other common adverse effects are fever, itching or rash, tingling or numbness of joint, shortness of breath, rapid weight gain, polycythemia, hypokalemia, congestive heart failure, pulmonary edema, and vascular thrombosis. 

Anaphylaxis can occur due to sensitivity to cobalt moiety or cobalamin molecule. 

Cyanocobalamin should be used cautiously in patients with Leber optic nerve atrophy because it can increase disease severity. Cautious use is also recommended in renal failure due to the presence of the aluminum component in cyanocobalamin.