Continuing Education Activity

Hydroxocobalamin is a medication used in the management and treatment of vitamin B12 deficiency and acute cyanide toxicity. It is in the anti-anemic class of drugs. This activity outlines the indications, action, and contraindications for hydroxocobalamin as a valuable agent in managing macrocytic anemia and acute cyanide toxicity. 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 treatment of patients with vitamin B12 deficiency and related conditions.

Objectives:

• Identify the mechanism of action of hydroxocobalamin.
• Describe the potential adverse effects of hydroxocobalamin.
• Review the appropriate monitoring for patients using hydroxocobalamin.
• Explain the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients receiving hydroxocobalamin.

Indications

Hydroxocobalamin is a form of manufactured, injectable vitamin B12. Clinicians use it in the prevention and treatment of macrocytic anemia associated with vitamin B12 deficiency. It may also be part of therapy to treat Leber optic atrophy (an inherited optic neuropathy associated with a deficiency in vitamin B12).[1] It is also an antidote in cases of cyanide poisoning,[2] including nutritional optic neuropathy (a visual disorder caused by tobacco that contained cyanide).[3] Hydroxocobalamin is particularly useful in the treatment of vitamin B12 deficiency secondary to conditions that impair the absorption of vitamin B12 from the GI tract, including malabsorption and pernicious anemia.

The FDA-approved form of intravenous (IV) hydroxocobalamin is used for the treatment of cyanide poisoning.[4]

Mechanism of Action

Hydroxocobalamin is a precursor of methylcobalamin and adenosylcobalamin, which are the active forms of vitamin B12.[5] Methylcobalamin and adenosylcobalamin are both cofactors involved in DNA and amino acid synthesis, fatty acid metabolism, and maintenance of nerve function.[6] The methylcobalamin component in hydroxocobalamin plays a role in the development of the nervous system during childhood and hematopoiesis. Adenosylcobalamin is involved with the metabolism of carbohydrates, amino acids, and fatty acids and is thus, involved in myelin formation. Therefore, the role of vitamin B12 highlights the clinical features that may present in vitamin B12 deficiency and the indications for the use of hydroxocobalamin. Methylcobalamin is a cofactor for the enzyme methionine synthase, an essential enzyme in the formation of methionine from homocysteine. This reaction is critical in the synthesis of purines and pyrimidines needed for DNA synthesis and red blood cell formation.[7]

Hydroxocobalamin can serve as an antidote for cyanide poisoning.[2] Cyanide binds to the cytochrome c oxidase, a terminal complex in the electron transport chain. This process leads to inhibition of ATP production and cellular oxygen utilization. As a result, cellular respiration becomes blocked, resulting in rapid death. Hydroxocobalamin contains cobalt compounds that can bind to and detoxify cyanide by intercepting the cyanide before it inhibits cellular respiration.[8] The hydroxocobalamin rapidly forms cyanocobalamin by removing the cyanide from tissues. The kidneys then excrete the cyanocobalamin in the urine.[4]

Hydroxocobalamin binds to transcobalamins. Transcobalamin-II is the main serum transport protein that delivers hydroxocobalamin to the tissues.[9] Vitamin B12 is stored in the liver and secreted into bile, where it undergoes recycling via the enterohepatic circulation. Its excretion is predominantly via the fecal route. Elevated levels of B12 can occur with parenteral administration. In such cases, the kidneys excrete any excess circulating B12 into the urine.[10]

Administration

Hydroxocobalamin is given parenterally, either as an intramuscular or intravenous injection. Cyanocobalmin administration can be via the oral, sublingual, intramuscular, or subcutaneous routes. Cyanocobalamin use is common in the United States, whereas hydroxocobalamin is the more preferred formulation in Europe for the treatment of vitamin B12 deficiency. Hydroxocobalamin requires less frequent administration (every three months) compared to oral cyanocobalamin supplementation. The parenteral method of administration is particularly useful to treat vitamin B12 deficiency caused by malabsorption states in which oral administration is ineffective.[11]

When treating vitamin B12 deficiency anemia with hydroxocobalamin, the dosage of each intramuscular injection of hydroxocobalamin is usually 1 mg given as a total of 5 to 10 doses administered every other day (3 times a week over two weeks) followed by every three months after that for maintenance. The duration of treatment is assessed based on the patient’s therapeutic response.[12]

The recommendation is to take the following precautions when treating B12 or folate deficiency. 

In a patient with folate deficiency, evaluation for coexistent B12 deficiency is necessary. If folate alone is supplemented in a B12 deficient patient, the B12 associated hematologic abnormalities may improve; however, neurological symptoms can worsen.  

One of the neurological disorders associated with B12 deficiency is subacute combined degeneration of the cord (SCD), a condition characterized by demyelination of the dorsal and lateral columns of the spinal cord. B12 plays a vital role in myelin production. The active form of B12 (adenosylcobalamin) serves as a cofactor in converting methylmalonyl-CoA to succinyl-CoA, an essential step in lipid synthesis. Without adenosylcobalamin, abnormal fatty acids incorporate into neuronal lipids interfering with normal myelin formation. Additionally, B12 deficiency can cause abnormal DNA synthesis, potentially hindering oligodendrocyte growth, adversely affecting myelin production.

Alternatively, it is also essential to recognize that folate deficiency indirectly leads to a B12 deficient state. In the cells, folate converts to its active form methyltetrahydrofolate (MTHF). MTHF acts as a donor of methyl groups to B12 (cobalamin), forming methylcobalamin. In the absence of this methylation, methylcobalamin (active form) is not produced and is unavailable for use leading to signs and symptoms of B12 deficiency.[13]

In cyanide poisoning, intravenous (IV) hydroxocobalamin should be used. The FDA approves the immediate use of an injection kit for this purpose.[4]

Adverse Effects

Hydroxocobalamin is generally a well-tolerated drug. The adverse effects stem from hypersensitivity reactions to cobalt or other components of the hydroxocobalamin injection. These adverse effects include; exanthema (rash), Itching, fever, nausea, dizziness, rigors, and hot flushes. Anaphylaxis is rare.[14]

Intramuscular injections can be painful for the patient. There is a risk of needle stick injury to the healthcare professionals delivering the injection. Further, it is associated with higher costs as it typically requires administration by a trained professional at home or a healthcare facility.[15][11]

Contraindications

There are no absolute contraindications to the use of hydroxocobalamin.

If hypersensitivity to hydroxocobalamin or any of its components is suspected, the drug should be avoided.

Monitoring

It is essential to confirm vitamin B12 deficiency before starting therapy and a follow-up plan for the monitoring of the patient’s response. If there is severe anemia associated with vitamin B12 deficiency, the patient’s response should lead to a marked increase in reticulocytes (precursors of red blood cells) by one-to-two weeks. In mild deficiencies of B12, this is less important, and follow-up should be done at two-to-three months after initiation of hydroxocobalamin. These measurements should include vitamin B12 levels as well as homocysteine and methylmalonic acid levels.[15] Both homocysteine and methylmalonic acid are indicators for vitamin B12 levels and demonstrate the patient’s response to hydroxocobalamin.[7]

Toxicity

There have been no reports of any known toxicity to hydroxocobalamin. As a result, there is no amount of hydroxocobalamin considered as a vitamin B12 overdose. There is no antidote.

Enhancing Healthcare Team Outcomes

An interprofessional team approach to managing patients requiring injections with hydroxocobalamin is essential in establishing an effective treatment regimen and assessment of patient response. This interprofessional team includes clinicians, mid-level practitioners, pharmacists, and nursing staff, all working collaboratively and sharing information to achieve optimal patient outcomes. It is important to emphasize that although rare, there may be hypersensitivity or allergic reactions to components of the hydroxocobalamin injection in some individuals. Open communication among members of the healthcare team is essential under these circumstances. There should be coordination between the nurse or practitioner administering the injection and the prescriber to ensure appropriate administration and monitoring of therapeutic response. The pharmacists can verify dosing and watch for potential interactions. All members can counsel the patient on administration and signs of therapeutic effectiveness as well as possible adverse reactions. There should be clear communication with patients on the quantity and frequency of injections needed. This information should be given initially by the prescriber and then again by the nurse or other healthcare provider administering the injection.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Pott JW, Wong KH. Leber's hereditary optic neuropathy and vitamin B12 deficiency. Graefes Arch Clin Exp Ophthalmol. 2006 Oct;244(10):1357-9. [PubMed: 16523300]

2.

Thompson JP, Marrs TC. Hydroxocobalamin in cyanide poisoning. Clin Toxicol (Phila). 2012 Dec;50(10):875-85. [PubMed: 23163594]

3.

Rizzo JF, Lessell S. Tobacco amblyopia. Am J Ophthalmol. 1993 Jul 15;116(1):84-7. [PubMed: 8328548]

4.

Purvis MV, Rooks H, Young Lee J, Longerich S, Kahn SA. Prehospital hydroxocobalamin for inhalation injury and cyanide toxicity in the United States - analysis of a database and survey of ems providers. Ann Burns Fire Disasters. 2017 Jun 30;30(2):126-128. [PMC free article: PMC5627550] [PubMed: 29021725]

5.

Thakkar K, Billa G. Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion. Eur J Clin Nutr. 2015 Jan;69(1):1-2. [PubMed: 25117994]

6.

Cassileth B. Vitamin B12. Oncology (Williston Park). 2010 Nov 15;24(12):1176. [PubMed: 21141702]

7.

O'Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010 Mar;2(3):299-316. [PMC free article: PMC3257642] [PubMed: 22254022]

8.

Suman SG, Gretarsdottir JM. Chemical and Clinical Aspects of Metal-Containing Antidotes for Poisoning by Cyanide. Met Ions Life Sci. 2019 Jan 14;19 [PubMed: 30855115]

9.

Teplitsky V, Huminer D, Zoldan J, Pitlik S, Shohat M, Mittelman M. Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults. Isr Med Assoc J. 2003 Dec;5(12):868-72. [PubMed: 14689755]

10.

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin, and Choline. National Academies Press (US); Washington (DC): 1998. [PubMed: 23193625]

11.

Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, Hood K, McCaddon A, McDowell I, Papaioannou A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004655. [PMC free article: PMC5112015] [PubMed: 16034940]

12.

Skouby AP. Dosage of hydroxocobalamin for vitamin B12 deficiency. Acta Med Scand. 1970 Jul-Aug;188(1):31-6. [PubMed: 5472640]

13.

Marshall R, Milburn JM. Clinical images - a quarterly column: subacute combined degeneration of the spinal cord. Ochsner J. 2013 Summer;13(2):183-5. [PMC free article: PMC3684324] [PubMed: 23789001]

14.

James J, Warin RP. Sensitivity to cyanocobalamin and hydroxocobalamin. Br Med J. 1971 May 01;2(5756):262. [PMC free article: PMC1796408] [PubMed: 5572387]

15.

Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003 Mar 01;67(5):979-86. [PubMed: 12643357]

Disclosure: Edris Ramezanpour Ahangar declares no relevant financial relationships with ineligible companies.

Disclosure: Pavan Annamaraju declares no relevant financial relationships with ineligible companies.