Hydroxocobalamin (Vitamin B12) Injection

Cobalamin is vitamin B12 which can only be synthesized by microorganisms and can only be sourced from an animal product-based diet. A deficiency of cobalamin can cause megaloblastic anemia which could be related to deficient intake of vitamin B12 or deficient intrinsic factor, among other factors. The type of anemia, resulting from a lack of intrinsic factors is referred to as pernicious anemia.^[1]

Hydroxocobalamin (OHCbl) is a natural form of vitamin B12 which is available commercially. It is administrated parenterally either as an intravenous or intramuscular injection. This form of cobalamin is bioidentical to the B12 forms occurring in human physiology.^[2] Initially present as a manufacturing impurity and result of photolysis in commercial cyanocobalamin (under the trade name Cytamen), hydroxocobalamin was later found to be superior for many clinical conditions.^[3]

Doses of OHCbl are quite efficient for the prevention and treatment of pernicious anemia, as an antidote in cases of cyanide poisoning as well as for the treatment of Leber’s optic atrophy and tobacco amblyopia. Pernicious anemia is a fatal condition where a deficiency of vitamin B12 affects the generation of healthy red blood cells and the proper functioning of the nervous system.^[4] In some individuals, an auto-immune response inhibits the production of a protein called intrinsic factor which is present in normal stomach secretion. It is responsible for vitamin B12 absorption and its absence causes clinical manifestation of its deficiency. Surgery involving stomach areas where cells responsible for intrinsic factors are affected could also lead to loss of B12 absorption. Besides this, several diseases like celiac disease, Crohn’s disease as well as HIV can interfere with vitamin B12 absorption. Other causes include wrong types of bacteria in the small intestine, some antibiotics, and B12 feeding tapeworm.^[5]

OHCbl is found to be safe and cost-effective along with being efficient against pernicious anemia to be listed as an anti-anemic in the list of essential medicines for children published by W.H.O.^[6]

As an antidote for cyanide poisoning, hydroxocobalamin has shown many benefits over alternative antidotes. It has a very rapid response, its by-products are non-toxic and can be easily eliminated from the body, it can be used safely even with non-poisoned patients and it does not affect the oxygen-carrying capability of blood. It has a long history of being used as an anti-dote safely against cyanide poisoning.^[7] The only limitation is that it needs to be administered intravenously for a significant period of time and might need a hospital setting.

Tobacco amblyopia is caused by tobacco consumption and can be treated with hydroxocobalamin. A notable difference in improved visual acuity and color vision was reported when OHCbl was administrated IM in patients suffering from it and the performance was superior to cyanocobalamin.^[8]

Hydroxocobalamin is converted intracellularly into methylcobalamin and adenosylcobalamin. Methylcobalamin and adenosylcobalamin are active forms of vitamin B12 and play several important roles together in the body ranging from the metabolism of carbohydrates, proteins, and fats to the development of the nervous system and DNA synthesis. However, they are not interchangeable.^[9] While methylcobalamin is specifically important for hematopoiesis, adenosylcobalamin is important for myelin synthesis. Thus, hydroxocobalamin can be used against a wider clinical manifestation of B12 deficiency.

Purines and pyrimidines needed for DNA synthesis and red blood cell formation are dependent on methylcobalamin as a co-enzyme for the conversion of homocysteine to methionine. This is accompanied by the conversion of methyltetrahydrofolate to tetrahydrofolate.^[10] In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Most requirement of Vitamin B12 is by cells that need to undergo rapid growth such as epithelial cells, bone marrow, and myeloid cells.

During a study for its efficacy as a B12 supplement, hydroxocobalamin was found to show better retention over cyanocobalamin (CnCbl), was absorbed more slowly from the site of injection, maintained higher and longer blood levels, and was eliminated more slowly from urine.^[11] Thus, it may be construed as a superior alternative to cyanocobalamin in most cases of B12 deficiency. However, in specific cases such as when cobalamin(Cbl) deficiency is caused by a lack of transcobalamin II (TCII) or of receptors to TCII-Cbl, OHCbl may not be the preferred form of treatment and CnCbl with its frequent dosages should be superior.^[9]

In the case of cyanide poisoning, the high affinity of cyanide for cobalt-containing compounds helps it to bind with different forms of cobalamin (a vitamin with cobalt in its core). Hydroxocobalamin reacts stoichiometrically with the cyanide group and rapidly removes cyanide from tissues to form cyanocobalamin which is non-toxic and can be eliminated using both renal and hepatic pathways.^[12]

Cyanide binds preferentially to hydroxocobalamin over cytochrome oxidase (a3) within the mitochondria and makes hydroxocobalamin an effective antidote. However, hydroxocobalamin does not impact the oxygen-carrying capability of the user unlike methemoglobin formed on the use of CN Antidote Kit. This is especially helpful in the case of fire victims who may have hemoglobin in their blood poisoned by carbon monoxide and have their oxygen-carrying capability already impaired. An additional advantage is that the by-product formed ie. cyanocobalamin can slowly release cyanide in the liver, which allows hepatic rhodanese to convert it to thiocyanate which can also be renally excreted without overwhelming this natural elimination pathway of cyanide.^[13]

Hydroxocobalamin holds FDA approval for its use in cyanide toxicity with only mild side effects noted during treatment in some patients.^[14] It has been used for over three decades in Europe where it has demonstrated its safety profile in several studies.

Hydroxocobalamin should be used with caution in patients with any known anaphylactic reaction to the drug or any of the formulation components.^[15] It is also contraindicated for patients hypersensitive to cobalt and cyanocobalamin. Cases have been reported where patients who tolerated cyanocobalamin without any adverse effects were found to be allergic to hydroxocobalamin.^[16]

Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with hydroxocobalamin, or cyanocobalamin, may unmask this condition.^[17]

Postmarketing reports have associated intravenous hydroxocobalamin therapy when used as a cyanide antidote with the development of renal impairment and crystalluria with hemodialysis being necessary in some cases for recovery. It is recommended to monitor the renal function of the patients for 7 days following administration of hydroxocobalamin.^[18]

Because of the rapid restoration of erythropoiesis in the bone marrow when severe megaloblastic anemia is treated with hydroxocobalamin, hypokalemia, that is, low serum potassium can occur.^[19][20]] Use of hydroxocobalamin for treating megaloblastic anemia in combination with folate is also known to cause tremors and thrombocytosis.^[21] Therefore, potassium levels and platelet counts should be closely monitored when hydroxocobalamin is used for the treatment of megaloblastic anemia.

The red color induced by OHCbl can interfere with several lab reports including bilirubin, creatinine, magnesium, serum iron, serum aspartate aminotransferase, COHb, methemoglobin, and oxyhemoglobin tests. Caution is advised when being administered to dialysis patients since it can also create a false alarm within dialysis machines and shut down the machine due to what is referred to as a “blood leak.”^[22]

Hydroxocobalamin can absorb visible UV light and therapy with this medication may cause photosensitivity. Its use can induce erythema and although it is unknown whether hydroxocobalamin-induced erythema increases the risk for photosensitivity, it is recommended that patients avoid direct sunlight until the redness of skin caused by usage of hydroxocobalamin has resolved.^[23]

Simultaneous administration of blood products including whole blood, packed red cells, platelets, and fresh frozen plasma, in the same intra-venous line as hydroxocobalamin should be avoided.^[24]

Bacillus Calmette-Guerin Vaccine, BCG medications known to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to hydroxocobalamin, vitamin B12 therapy.^[28]

Limited evidence from case reports indicates that chloramphenicol which is a bacteriostatic antibiotic can interfere with the red blood cell response to supplemental vitamin B12 in some patients through interference with erythrocyte maturation.^[29]

Although generally useful for cancer patients it has been known to interfere with chemotherapy by depletion of extracellular cysteine in combination with ascorbate.^[30]

Metformin, used in the treatment of diabetes, can possibly affect the intestinal cells involved in intrinsic factor metabolism and calcium-dependent absorption of vitamin B12 leading to reduced assimilation of the vitamin. It may also occur due to other factors such as increased bacterial overgrowth.^[31][32]

Histamine H2 receptor antagonists used to treat peptic ulcer disease and proton pump inhibitors used to treat gastroesophageal reflux disease can affect absorption of B12 and it is recommended to monitor the vitamin status in patients using them for prolonged periods.^[33] Antineoplastics are antimetabolites for B12 that can reduce its hematologic response.^[34]

Hydroxocobalamin has been found to be physically incompatible when mixed in solution with diazepam, dobutamine, dopamine, fentanyl, nitroglycerin, pentobarbital, propofol, and thiopental. It is chemically incompatible with sodium thiosulfate, sodium nitrite, and ascorbic acid.^[30]

Reddening of skin, allergic reactions, headache, and erythema at the injection site are some common side effects of this drug. OHCbl has been known to induce chromaturia in healthy volunteers. However, red-colored urine is harmless and resolves itself within 2 to 3 days but it can interfere with laboratory tests.

Anaphylactic reaction has been observed and documented in some patients but discontinuation of therapy resolved the symptoms within a few weeks. It has been observed that predisposing factors in certain patients might lead to these symptoms.^[35]

A transient increase in blood pressure also has been seen due to hydroxocobalamin’s inhibition of nitric oxide synthase and direct clearing of nitric oxide from the blood. However, it is generally considered beneficial and should not be treated but close observation is recommended.^[31]

No allergic effects against OHCbl were seen in a study at dosages below 2.5 gm although higher dosages from 5 g to 7.5g showed effects in few volunteers ranging from itching, facial erythema, swelling, eye reddening, shivering, dyspnoea, facial oedema, and spontaneous exanthema.^[36] Pustular rash was the most common among the side effects. Generally, clinically serious cases effects are not seen with OHCbl, however, in rare cases, anaphylactic shock and loss of consciousness have been observed even with small dosages when used in the treatment of pernicious anemia in patients which were known to be tolerant to cyanocobalamin.^[16]

Hydroxocobalamin is FDA-approved for use in pregnant patients in case of cyanide poisoning including suspected cases since 2010. Although adequate studies have still not been performed to ascertain its safety profile and some animal models have shown increased mortality of fetuses in high doses, it’s the only anti-dote known to be safe enough to be used in pregnant patients in case of cyanide toxicity. It can not only eliminate the effects of cyanide but also help reduce the effects of carbon monoxide which may have co-occurred especially in the case of fire victims.^[25]

For any other use, hydroxocobalamin is a pregnancy category C drug and should be used only if the potential benefit outweighs the potential risk to the fetus.^[18]

As per the WHO Model List of Essential Drugs when used as an anti-anemic hydroxocobalamin is compatible with breastfeeding.^[26] During treatment for cyanide poisoning with hydroxocobalamin, however, breastfeeding is not recommended since it may be excreted from breast milk and could carry cyanide with it. There is no data to determine when breastfeeding may be safely restarted following administration.^[27]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour them down a sink or drain.

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