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Hydroxocobalamin (Vitamin B12) Injection

Overview of Hydroxocobalamin (Vitamin B12) Injection

Cobalamins are vitamin B12 which can only be synthesized by microorganisms and can only be sourced from animal product-based diet. Deficiency of cobalamin can cause megaloblastic anaemia which could be related to deficient intake of vitamin B12 or deficient intrinsic factor, among other factors. The type of anaemia, resulting from lack of intrinsic factor is referred to as pernicious anaemia. 

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. 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.

Doses of OHCbl are quite efficient for prevention and treatment of pernicious anaemia, as an antidote in cases of cyanide poisoning as well as for the treatment of Leber’s optic atrophy and tobacco amblyopia. Pernicious anaemia is a fatal condition where deficiency of vitamin B12 affects generation of healthy red blood cells and proper functioning of nervous system. In some individuals, an auto-immune response, inhibits production of a protein called intrinsic factor which is present in normal stomach secretion. It is responsible for vitamin B12 absorption and its absence causing clinical manifestation of its deficiency. Surgery involving stomach areas where cells responsible for intrinsic factor 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. Others causes include wrong types of bacteria in small intestine, some antibiotics and B12 feeding tapeworm. 5

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

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 oxygen carrying capability of blood. It has a long history of being used as an anti-dote safely against cyanide poisoning.  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 of 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. 

Hyroxocobalamin 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 metabolism of carbohydrates, proteins and fats to development of nervous system and DNA synthesis. However, they are not interchangeable. While methylcobalamin is specifically important for hematopoiesis, adenosylcobalamin is important for myelin synthesis. Thus, hyroxocobalamin 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 conversion of homocysteine to methionine. This is accompanied by the conversion of methyltetrahydrofolate to tetrahydrofolate. 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 who need to undergo rapid growth such as epithelial cells, bone marrow and myeloid cells.

During a study for its efficacy as 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.  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 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.

In case of cyanide poisoning, 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 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. 

Cyanide bonds preferentially to hydroxocobalamin over cytochrome oxidase (a3) within the mitochondria and makes hydroxocobalamin an effective anti-dote. However, hydroxocobalamin does not impact the oxygen carrying capability of the user unlike methemoglobin formed on use of CN Antidote Kit. This is especially helpful in case of fire victims who may have haemoglobin in their blood poisoned by carbon monoxide and have its 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.

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

When ingested using oral route, cobalamin is attached to R-type binders with high affinity for B12 like haptocorrin which is a salivary glycoprotein.  This complex is disintegrated by pancreatic proteases in the duodenum to be further absorbed via the intrinsic factor protein in the intestine.  In human plasma, around 20% of cobalmin (Cbl) is bound to transcobalamin II  whereas the bulk of it is attached to haptocorrin.

Intramuscular Route

Following IM administration, B12 is rapidly assimilated from the site reaching peak plasma in 1 hour and approximately 50% of the dose remains at the injection site 2.5 hours after administration. Unlike cyanocobalamin (CNCbl), hydroxobalamin (OH-Cbl) can also associate non-specifically with plasma proteins, especially with albumin which serves as a transport protein for OHCbl. Whereas in case of CnCbl, the entire Cbl dosage is made available to cells via TCII, the excess of which is excreted in urine, in case of OHCbl, higher plasma level of Cbl is maintained in albumin which are not readily available for liver cells to be converted and stored as co-enzyme B12. In presence of TCII, the albumin-OHCbl complex can dissociate to bind with TCII which can then be made available to human cell for conversion to coenzyme B12. It has also been seen that rate of absorption of TCII-OH-Cbl is higher than TCII-CnCbl and the rate increasing step was the phase of internalization of TCII-Cbl for conversion to active co-enzyme. It was specifically not due to effective attachment to receptors of TCll-Cbl nor due to a more rapid regeneration of receptors.

OH-Cbl injections maintain higher plasma level of Cbl due to its ability to associate non-specifically with albumin and thus makes B12 available better and for a longer duration.

Hydroxocobalamin is excreted in both the bile and urine. Following the IM administration of 500—1000 mcg, 16—66% of the dose was excreted in the urine within 72 hours with the majority being eliminated in the first 24 hours.

Intravenous administration

In case of intravenous administration of hydroxocobalamin, its hydroxo ligand is substituted to form cobalamin-(III) complexes in a binding process with plasma proteins and low molecular weight physiological compounds forming.

In a study, dose-proportional pharmacokinetics were observed following single dose intravenous administration of 2.5 to 10 g of hydroxocobalamin in healthy volunteers. Mean free (hydroxocobalamin not specifically bound to TCII or R-binders) and total cobalamins-(III) Cmax values of 113 and 579 μg eq/mL, respectively, were determined following a dose of 5 g of hydroxocobalamin. Similarly, mean free and total cobalamins-(III) Cmax values of 197 and 995 μg eq/mL, respectively, were determined following the dose of 10 g of hydroxocobalamin. The predominant mean half-life of free and total cobalamins-(III) was found to be approximately 26 to 31 hours at both the 5 g and 10 g dose level. Similar to IM, majority of the dosage was eliminated in the first 24 hours with 50-60% of the dose removed in the first 72 hours. Red-coloured urine was, however, observed for up to 35 days following the intravenous infusion.

In normal conditions, excretion of B12 is predominantly via the fecal route. Parenteral administration of hydroxocobalamin can cause its level to rise beyond normal in which case, the excess B12 is eliminated in urine after filtration by the kidneys. 

Hydroxocobalamin should be used with caution in patients with any known anaphylactic reaction to the drug or any of the formulation components. 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.

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

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 during of the patients for 7 days following administration of hydroxocobalamin.

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

The red colour induced by OHCbl can interfere in 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 shuts down the machine due to what is referred to as “blood leak.”

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 causes by usage of hydroxocobalamin has resolved.

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. 

Hydroxocobalamin is FDA approved for use in pregnant patients in case of cyanide poisoning included 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 foetus 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 effects of cyanide but also helps reduce effects of carbon monoxide which may have co-occurred especially in case of fire victims. 

For any other use, hydroxocobalamin is pregnancy category C drug and should be used only if the potential benefit outweighs the potential risk to the foetus. 

As per WHO Model List of Essential Drugs when used as an anti-anaemic hydroxocobalamin is compatible with breastfeeding.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. 

Reddening of skin, allergic reactions, headache, and erythema at injection site are some common side effects of this drug. OHCbl has been known to induce chromaturia in healthy volunteers. However, red coloured 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 few weeks. It has been observed that predisposing factor in certain patients might lead to these symptoms.

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.

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. Pustular rash was 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 treatment of pernicious anaemia in patients which were known to be tolerant to cyanocobalamin. 

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 down a sink or drain.