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Hydroxocobalamin has a wide therapeutic index.10,18,46 Large doses have been administered to animals with no adverse effects.35,40,42 The LD50 (median lethal dose in 50% of test subjects) in mice is 2 g/kg.
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Red discoloration of mucous membranes, serum, and urine may occur and last from 12 hours to many days after therapy.10,14,18 Patients should be warned to avoid direct sun exposure while their skin remains red for fear of a photosensitivity reaction.14 Allergic reactions including anaphylaxis and angioedema are reported, but serious allergic reactions are rare.5,6,11,38 Prior chronic exposure to hydroxocobalamin or cyanocobalamin for treatment of vitamin B12 deficiency is associated rarely with development of anaphylaxis.25 A study in 102 healthy volunteers demonstrated that chromaturia is universal, and as the dose increases from 2.5 to 10 g, the incidence of erythema, rash (predominantly acneiform), headache, injection site reaction, nausea, pruritus, chest discomfort, and dysphagia increases.46 The dermatologic manifestations are quite variable, both rapid and delayed onset with protracted courses may occur. Of 102 volunteers randomized to receive hydroxocobalamin, 24 experienced a clinically significant rise in diastolic blood pressures, up to 124 mm Hg. However, only three of them also had clinically significant elevations in systolic blood pressure. These elevations in blood pressure resolved within 4 hours of the end of the infusion. Urinary oxalate crystals were reported in patients receiving hydroxocobalamin whether or not the patient is exposed to cyanide.14
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Colorimetric assays are most likely to be adversely affected because both hydroxocobalamin and cyanocobalamin have an intensely red color. Many clinical chemistry laboratory tests can be artificially increased, decreased, or unpredictable.9,14, Hematology tests including hemoglobin, MCH, MCHC, and basophils are artificially increased.14 Coagulation tests are unpredictable. Urinalysis tests are usually artificially increased, but pH can also be artificially low with low doses of hydroxocobalamin.14 An in vitro study found statistically significant alterations in serum concentrations of aspartate aminotransferase (AST), total bilirubin, creatinine, magnesium, and iron after hydroxocobalamin administration.13 Although an in vitro study demonstrated a considerable false increase in carboxyhemoglobin concentrations following hydroxocobalamin administration when measured by cooximetry, other authors suggest that the interference is minimal and results in slight overestimates depending on the instrument and the concentration of hydroxocobalamin.4,22,32 Inconsequential increases of 1% to 5.7% in the carboxyhemoglobin level were reported in another study.22 However, more worrisome is the report of two instances where the carboxyhemoglobin levels were falsely low by a factor of 4 to 14 times.34
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Because of the inaccuracies in laboratory determinations, blood should be drawn before the administration of hydroxocobalamin whenever possible. This is particularly important in fire victims when carboxyhemoglobin concentrations may be necessary for management decisions.