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HYDROXOCOBALAMIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hydroxocobalamin, a cobalt-containing chelator, reverses cyanide toxicity by combining with cyanide to form cyanocobalamin (vitamin B12), a nontoxic metabolite excreted in the urine.

Specific Substances

    1) Cobinamide, dihydroxide, dihydrogen phosphate (ester), mono (inner salt), 3'- ester with 5,6- dimethyl-1-alpha-D-ribofuranosylbenzimidazole
    1.2.1) MOLECULAR FORMULA
    1) C62-H89-Co-N13-O15-P (RTECS, 2006)

Available Forms Sources

    A) FORMS
    1) Hydroxocobalamin, for use in the treatment of cyanide toxicity, is available in 2.5 g bottles as a lyophilized powder. The lyophilized powder for injection is prepared by dilution with 100 mL of normal saline (Prod Info CYANOKIT(R) 2.5g IV injection, 2006). This formulation of hydroxocobalamin for use as a cyanide antidote was submitted for FDA approval in 2006.
    2) NOTE: The commercially available hydroxocobalamin preparations (1 mg/mL for intramuscular injection) available in the US as of 2006 are used for the treatment of cobalamin deficiency (Prod Info hydroxocobalamin intramuscular solution, 2000). They are not intended for use in the treatment of cyanide poisoning.
    a) It would require FOUR to FIVE LITERS of this preparation for an adequate antidote dose, and therefore this PREPARATION SHOULD NOT BE USED.
    B) USES
    1) Hydroxocobalamin, a precursor of vitamin B12 and a cobalt-containing chelator, reverses cyanide toxicity by complexing with cyanide on a one-to-one molar ratio to form cyanocobalamin, which is excreted renally (Ries & Dart, 2005).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Hydroxocobalamin is an antidote approved for the treatment of known or suspected cyanide poisoning. This product is not to be confused with the commercially available hydroxocobalamin preparation (1000 mcg/mL for intramuscular injection) used for the treatment of cobalamin deficiency. This product is not intended for use in the treatment of cyanide poisoning. It would require 4 to 5 liters of this preparation for an adequate antidote dose, and therefore it should NOT be used.
    B) PHARMACOLOGY: Hydroxocobalamin is a vitamin B12a precursor. This cobalt-centered metalloprotein complexes with cyanide on a one-to-one molar ratio to form cyanocobalamin (vitamin B12), which is excreted renally. Hydroxocobalamin reactivates the mitochondrial enzymes involved in the respiratory process.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (greater than 5%): Transient chromaturia, erythema, rash, increased blood pressure, nausea, headache, and injection site reactions. OTHER EFFECTS: Peripheral edema, dizziness, allergic reactions, urticaria, pruritus, and pink or reddish discoloration of skin and mucous membranes.
    E) WITH POISONING/EXPOSURE
    1) Limited overdose data available. Overdose effects are expected to be an extension of adverse effects reported with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Hydroxocobalamin is classified as FDA pregnancy category C.

Laboratory Monitoring

    A) No specific laboratory tests are needed in patients exposed to hydroxocobalamin who are NOT also cyanide poisoned.
    B) Monitor blood pressure and heart rate during infusion of hydroxocobalamin.
    C) Laboratory tests should include serum electrolytes for assessment of renal function and hydration status.
    D) In suspected cyanide exposures, initial laboratory tests should include CBC, arterial and venous blood gases, serum electrolytes and lactate, assessment of renal function, chest x-ray (following inhalation exposure or if the patient has abnormal respiratory signs and symptoms), and whole blood cyanide levels.
    E) Refer to "Cyanide" management for further information on cyanide exposures.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Hypertension associated with infusion is generally mild and resolves within 4 hours of completion of infusion. Therapy is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Refer to "Cyanide" management for further information on the treatment of cyanide exposures.
    C) DECONTAMINATION
    1) Administered intravenously; ingestion is unlikely; decontamination is not necessary.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) ACUTE ALLERGIC REACTION
    1) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis may be effective in the event of significant toxicity from hydroxocobalamin or overdose; however, hydroxocobalamin has a deep red color which can interfere with the performance of hemodialysis machines.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management of patients with hydroxocobalamin overdose after cyanide exposure. A patient with an inadvertent exposure to just hydroxocobalamin (without cyanide exposure), that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Any exposure to cyanide salts or cyanide gas should be referred to a healthcare facility. Patients who remain asymptomatic with normal laboratory studies can be discharged after 6 hours.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Any patient with symptomatic poisoning should be admitted to an intensive care unit.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing symptomatic patients.
    I) PITFALLS
    1) Missing an ingestion of another chemical or other possible etiologies for a patient’s symptoms. When managing a suspected hydroxocobalamin overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Vd: In patients with cyanide poisoning: 0.45 L/kg. Protein binding: (intravenous) binds significantly to plasma proteins and low molecular weight physiological compounds, and forms cobalamin-(III) complexes by replacing the hydroxo ligand. Excretion: renal: At least 60% to 70% of a dose (total calculated urinary excretion). Elimination half-life: No cyanide exposure: approximately 10 hours (range, 3 to 20 hours). With cyanide exposure: approximately 19 hours. Cyanocobalamin: approximately 9 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypertension or acute allergic reaction.

Range Of Toxicity

    A) TOXICITY: Overdose data are limited. No lethal human doses have been reported. Range of toxicity is not well described. Up to 15 grams have been given with no adverse effects reported.
    B) THERAPEUTIC DOSES: ADULT: 5 g IV over 15 min (approximately 15 mL/min), may repeat an additional 5 g IV over 15 min to 2 hours as needed, for a total dose of 10 g. PEDIATRIC: In a non-US marketing experience, hydroxocobalamin 70 mg/kg was used to treat pediatric patients with cyanide toxicity. Additional doses may be given in cases of severe cyanide poisoning.

Clinical Effects

Summary Of Exposure

    A) USES: Hydroxocobalamin is an antidote approved for the treatment of known or suspected cyanide poisoning. This product is not to be confused with the commercially available hydroxocobalamin preparation (1000 mcg/mL for intramuscular injection) used for the treatment of cobalamin deficiency. This product is not intended for use in the treatment of cyanide poisoning. It would require 4 to 5 liters of this preparation for an adequate antidote dose, and therefore it should NOT be used.
    B) PHARMACOLOGY: Hydroxocobalamin is a vitamin B12a precursor. This cobalt-centered metalloprotein complexes with cyanide on a one-to-one molar ratio to form cyanocobalamin (vitamin B12), which is excreted renally. Hydroxocobalamin reactivates the mitochondrial enzymes involved in the respiratory process.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (greater than 5%): Transient chromaturia, erythema, rash, increased blood pressure, nausea, headache, and injection site reactions. OTHER EFFECTS: Peripheral edema, dizziness, allergic reactions, urticaria, pruritus, and pink or reddish discoloration of skin and mucous membranes.
    E) WITH POISONING/EXPOSURE
    1) Limited overdose data available. Overdose effects are expected to be an extension of adverse effects reported with therapeutic use.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) A transient increase in blood pressure with an associated decrease in heart rate has been observed during infusion of hydroxocobalamin. The blood pressure changes peaked towards the end of infusion and returned to baseline within 4 hours of completing the hydroxocobalamin infusion (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006; Forsyth et al, 1993).
    2) In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, a mean increase in systolic and diastolic blood pressure of 23 and 18 mm Hg, respectively, occurred in 18% (12/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 28% (5/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, swelling, irritation, and redness of eyes was associated with hydroxocobalamin therapy (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, throat tightness and dry throat were associated with hydroxocobalamin therapy (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) FINDING OF INCREASED BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double-blind, randomized, placebo-controlled dose study in 136 healthy adult patients, increases in blood pressure occurred in 18% (12/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 28% (5/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo. The mean increase in systolic and diastolic blood pressure of 23 and 18 mmHg, respectively, occurred with a compensatory decrease in heart rate during infusion of hydroxocobalamin. The blood pressure changes peaked towards the end of infusion and returned to baseline within 4 hours of completing the hydroxocobalamin infusion. In addition, systolic hypertension (180 mm Hg or greater) occurred in 2.9% (3/102), and diastolic hypertension (110 mm Hg or greater) occurred in 23.5% (24/102). There were no adverse sequelae from these rises (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006; Forsyth et al, 1993).
    B) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, peripheral edema was associated with hydroxocobalamin therapy (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, dyspnea was associated with hydroxocobalamin therapy (Uhl et al, 2006; Prod Info Cyanokit(R) IV injection, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a study with healthy volunteers, 15% of the subjects (n=16/102) complained of headache after receiving hydroxocobalamin in doses ranging from 2.5 to 10 grams vs 2.9% (1/34) in the placebo group (Uhl et al, 2006).
    b) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, headache occurred in 6% (4/66) of patients receiving a 5 gram dose compared with 5% (1/18) in placebo, and in 33% (6/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, dizziness was associated with hydroxocobalamin therapy (Prod Info Cyanokit(R) IV injection, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a study of healthy volunteers, 9% of the subjects (n = 9/102) became nauseated after receiving hydroxocobalamin in doses ranging from 2.5 to 10 grams (Uhl et al, 2006).
    b) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, nausea occurred in 6% (4/66) of patients receiving a 5 gram dose compared with 5% (1/22) in placebo, and in 11% (2/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Prod Info Cyanokit(R) IV injection, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINE COLOR ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Pink discoloration of the urine occurs in most patients with therapeutic dosing. The pink color is pronounced for up to three days following administration of hydroxocobalamin and resolves as hydroxocobalamin is eliminated from the body (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006; Forsyth et al, 1993).
    b) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, chromaturia occurred in 100% (66/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 100% (18/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo. All patients recovered over the next 7 to 35 days without adverse sequelae (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DECREASED LYMPHOCYTE COUNT
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, lymphocyte percent decreases occurred in 8% (5/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 17% (3/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Uhl et al, 2006; Prod Info Cyanokit(R) IV injection, 2011). No adverse events were noted.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pink or reddish discoloration of the skin and mucous membranes occurs in most patients with therapeutic dosing and resolves as hydroxocobalamin is eliminated from the body (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006; Forsyth et al, 1993).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, a rash (predominantly acneiform) occurred in 20% (13/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 44% (8/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).
    C) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, infusion site reaction occurred in 6% (4/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 39% (7/18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).
    D) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: In a double blind, randomized, placebo-controlled dose study in 136 healthy adult patients, erythema occurred in 94% (62/66) of patients receiving a 5 gram dose compared with 0% in placebo, and in 100% (n=18) of patients receiving a 10 gram dose of hydroxocobalamin compared with 0% in placebo (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).
    E) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria and pruritus have occasionally been associated with hydroxocobalamin injections (Prod Info Cyanokit(R) IV injection, 2011; Uhl et al, 2006).
    F) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Photosensitivity has been associated with hydroxocobalamin injections due to the absorption of visible light in the UV spectrum (Prod Info Cyanokit(R) IV injection, 2011).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) HEALTHY VOLUNTEERS: Two minor acute allergic reactions were reported during the infusion of hydroxocobalamin in healthy volunteers. The allergic symptoms included facial erythema and edema, shivering, dyspnea, spontaneous exanthema and urticaria, and responded to antihistamines (Uhl et al, 2006).
    b) Allergic reactions including anaphylaxis, chest tightness, edema, urticaria, pruritus, dyspnea, and rash have been associated with hydroxocobalamin therapy (Prod Info Cyanokit(R) IV injection, 2011).
    c) Anaphylactic and anaphylactoid reactions have NOT been reported with acute treatment of cyanide-poisoned patients.
    d) CHRONIC THERAPY: Allergic reactions have been reported with long-term intramuscular use of hydroxocobalamin for the treatment of pernicious anemia. There are no reports of acute allergic reactions with single high-dose hydroxocobalamin for the treatment of cyanide poisoning (Prod Info Cyanokit(R) IV injection, 2011; Branco-Ferreira et al, 1997).

Reproductive

    3.20.1) SUMMARY
    A) Hydroxocobalamin is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info Cyanokit(R) IV injection, 2011).
    B) ANIMAL STUDIES
    1) RATS; RABBITS: In animal studies, pregnant rats and rabbits administered 75, 150 or 300 mg/kg/day during organogenesis resulted in maternal toxicity and reduced numbers of live births due to embryofetal resorption in the high dose groups as well as decreased live fetal weight in high dose rats. In rats, fetuses from both the mid and high dose groups experienced short, rudimentary or small front and/or hind legs while rabbit litters and fetuses experienced dose dependent gross soft tissue and skeletal anomalies including domed heads, flat, bowed, or large ribs, dilated ventricles of the brain, thickened stomach wall, enlarged anterior or posterior fontanelles of the ventricles of the brain, and flexed, rigid flexor or medially rotated forelimbs/hindlimbs. Incomplete skeletal ossification was exhibited by both rats and rabbits (Prod Info Cyanokit(R) IV injection, 2011).
    2) MICE: No teratogenic effects were observed among the offspring of mice treated during pregnancy with hydroxocobalamin in doses of 3000 to 12,000 times those used therapeutically for vitamin deficiency in humans (TERIS , 2000).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY
    1) Hydroxocobalamin was safely used in a healthy, pregnant woman during her fourth week of gestation. She was inadvertently enrolled in a safety trial during which she received a dose of hydroxocobalamin 5 grams intravenously. Her pregnancy was uneventful, and she delivered a healthy baby at term (Prod Info CYANOKIT(R) IV injection, 2006).
    2) In a retrospective study, a pregnant woman received hydroxocobalamin in combination with sodium thiosulfate during her fourth month of gestation. She was treated with hydroxocobalamin 10 grams in addition to sodium thiosulfate within 24 hours of potassium cyanide ingestion. While the mother survived without sequelae, her fetus suffered intrauterine death that was suspected to have occurred prior to the cyanide ingestion and hydroxocobalamin administration (Prod Info CYANOKIT(R) IV injection, 2006).
    B) PREGNANCY CATEGORY
    1) Hydroxocobalamin is classified as FDA pregnancy category C (Prod Info Cyanokit(R) IV injection, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether hydroxocobalamin is excreted into human breast milk, but given the drug's indication in life-threatening situations, breastfeeding is not a contraindication to its use. The potential for adverse effects in the nursing infant from exposure to the drug are unknown. Because many drugs are excreted in human milk, there is the potential for adverse reactions in nursing infants. Due to the lack of human safety information, the manufacturer recommends to discontinue nursing following hydroxocobalamin exposure (Prod Info Cyanokit(R) IV injection, 2011). Timing on safely restarting breast-feeding after hydroxocobalamin administration is unknown (Prod Info CYANOKIT(R) IV injection, 2006).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info Cyanokit(R) IV injection, 2011).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS13422-51-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are needed in patients exposed to hydroxocobalamin who are NOT also cyanide poisoned.
    B) Monitor blood pressure and heart rate during infusion of hydroxocobalamin.
    C) Laboratory tests should include serum electrolytes for assessment of renal function and hydration status.
    D) In suspected cyanide exposures, initial laboratory tests should include CBC, arterial and venous blood gases, serum electrolytes and lactate, assessment of renal function, chest x-ray (following inhalation exposure or if the patient has abnormal respiratory signs and symptoms), and whole blood cyanide levels.
    E) Refer to "Cyanide" management for further information on cyanide exposures.
    4.1.2) SERUM/BLOOD
    A) GENERAL
    1) HYDROXOCOBALAMIN THERAPY: Minor alterations in WBC, PTT and serum sodium levels have been reported with therapeutic use, but were not clinically significant (Forsyth et al, 1993). Obtain laboratory levels as clinically indicated in patients that become symptomatic following hydroxocobalamin use.
    B) ACID/BASE
    1) Obtain blood for arterial blood gases, venous pO2 or measured venous %O2 saturation following cyanide exposure.
    C) BLOOD/SERUM CHEMISTRY
    1) Following cyanide exposure, obtain blood for electrolytes, serum lactate, and whole blood cyanide levels.
    4.1.4) OTHER
    A) OTHER
    1) LABORATORY INTERFERENCE
    a) Hydroxocobalamin in serum has been shown to interfere with several automated colorimetric chemistry assays, including assays for aspartate aminotransferase, total bilirubin, creatinine, magnesium, and iron (Curry et al, 1994; Prod Info CYANOKIT(R) IV injection, 2006).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite treatment should be admitted. Any patient with symptomatic cyanide poisoning should be admitted to an intensive care unit.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management of patients with hydroxocobalamin overdose after cyanide exposure. A patient with an inadvertent exposure to just hydroxocobalamin (without cyanide exposure), that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing symptomatic patients.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Any exposure to cyanide salts or cyanide gas should be referred to a healthcare facility. Patients who remain asymptomatic with normal laboratory studies can be discharged after 6 hours.

Monitoring

    A) No specific laboratory tests are needed in patients exposed to hydroxocobalamin who are NOT also cyanide poisoned.
    B) Monitor blood pressure and heart rate during infusion of hydroxocobalamin.
    C) Laboratory tests should include serum electrolytes for assessment of renal function and hydration status.
    D) In suspected cyanide exposures, initial laboratory tests should include CBC, arterial and venous blood gases, serum electrolytes and lactate, assessment of renal function, chest x-ray (following inhalation exposure or if the patient has abnormal respiratory signs and symptoms), and whole blood cyanide levels.
    E) Refer to "Cyanide" management for further information on cyanide exposures.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Administered intravenously; ingestion is unlikely; decontamination is not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Hypertension associated with infusion is generally mild and resolves within 4 hours of completion of infusion. Therapy is generally not necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Refer to "Cyanide" management for further information on the treatment of cyanide exposures.
    3) Administered intravenously; refer to parenteral treatment section for more information.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis may be effective in the event of significant toxicity from hydroxocobalamin or overdose; however, hydroxocobalamin has a deep red color which can interfere with the performance of hemodialysis machines (Prod Info Cyanokit(R) IV injection, 2011).
    B) HEMODIALYSIS INTERFERENCE
    1) Dialysis machines have a spectrophotometric safety measure that can shut down after detecting blood leaking across the dialysis membrane. Hydroxocobalamin has a deep red color and can permeate the dialysis membrane, coloring the dialysate and causing the hemodialysis machine to shut down erroneously. In one case report, a patient with cyanide poisoning underwent dialysis after receiving 5 g of IV hydroxocobalamin because of refractory acidemia, reduced kidney function and hyperkalemia. A blood leak alarm caused the dialysis machine to shut down erroneously, delaying therapy, and resulting in the death of the patient (Stellpflug et al, 2013).
    2) In one study, hemodialysis machines from different manufacturers were tested for blood leak alarm interference. Hydroxocobalamin and normal saline solutions (colored red with Red Dye 40) were infused into the Fresenius 2008K(TM) and the Gambro Phoenix X36(TM) hemodialysis machines. These agents triggered the blood leak alarm and stopped the Fresenius 2008K(TM) machine but not the Gambro Phoenix X36(TM). It was determined that this interference was colorimetric due to normal saline with Red Dye 40, independent of hydroxocobalamin or even cyanocobalamin (Sutter et al, 2012).

Range Of Toxicity

Summary

    A) TOXICITY: Overdose data are limited. No lethal human doses have been reported. Range of toxicity is not well described. Up to 15 grams have been given with no adverse effects reported.
    B) THERAPEUTIC DOSES: ADULT: 5 g IV over 15 min (approximately 15 mL/min), may repeat an additional 5 g IV over 15 min to 2 hours as needed, for a total dose of 10 g. PEDIATRIC: In a non-US marketing experience, hydroxocobalamin 70 mg/kg was used to treat pediatric patients with cyanide toxicity. Additional doses may be given in cases of severe cyanide poisoning.

Therapeutic Dose

    7.2.1) ADULT
    A) The initial dose is 5 g IV infusion over 15 min (approximately 15 mL/min); may repeat an additional 5 g IV over 15 min to 2 hours as needed, for a total dose of 10 g (Prod Info Cyanokit(R) IV injection, 2011)
    B) PREHOSPITAL ADMINISTRATION
    1) RETROSPECTIVE REVIEW: In an 8 year review of cases involving smoke inhalation victims (n= 101) treated with hydroxocobalamin in the pre-hospital setting, hydroxocobalamin was administered by trained nurses within 15 minutes of initiation of care at doses of 5 grams for adults and 70 mg/kg for pediatric patients. Survival status was known for 72 of the victims. The overall survival rate was 41.7% (n = 30 of 72). For the 42 victims who died, the main cause of death was cardiac arrest followed by multi-organ failure and cerebral anoxia (Fortin et al, 2006).
    C) SMOKE INHALATION VICTIMS
    1) In a prospective, uncontrolled, open-label study (n=69), intravenous hydroxocobalamin was effective in reversing cyanide poisoning among smoke or fire inhalation victims (over the age of 15 years) exposed to cyanide. Forty-two patients had potentially toxic pre-treatment cyanide serum levels. Following treatment of intravenous hydroxocobalamin 5 grams (g) (range, 4 g to 15 g), 28/42 (67%) patients survived. However, 9 of the 50 survivors developed neurological sequelae, including dementia, confusion, psychomotor retardation, anterograde amnesia, intellectual deterioration, moderate cerebellar syndrome, aphasia, and memory impairment. Thirteen of the 19 subjects who did not survive presented with cardiac arrest at the time of treatment initiation (Borron et al, 2007; Prod Info CYANOKIT(R) IV injection, 2006).
    2) In 2 retrospective, uncontrolled studies among patients exposed to cyanide from fire or smoke inhalation, treatment of hydroxocobalamin up to 15 grams resulted in 56% (34 of 61 subjects) survival rates in one study, and 42% (30 of 72 subjects) survival rates in the second study (Prod Info CYANOKIT(R) IV injection, 2006).
    D) CYANIDE POISONING BY INGESTION OR INHALATION
    1) In a retrospective, uncontrolled study (n=14), intravenous hydroxocobalamin was effective in reversing cyanide poisoning among patients exposed to cyanide by ingestion or inhalation. Eleven patients had confirmed serum cyanide levels above the lethal threshold. Following treatment of intravenous hydroxocobalamin 5 to 20 grams (g), 10 (71%) patients survived. However, 1 survivor developed postanoxic encephalopathy with memory impairment from cyanide poisoning. One of the 4 non-survivors presented with cardiac arrest at the time of treatment initiation (Borron et al, 2007; Prod Info CYANOKIT(R) IV injection, 2006).
    2) Intravenous hydroxocobalamin alone or in combination with sodium thiosulfate is effective in treating acute cyanide poisoning (Marrs, 1988; Hall & Rumack, 1987; Holland & Kozlowski, 1986). The mechanism of action of hydroxocobalamin is exchange of its hydroxy groups for cyanide to form cyanocobalamin, which is rapidly excreted in the urine. Up to 50 times more hydroxocobalamin than cyanide is required (Anon, 1977); doses of 4 grams combined with sodium thiosulfate 8 grams have been used in France. Patients should also be treated with oxygen.
    E) ANIMAL STUDIES
    1) An efficacy study using a canine model compared hydroxocobalamin 75 mg/kg (n = 19) and 150 mg/kg (n = 18) to a saline placebo (n = 17) for the treatment of cyanide poisoning. Hydroxocobalamin infusion was associated with rapid improvement of hemodynamic stability. Mortality was significantly lower in the treatment group. On Day 15, the mortality rate was 0% for the group treated with 150 mg/kg of hydroxocobalamin, 21% for the group treated with 75 mg/kg hydroxocobalamin, and 82% for the placebo group. Of the animals that were treated with hydroxocobalamin and survived, no neurologic or other sequelae were noted (Borron et al, 2006).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients in the United States (US); however, 70 mg/kg doses have been used in non-US markets (Prod Info Cyanokit(R) IV injection, 2011).

Maximum Tolerated Exposure

    A) Up to 15 grams of hydroxocobalamin have been given with no adverse effects reported (Borron et al, 2005).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) HYDROXOCOBALAMIN - Plasma levels ranged from 150 to 500 micromol/L in poisoned patients treated with 5 grams (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    2) CYANOCOBALAMIN - The maximum plasma concentration of cyanocobalamin in smoke inhalation victims (n = 10) treated with 5 g hydroxocobalamin was measured at 212.4 +/- 30.9 micromol/L (Houeto et al, 1996).

Workplace Standards

    A) ACGIH TLV Values for CAS13422-51-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS13422-51-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS13422-51-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS13422-51-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Hydroxocobalamin is a vitamin B12a precursor. This cobalt-centered metalloprotein complexes with cyanide on a one-to-one molar ratio to form cyanocobalamin (vitamin B12), which is excreted renally (Hall & Rumack, 1987; Prod Info CYANOKIT(R) 2.5g IV injection, 2006).
    B) Hydroxocobalamin reactivates the mitochondrial enzymes involved in the respiratory process (Prod Info CYANOKIT(R) 2.5g IV injection, 2006).

Physicochemical

Physical Characteristics

    A) Dark red crystals (Prod Info CYANOKIT(R) 2.5g IV injection, 2006)

Molecular Weight

    A) 1346 (Prod Info CYANOKIT(R) 2.5g IV injection, 2006)

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