Pharmacologic Category

Antidote; Vitamin, Water Soluble

Dosing: Adult

Cyanide poisoning: IV: Note: If cyanide poisoning is suspected, antidotal therapy must be given immediately. Initial: 5 g as single infusion; may repeat a second 5 g dose depending on the severity of poisoning and clinical response. Maximum cumulative dose: 10 g.

Vasoplegic syndrome (off-label use): Note: Consider in patients who are refractory to methylene blue or as an alternative to methylene blue in patients who are at risk of serotonin syndrome or have glucose-6-phosphate dehydrogenase deficiency (Ortoleva 2019). Dosing is not standardized; refer to institutional protocols.

IV: 5 to 10 g over 10 to 15 minutes (An 2018; Cai 2017; Ortoleva 2019; Roderique 2014; Shah 2018).

Continuous IV infusion: Initial: IV bolus 125 to 250 mg, followed by continuous IV infusion rate of 250 to 500 mg/hour (Boettcher 2017; Woehlck 2016).

Vitamin B12 deficiency: Note: Oral cobalamin (eg, cyanocobalamin) may be used for less severe deficiencies and/or maintenance therapy (Devalia 2014).

Mild: IM: 1,000 mcg once weekly (usual dose) or up to 3 times weekly, until deficiency is corrected, then follow with a maintenance dose of 1,000 mcg every other month; longer intervals (eg, every 3 months) for maintenance dosing may also be used (Devalia 2014; Schrier 2019).

Severe: IM: 1,000 mcg every other day for up to 3 weeks then evaluate need for continuation of every other day administration; then follow with a maintenance dose of 1,000 mcg every other month (Devalia 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Dosing: Pediatric

Note: Verify dosing units due to large difference in dose for different indications; pediatric dosage may be presented in mg or mcg.

Cyanide poisoning (Cyanokit): Limited data available: Infants, Children, and Adolescents: Note: If cyanide poisoning is suspected, antidotal therapy must be given immediately: IV/Intraosseous: 70 mg/kg as a single infusion; maximum dose: 5,000 mg/dose; may repeat a second dose of 70 mg/kg (maximum dose: 5,000 mg/dose) depending on the severity of poisoning and clinical response (Mintegi 2013)

Pernicious anemia: Note: Concurrent folic acid supplementation may also be needed.

Mild to moderate: Infants, Children, and Adolescents: IM: Initial: 100 mcg/day for ≥2 weeks to target total dose range: 1,000 to 5,000 mcg; maintenance: 30 to 50 mcg/month.

Severe, complicated (eg, neurologic involvement): Multiple regimens reported, optimal dose not established: Infants, Children, and Adolescents: IM: Initial: 1,000 mcg daily for 7 days or every other day for 7 to 14 days (Devalia 2014; Goraya 2015; Orkin 2015; Skouby 1987; Stabler 2013); some experts suggest treatment until clinical improvement of neurologic symptoms observed (Devalia 2014); then follow with maintenance: 1,000 mcg every 2 to 3 months (Devalia 2014; Stabler 2013). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Orkin 2015).

Vitamin B12 deficiency: Limited data available; dosing regimens variable:

Dietary deficiency: Infants (breastfed with vitamin B12 deficient mothers): Infants ≥6 weeks: IM: 400 mcg once (Bjørke-Monsen 2008; Bjørke-Monsen 2011; Torsvik 2015)

Malabsorption: Infants, Children, and Adolescents: IM: 250 to 1,000 mcg daily or every other day for 1 week, then weekly for 4 to 8 weeks, and then monthly for life; younger children should receive monthly doses of 100 mcg (Bjørke-Monsen 2011; Kliegman 2016; Stabler 2013). For infants and young children, some experts have recommended doses as low as 50 to 100 mcg (Orkin 2015).

Dosing: Renal Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Use: Labeled Indications

IM injection: Treatment of pernicious anemia; treatment of vitamin B12 deficiency due to dietary deficiencies or malabsorption diseases, inadequate secretion of intrinsic factor, competition for vitamin B12 by intestinal parasites/bacteria, or inadequate utilization of B12 (eg, during neoplastic treatment)

IV infusion (Cyanokit): Treatment of cyanide poisoning (known or suspected)

Use: Off-Label: Adult

Vasoplegic syndromeLevel of Evidence [C]

Data from multiple case reports and a case series suggest that use of hydroxocobalamin may be beneficial in the treatment of vasoplegic syndrome and may be used as an alternative to or in patients who are refractory to methylene blue, in patients with glucose-6-phosphate dehydrogenase deficiency, or risk factors for serotonin syndrome during cardiac surgery Ref or liver transplantation Ref.

Level of Evidence Definitions

Level of Evidence Scale

Comparative Efficacy

• HYDROXOCOBALAMIN FOR INJECTION

Administration: IM

Administer 1000 mcg/mL solution IM only

Administration: IV

Cyanokit: Administer initial dose by IV infusion over 15 minutes; if a second dose is needed, administer the second dose over 15 minutes to 2 hours. Hydroxocobalamin is chemically incompatible with sodium thiosulfate and sodium nitrite and separate IV lines must be used if concomitant administration is desired (the safety and efficacy of coadministration are not established)

Administration: Pediatric

Parenteral:

IM: Administer 1,000 mcg/mL injection IM only; do not administer SubQ

IV/Intraosseous (Cyanokit): Administer as IV infusion over 15 minutes; if second dose is needed, administer second dose over 15 minutes to 2 hours depending upon the patient's clinical state; intraosseous may be used in pediatric patients (Mintegi 2013). Hydroxocobalamin is chemically incompatible with sodium thiosulfate and sodium nitrite; separate IV lines must be used if concomitant administration is desired.

Storage/Stability

Solution for IM injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

IV infusion (Cyanokit): Prior to reconstitution, store at 25°C (77°F): excursions permitted to 15°C to 30°C (59°F to 86°F).

Temperature variation exposure allowed for transport of lyophilized form:

Usual transport: ≤15 days at 5°C to 40°C (41°F to 104°F)

Desert transport: ≤4 days at 5°C to 60°C (41°F to 140°F)

Freezing/defrosting cycles: ≤15 days at -20°C to 40°C (-4°F to 104°F)

Following reconstitution, store up to 6 hours at ≤40°C (104°F); do not freeze. Discard any remaining solution after 6 hours.

Preparation for Administration: Adult

IV infusion (Cyanokit): Reconstitute each 5 g vial with 200 mL of NS using provided sterile transfer spike. If NS is unavailable, may use LR or D5W. Invert or rock each vial for 60 seconds prior to infusion; do not shake. Discard if solution is not dark red.

Preparation for Administration: Pediatric

Parenteral: IV/Intraosseous (Cyanokit): Reconstitute each 5 g vial with 200 mL of NS using provided sterile transfer spike. If NS is unavailable, may use LR or D5W. Gently invert vial for 60 seconds prior to infusion; do not shake. Resulting solution should be dark red in color; discard if solution is not dark red.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to help with some kinds of anemia.

• It is used to treat or prevent low vitamin B12.

• It is used to treat cyanide poisoning.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Diarrhea

• Nausea

• Vomiting

• Abdominal pain

• Injection site irritation

• Heartburn

• Flushing

• Agitation

• Acne

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Swelling

• Severe headache

• Severe dizziness

• Passing out

• Black, tarry, or bloody stools

• Trouble swallowing

• Trouble with memory

• Vision changes

• Severe eye irritation

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Contraindications

IM: Hypersensitivity to hydroxocobalamin or any component of the formulation

IV (Cyanokit): There are no contraindications listed in the manufacturer's labeling.

Warnings/Precautions

Concerns related to adverse effects:

• Hypertension: Cyanide poisoning: Increased blood pressure (≥180 mm Hg systolic or ≥110 mm Hg diastolic) may occur with infusion; elevations usually noted at the beginning of the infusion, peak toward the end of the infusion, and return to baseline within 4 hours following the end of the infusion. May offset hypotension induced by nitrite administration or cyanide; monitor blood pressure during treatment.

• Photosensitivity: May cause photosensitivity; avoid direct sunlight while skin remains discolored.

• Renal injury: Renal injury, requiring hemodialysis for recovery in some cases, has been reported and may include acute renal failure with acute tubular necrosis, renal impairment, and urine calcium oxalate crystals; monitor renal function for ≥7 days following therapy.

Disease-related concerns:

• Anemia: Appropriate use: Neurologic manifestations of vitamin B12 deficiency will not be prevented with folic acid unless vitamin B12 is also given; spinal cord degeneration might also occur when folic acid is used as a substitute for vitamin B12 in anemia prevention.

• Polycythemia vera: Vitamin B12 deficiency masks signs of polycythemia vera; vitamin B12 administration may unmask this condition.

Special populations:

• Fire victims: Fire victims may present with both cyanide and carbon monoxide poisoning. In this scenario, hydroxocobalamin is the agent of choice for cyanide intoxication since the traditional cyanide antidote that contains sodium nitrite produces methemoglobinemia and may worsen tissue hypoxia. Hydroxocobalamin can discolor the skin and exudates, complicating the assessment of burn severity.

Dosage form specific concerns:

• Cyanokit: Use caution or consider alternatives in patients known to be allergic to, or who have experienced anaphylaxis with hydroxocobalamin or cyanocobalamin. Collection of pretreatment blood cyanide concentrations does not preclude administration and should not delay administration in the emergency management of suspected or confirmed cyanide toxicity. Only pretreatment cyanide concentrations may be useful since postinfusion concentrations may be inaccurate. Treatment of cyanide poisoning should include external decontamination and supportive therapy. Use caution with concurrent use of other cyanide antidotes; safety has not been established. Consider consultation with a poison control center at 1-800-222-1222.

• Solution for IM injection: Treatment of severe vitamin B12 megaloblastic anemia may result in thrombocytosis and severe hypokalemia, sometimes fatal, due to intracellular potassium shift upon anemia resolution. Use caution in folic acid deficient megaloblastic anemia; administration of vitamin B12 alone is not a substitute for folic acid and might mask true diagnosis. Blunted therapeutic response to vitamin B12 may occur in certain conditions (eg, infection, uremia, concurrent iron or folic acid deficiency) or in patients on medications with bone marrow suppressant properties (eg, chloramphenicol). Approved for use as IM injection only.

Other warnings/precautions:

• Administration: Hydroxocobalamin may interfere with and/or trip alarms in patients who use hemodialysis machines that rely on colorimetric technology.

Geriatric Considerations

Evidence exists that people, particularly elderly, whose serum cobalamin concentrations are <500 pg/mL, should receive replacement parenteral therapy. This recommendation is based upon neuropsychiatric disorders and cardiovascular disorders associated with lower serum cobalamin concentrations.

Pregnancy Considerations

Hydroxocobalamin crosses the placenta (Huemer 2005; Roderique 2012).

Data on the use of hydroxocobalamin in pregnancy for the treatment of cyanide poisoning and cobalamin defects are limited (Brunel-Guitton 2010; Huemer 2005; Roderique 2012).

Cyanide crosses the placenta. Cyanide poisoning can be fatal for the pregnant female and fetus if untreated; treatment should not be withheld due to pregnancy. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant females if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Breast-Feeding Considerations

Hydroxocobalamin is present in breast milk.

Endogenous vitamin B12 milk concentrations are similar to maternal serum concentrations (IOM 1998). Breastfeeding is not recommended by the manufacturer during maternal treatment for cyanide poisoning. Hydroxocobalamin is considered compatible with breastfeeding when used for treatment of anemia (WHO 2002).

Adverse Reactions

IM injection: Frequency not defined:

Dermatologic: Pruritus, skin rash (transient)

Gastrointestinal: Diarrhea (mild, transient)

Hypersensitivity: Anaphylaxis

Local: Pain at injection site

Miscellaneous: Swelling (feeling of swelling of the entire body)

IV infusion:

>10%:

Cardiovascular: Increased blood pressure (18% to 28%)

Central nervous system: Headache (6% to 33%)

Dermatologic: Erythema (94% to 100%; may last up to 2 weeks), skin rash (20% to 44%; predominantly acneiform eruption; can appear 7 to 28 days after administration and usually resolves within a few weeks)

Gastrointestinal: Nausea (6% to 11%)

Genitourinary: Urine discoloration (100%; may last up to 5 weeks after administration), calcium oxalate nephrolithiasis (56% to 61%)

Hematologic & oncologic: Lymphocytopenia (8% to 17%)

Local: Infusion site reaction (6% to 39%)

Frequency not defined:

Cardiovascular: Chest discomfort, peripheral edema

Central nervous system: Dizziness, memory impairment, restlessness

Dermatologic: Pruritus, urticaria

Endocrine & Metabolic: Hot flash

Gastrointestinal: Abdominal distress, diarrhea, dyspepsia, dysphagia, hematochezia, vomiting

Hypersensitivity: Hypersensitivity reaction

Ophthalmic: Eye irritation, eye redness, swelling of eye

Respiratory: Dry throat, dyspnea, pharyngeal edema

<1%, postmarketing, and/or case reports: Acute renal failure, acute tubular necrosis, angioedema, calcium oxalate nephrolithiasis (Legrand 2016), methemoglobinemia (Jiwani 2017), renal insufficiency

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Chloramphenicol (Systemic): May diminish the therapeutic effect of Vitamin B12. Risk C: Monitor therapy

Test Interactions

The following values may be affected, in vitro, following hydroxocobalamin 5 g dose. Interference following hydroxocobalamin 10 g dose can be expected to last up to an additional 24 hours. Note: Extent and duration of interference dependent on analyzer used and patient variability (Shapeton 2019).

Falsely elevated:

Basophils, hemoglobin, MCH, and MCHC [duration: 12-16 hours]

Albumin, alkaline phosphatase, cholesterol, creatinine, glucose, total protein, and triglycerides [duration: 24 hours]

Bilirubin [duration: up to 4 days]

Urinalysis: Glucose, protein, erythrocytes, leukocytes, ketones, bilirubin, urobilinogen, nitrite [duration: 2-8 days]

Falsely decreased: ALT and amylase [duration: 24 hours]

Unpredictable:

AST, CK, CKMB, LDH, phosphate, and uric acid [duration: 24 hours]

PT (quick or INR) and aPTT [duration: 24-48 hours]

Urine pH [duration: 2-8 days]

May also turn both the plasma and urine a pinkish color and interfere with colorimetric or spectrophotometric tests (Wong 2016); may cause hemodialysis machines to shut down due to false detection of a blood leak from the blood-like appearance of the solution.

Monitoring Parameters

Vitamin B12, hematocrit, hemoglobin, reticulocyte count, red blood cell counts, folate and iron levels should be obtained prior to treatment and periodically during treatment.

Cyanide poisoning: Blood pressure and heart rate during and after infusion, serum lactate levels, venous-arterial PO2 gradient. Pretreatment cyanide levels may be useful as post infusion levels may be inaccurate. Renal function, including but not limited to BUN and SCr, for ≥7 days following therapy.

Megaloblastic anemia: In addition to normal hematological parameters, serum potassium and platelet counts should be monitored during therapy, particularly in the first 48 hours of treatment.

Advanced Practitioners Physical Assessment/Monitoring

Teach patient appropriate injection technique and needle disposal and appropriate nutrition. Cyanide toxicity: Monitor blood pressure and heart rate during infusion.

Nursing Physical Assessment/Monitoring

Teach patient appropriate injection technique and needle disposal and appropriate nutrition. Cyanide toxicity: Monitor blood pressure and heart rate during infusion.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intramuscular, as acetate:

Generic: 1000 mcg/mL (30 mL)

Solution Reconstituted, Intravenous:

Cyanokit: 5 g (1 ea)

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intramuscular:

Generic: 1000 mcg/mL (10 mL, 30 mL)

Solution Reconstituted, Intravenous:

Cyanokit: 5 g (1 ea)

Anatomic Therapeutic Chemical (ATC) Classification

• B03BA03
• V03AB33

Generic Available (US)

May be product dependent

Pricing: US

Solution (Hydroxocobalamin Acetate Intramuscular)

1000 mcg/mL (per mL): $1.28

Solution (reconstituted) (Cyanokit Intravenous)

5 g (per each): $985.58

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Hydroxocobalamin (vitamin B12a) is a precursor to cyanocobalamin (vitamin B12). Cyanocobalamin acts as a coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis, used in cell replication and hematopoiesis. In the presence of cyanide, each hydroxocobalamin molecule can bind one cyanide ion by displacing it for the hydroxo ligand linked to the trivalent cobalt ion, forming cyanocobalamin, which is then excreted in the urine.

Pharmacodynamics/Kinetics

Following IV administration of Cyanokit:

Distribution: Vdss:Free cobalamins-(III): 280.7 to 349.5 L; Total cobalamins-(III): 21.8 to 25.6 L

Protein binding: Significant; forms various cobalamin-(III) complexes

Metabolism: Does not undergo metabolism

Half-life elimination: 26 to 31 hours

Excretion: Urine (50% to 60% within initial 72 hours)

Pharmacodynamics/Kinetics: Additional Considerations

Gender: When normalized for body weight, men and women revealed no major pharmacokinetic differences.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Index Terms

Vitamin B12a

References

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Brand Names: International

Aquo-Cytobion (DE); Articlox (GR); B12 Depot-Rotexmedica (DE); B12-Depot-Hevert (DE); B12-Depot-Vicotrat (DE); Behepan (SE); Benzoral (AR); Berubi-long (DE); Bradirubra (IT); Cobalamin Depot (EG); Cobalin-H (AE, GB, MT); Cobalparen (DE); Cobalvit (IT); Cohemin Depot (FI); Cyano Kit (JP); Cyanokit (BE, ES, FR, HR, MT, PL); Cynomin H (BD); Depovit-B 12 (EG); Depovit-B12 (AE); Dodecavit (FR); Doleven (JP); Dosixbe (AR); Emicobal (EG); Forta B 5.000 (BE); Forta B12 (BE, LU); Hepavit (AT); Hycomin (KR); Hydrocobamine (NL); Hydroxo 5.000 (FR, LU); Hydroxo-B 12 (AU); Idroxocobalamina (IT); Lanobin (KR); Lisoneurin (AR); Lophakomp-B 12 Depot (DE); Megamilbedoce (ES); Minedrox (PE); Neo-B12 (AU); Neo-Cytamen (GB, IE, IT, NZ); Novidroxin (DE); Novobedouze (BE, LU); OH B12 (IT); OHB12 (PT); Rasedon 500 (JP); Rubranova (BR); Tarupain (KR); Twelvmin-s (JP); Vibeden (DK); Vitamin B12 Depot (NO); Vitamin B12-Depot-Injektopas (DE); Vitarubin-Depot (CH); Westhidroxo (MX)

Last Updated 2/5/20