Congenital transcobalamin deficiency: IM: 1,000 mcg twice weekly
Cobalamin C disease: Limited data available: IM: 1,000 mcg/dose once daily was used in a single full-term neonate in conjunction with carnitine and folinic acid (Kind 2002)
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).
There are no dosage adjustments provided in manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in manufacturer's labeling (has not been studied).
(For additional information see "Hydroxocobalamin (vitamin B12a supplement and cyanide antidote): Drug information")
Cyanide poisoning: Note: If cyanide poisoning is suspected, antidotal therapy must be given immediately. Preferred in fire victims who present with both cyanide and carbon monoxide poisoning.
IV/IO: Initial: 5 g as single infusion over 15 minutes; may repeat a second 5 g dose over 15 minutes to 2 hours (total dose: 10 g) depending on the severity of poisoning and clinical response.
Hydrogen sulfide poisoning (off-label use): Note: May be beneficial if given immediately following exposure to hydrogen sulfide (Fujita 2011; Haouzi 2015; Truong 2007); use has not been validated in clinical trials (Holstege 2019). The dosing regimen used to treat cyanide poisoning should be utilized (expert opinion). Consultation with a clinical toxicologist or poison control center is highly recommended.
IV/IO: Initial: 5 g over 15 minutes; may repeat a second 5 g dose depending on the severity of poisoning and clinical response. Maximum cumulative dose: 10 g (Holstege 2019; expert opinion).
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, treatment:
Note: Folic acid supplementation may also be required. Oral vitamin B12 (eg, cyanocobalamin) may be used for less severe deficiency and/or maintenance therapy (Devalia 2014).
Severe/symptomatic anemia or neurologic/neuropsychiatric findings:
Initial therapy: IM: 1,000 mcg every other day or once daily for 1 to 2 weeks, then 1,000 mcg once weekly for 4 to 8 weeks (Devalia 2014; Mechanick 2020; Stabler 2013). Alternatively, if neurologic symptoms are present, may initiate 1,000 mcg every other day for up to 3 weeks or until no further improvement in signs or symptoms, then switch to 1,000 mcg once weekly for up to 12 weeks (Devalia 2014; Means 2021).
Maintenance therapy:
Note: Continue parenteral therapy until the deficiency has been corrected and signs and symptoms have resolved before switching to oral therapy (Means 2021).
IM: 1,000 mcg every 3 months; in patients with neurologic or neuropsychiatric symptoms, administer 1,000 mcg every 2 months (Devalia 2014).
Mild symptoms or asymptomatic: IM: 1,000 mcg once weekly for 4 weeks; maintenance dose: 1,000 mcg once every 2 to 3 months (Devalia 2014; Means 2021).
Duration of therapy: Continue indefinitely in patients with pernicious anemia or other irreversible cause of deficiency (eg, bariatric surgery); may discontinue therapy if a reversible cause of deficiency (eg, reduced dietary intake) has been addressed (Langan 2017; Stabler 2013; manufacturer's labeling).
There are no dosage adjustments provided in manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in manufacturer's labeling (has not been studied).
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)
Solution Reconstituted, Intravenous [preservative free]:
Cyanokit: 5 g (1 ea)
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intramuscular:
Generic: 1000 mcg/mL ([DSC])
Solution Reconstituted, Intravenous:
Cyanokit: 5 g (1 ea)
Parenteral:
IM: Administer 1,000 mcg/mL injection IM only; do not administer SubQ
IV/Intraosseous (Cyanokit): Administer using the IV administration set provided in the kit. 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. Use of intraosseous administration has been reported in adult patients in whom IV administration is not possible (Mastenbrook 2021); animal studies also support intraosseous administration as a viable alternative route of administration (Bebarta 2014; Elliot 2017).
IM: Administer 1,000 mcg/mL solution by IM injection only.
IV/ Intraosseous: Cyanokit: Administer using the IV administration set provided in the kit. 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). Use of intraosseous administration has been reported in patients in whom IV administration is not possible (Mastenbrook 2021); animal studies also support intraosseous administration as a viable alternative route of administration (Bebarta 2014; Elliot 2017).
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.
Pharmacy supply of emergency antidotes: Guidelines suggest that at least 10 g of hydroxocobalamin be stocked, especially in hospitals which serve industrial areas. Suggested amount is stated to be a sufficient quantity to treat 1 patient weighing 100 kg for an initial 8- to 24-hour period (Dart 2018); actual amount to be stocked should take into account site-specific and population-specific needs.
IM injection: Treatment of pernicious anemia (uncomplicated or accompanied by nervous system involvement); treatment of vitamin B12 deficiency due to dietary deficiencies, malabsorption diseases, inadequate secretion of intrinsic factor, competition for vitamin B12 by intestinal parasites/bacteria, or inadequate utilization of B12 (eg, during neoplastic treatment) (All indications: FDA approved in pediatric patients [age not specified] and adults)
IV infusion (Cyanokit): Treatment of cyanide poisoning (FDA approved in adults)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
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
IM: Hypersensitivity to hydroxocobalamin or any component of the formulation
IV (Cyanokit): There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Hypokalemia: According to the manufacturer, treatment of severe vitamin B12 megaloblastic anemia may result in severe hypokalemia, sometimes fatal, due to intracellular potassium shift upon anemia resolution; however, in more recent experience, while some patients may experience hypokalemia with initial treatment, it is transient and unlikely to be clinically significant (Carmel 2008).
• Hypertension: Cyanide poisoning: Increased BP (≥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 BP 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.
• Thrombocytosis: Treatment of severe vitamin B12 megaloblastic anemia may result in thrombocytosis.
Disease-related concerns:
• Megaloblastic anemia: May mask previously unrecognized folate deficiency; vitamin B12 is not a substitute for folic acid.
• Polycythemia vera: Vitamin B12 deficiency masks signs of polycythemia vera; vitamin B12 administration may unmask this condition.
Special populations:
• Fire victims: 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.
Other warnings/precautions:
• Hemodialysis: Hydroxocobalamin may interfere with and/or trip alarms in patients who use hemodialysis machines that rely on colorimetric technology.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
Chloramphenicol (Systemic): May diminish the therapeutic effect of Vitamin B12. Risk C: Monitor therapy
Strict vegetarian or vegan diets (eg, without eggs or dairy products) may result in vitamin B12 deficiency (NIH 2021; manufacturer's labeling).
Adequate intake (IOM 1998):
1 to 6 months: 0.4 mcg daily.
7 to 12 months: 0.5 mcg daily.
Recommended intake (IOM 1998):
1 to 3 years: 0.9 mcg daily.
4 to 8 years: 1.2 mcg daily.
9 to 13 years: 1.8 mcg daily.
≥14 years: 2.4 mcg daily.
Pregnancy: 2.6 mcg daily.
Lactation: 2.8 mcg daily.
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).
Baseline: Serum vitamin B12, hemoglobin, hematocrit, erythrocyte and reticulocyte count, folate and iron levels; serum methylmalonic acid (MMA) and total homocysteine levels in untreated patients to confirm vitamin B12 deficiency (and extent of deficiency) (Stabler 2013)
With treatment: Serum vitamin B12 and peripheral blood counts should be monitored 1 month after beginning treatment, then every 3 to 6 months thereafter. Evaluate serum MMA and total homocysteine levels periodically to confirm adequate supplementation (Stabler 2013).
Additional indication-specific monitoring:
Megaloblastic/pernicious anemia: In addition to normal hematological parameters, serum potassium and platelet counts should be monitored during therapy. Note: Some patients may develop hypokalemia during initial treatment; however, this is unlikely to be clinically significant (Carmel 2008).
Cyanide poisoning: Blood pressure and heart rate during and after infusion, serum lactate levels, venous-arterial PO2gradient. Pretreatment cyanide levels may be useful as post infusion levels may be inaccurate.
Serum vitamin B12 levels: Normal: >300 pg/mL; vitamin B12 deficiency: <200 pg/mL (200 to 300 pg/mL borderline result, possible deficiency); megaloblastic anemia: <100 pg/mL
Cyanide poisoning: Blood cyanide levels may be used for diagnosis confirmation; however, reliable levels require prompt testing and proper storage conditions
Cyanide levels related to clinical symptomatology:
Tachycardia/flushing: 0.5 to mg/L
Obtundation: 1 to 2.5 mg/L
Coma: 2.5 to 3 mg/L
Death: >3 mg/L
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.
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)
Sex: When normalized for body weight, men and women revealed no major pharmacokinetic differences.
Cyanocobalamin is preferred over hydroxocobalamin as a treatment agent for anemia due to reports of antibody formation to the hydroxocobalamin-transcobalamin complex. Cyanide is a clear colorless gas or liquid with a faint bitter almond odor. Cyanide reacts with trivalent ions in cytochrome oxidase in the mitochondria leading to histotoxic hypoxia and lactic acidosis. Signs and symptoms of cyanide toxicity include headache, altered mental status, dyspnea, mydriasis, chest tightness, nausea, vomiting, tachycardia/hypertension (initially), bradycardia/hypotension (later), seizures, cardiovascular collapse, or coma. Guidelines suggest that at least 10 g be stocked. This is enough to treat one patient weighing 100 kg for an initial 8- to 24-hour period (Dart 2009). If several victims, consider initiating with half-dose of hydroxocobalamin up to 5,000 mg/dose (Mintegi 2013).
Solution (Hydroxocobalamin Acetate Intramuscular)
1000 mcg/mL (per mL): $1.28
Solution (reconstituted) (Cyanokit Intravenous)
5 g (per each): $985.58
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