Hydroxocobalamin

B03B - Vitamin B12 and folic acid ATC B03BA03 Small molecule approved 1982 Parenteral Natural product

JFDA label: Vit B12 Depot

Mechanism of Action

Sequestering Agent of Cyanide — Cyanide sequestering agent

Target	Action	Gene / class
Cyanide efficacy	SEQUESTERING AGENT

Indications

Approved

IM injection
IV infusion (Cyanokit)

Contraindications

Source: Lexicomp

IM: Hypersensitivity to hydroxocobalamin or any component of the formulation IV (Cyanokit®): There are no contraindications listed in the manufacturer’s labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Very Common Increased blood pressure

Not Known Chest discomfort · peripheral edema

Nervous system disorders (4)

Very Common Headache

Not Known Dizziness · memory impairment · restlessness

Renal and urinary disorders (1)

Very Common Urine discoloration

Blood and lymphatic system disorders (1)

Very Common Lymphocytopenia

Immune system disorders (2)

Not Known Allergic reaction (including anaphylaxis) · Anaphylaxis

Metabolism and nutrition disorders (1)

Not Known Hot flash

Gastrointestinal disorders (8)

Very Common Nausea

Not Known Abdominal distress · diarrhea · Diarrhea (mild, transient) · dyspepsia · dysphagia · hematochezia · vomiting

Skin and subcutaneous tissue disorders (5)

Very Common Erythema · skin rash

Not Known Pruritus · skin rash (transient) · urticaria

Eye disorders (3)

Not Known Eye irritation · eye redness · swelling of eye

General disorders and administration site conditions (3)

Very Common Infusion site reaction

Not Known Pain at injection site · Swelling (feeling of swelling of the entire body)

Other (1)

Not Known Frequency not defined:

Respiratory, thoracic and mediastinal disorders (3)

Not Known Dry throat · dyspnea · pharyngeal edema

Dosing

Source: Lexicomp

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. Vitamin B12 deficiency: IM: Initial: 30 mcg once daily for 5 to 10 days; maintenance: 100 to 200 mcg once per month. Note: Larger doses may be required in critically-ill patients or if patient has neurologic disease, an infectious disease, or hyperthyroidism.

(For additional information see "Hydroxocobalamin (vitamin B12a supplement and cyanide antidote): Pediatric drug information") Vitamin B12 deficiency: Infants, Children, and Adolescents: IM: 100 mcg once daily for ≥2 weeks (total dose: 1 to 5 mg); maintenance: 30 to 50 mcg once per month Cyanide poisoning (off-label use): Limited data available: Infants, Children, and Adolescents: IV, Intraosseous: Note: If cyanide poisoning is suspected, antidotal therapy must be given immediately; Initial: 70 mg/kg (maximum dose: 5,000 mg/dose) as a single infusion; 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).

Refer to adult dosing.

No dosage adjustments provided in manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

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.

Photosensitivity

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

Pregnancy & Lactation

Pregnancy

FDA category C Teratogenic

Animal studies are insufficient to determine the effect, if any, on pregnancy or fetal development. There are no adequate and well-controlled studies in pregnant women. Data on the use of hydroxocobalamin in pregnancy for the treatment of cyanide poisoning and cobalamin defects are limited. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Lactation

Contraindicated

It is not known if hydroxocobalamin is excreted in breast milk. Hydroxocobalamin may be administered in life-threatening situations; therefore, use in a breast-feeding woman is not contraindicated. Because of the unknown potential for adverse reactions in nursing infants, the patient should discontinue nursing.

Monitoring

Clinical pearl	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. 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.

Clinical pearl

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. 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.

Chemistry & Properties

Formula	C62H89CoN13O15P
Molecular weight	1346.38 g/mol
IUPAC name	cobalt(3+);[(2R,3S,4R,5S)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2R)-1-[3-[(1R,2R,3R,4Z,7S,9Z,12S,13S,14Z,17S,18S,19R)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7,12,17-tetrahydro-1H-corrin-21-id-3-yl]propanoylamino]propan-2-yl] phosphate;hydroxide
CAS	13422-51-0
PubChem CID	44475014

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.303 h
Volume of distribution	0.519 L/kg
Protein binding	75.2%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (4, DDInter)

Interacting drug	Severity	Management
Arsenic trioxide	moderate
Chloramphenicol	moderate
Iodide I-123	moderate
Iodide I-131	moderate

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Vit B12 Depot	Ampoule 1 mg/ml	3 amp	Abu Sharef Medical Stores	4.820
B12 Depot-Panpharma 1 mg IV/IM ampoule solution for injection	Injection 1 mg/ml	10 amp	Reda Jardaneh Drug Store	6.520