Cyanokit

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Cyanokit

Classes

Antidotes, Systemic
Cyanocobalamin/Vitamin B12 and Analog Supplements

Administration
Injectable Administration

Administer Cyanokit (hydroxocobalamin 25 mg/mL) as an IV infusion for cyanide poisoning.
Administer hydroxocobalamin 1,000 mcg/mL only as an IM injection; it is indicated for vitamin B12 deficiencies.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous Administration

Reconstitution of Cyanokit
Utilize the provided sterile transfer spike to transfer the diluent into the vials for reconstitution.
Reconstitute each 5 g vial with 200 mL of diluent (not provided) for a final concentration of 25 mg/mL. The preferred diluent is 0.9% Sodium Chloride Injection; however, 5% Dextrose Injection or Lactated Ringer's Injection may be used if 0.9% Sodium Chloride Injection is unavailable. Each vial has a line on it to represent 200 mL of diluent.
Rock or repeatedly invert the vial for at least 60 seconds to reconstitute. Do not shake.
Discard the reconstituted solution if it is not dark red or if particulate matter is present.
Storage: Reconstituted solution is stable for up to 6 hours at temperature not exceeding 40 degrees C (104 degrees F). Do not freeze.
IV Infusion of Cyanokit
Administer the first dose over 15 minutes.
If a second dose is necessary, administer dose over 15 minutes to 2 hours.
Of note, pediatric patients may not require the entire vial (5 g) for their dose; withdraw the appropriate dose from the vial prior to infusion.
Administer through a separate IV line. Hydroxocobalamin is chemically incompatible with sodium thiosulfate and sodium nitrite.

Intramuscular Administration

Hydroxocobalamin 1,000 mcg/mL injection
Inject deeply into a large muscle mass.

Adverse Reactions
Severe

anaphylactoid reactions / Rapid / Incidence not known
ventricular tachycardia / Early / Incidence not known
pleural effusion / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known

Moderate

hypertension / Early / 18.0-28.0
dysphagia / Delayed / 22.0-22.0
lymphopenia / Delayed / 8.0-17.0
erythema / Early / Incidence not known
dyspnea / Early / Incidence not known
edema / Delayed / Incidence not known
hot flashes / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
crystalluria / Delayed / Incidence not known

Mild

rash / Early / 20.0-44.0
headache / Early / 6.0-33.0
nausea / Early / 6.0-11.0
skin discoloration / Delayed / Incidence not known
urine discoloration / Early / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
shivering / Rapid / Incidence not known
diarrhea / Early / Incidence not known
vomiting / Early / Incidence not known
dyspepsia / Early / Incidence not known
abdominal pain / Early / Incidence not known
restlessness / Early / Incidence not known
dizziness / Early / Incidence not known
injection site reaction / Rapid / Incidence not known

Common Brand Names

Cyanokit, Primabalt-RP

Dea Class

Rx

Description

Parenteral preparation of the hydroxylated active form of vitamin B12
Used for known or suspected cyanide toxicity, megaloblastic anemia, pernicious anemia, and other states of vitamin B12 deficiencies
Does not cause methemoglobinemia or hypotension, and has been shown to bind both intra- and extracellular cyanide

Dosage And Indications
For the treatment of known or suspected cyanide toxicity or poisoning.
NOTE: Administer hydroxocobalamin without delay if clinical suspicion of cyanide poisoning is high. Administer in conjunction with airway, ventilatory, and circulatory support as well as management of seizures.
Intravenous dosage (Cyanokit) Adults

5 g IV infused over 15 minutes. A second 5 g dose infused over 15 minutes to 2 hours (depending on patient status), for a total to 10 g, may be administered based on clinical response and severity of cyanide poisoning.[33229]

Infants†, Children† and Adolescents†

70 mg/kg/dose (Max: 5 g/dose) IV infused over 15 minutes. A second 70 mg/kg/dose (Max: 5 g/dose) infused over 15 minutes to 2 hours (depending on patient status), for a total of 140 mg/kg (Max: 10 g), may be administered based on clinical response and severity of cyanide poisoning.

For the treatment of vitamin B12 deficiency, vitamin B12 deficiency megaloblastic anemia, or macrocytic anemia due to vitamin B12 deficiency. Intramuscular dosage Adults

1,000 mcg IM once daily or every other day for 1 week, then once weekly for 4 to 8 weeks, then monthly until recovery. 30 mcg IM once daily for 5 to 10 days followed by 100 to 200 mcg IM once monthly is the FDA-approved dosage.

Adolescents

1,000 mcg IM once daily or every other day for 1 week, then once weekly for 4 to 8 weeks, then monthly until recovery. 100 mcg IM once daily over a period of 2 or more weeks (total of 1 to 5 mg) then 30 to 50 mcg IM every 4 weeks is the FDA-approved dosage.

Children

Dosing is not well established in pediatric patients; guide by clinical response and laboratory measurements. 1,000 mcg IM once daily for 2 to 7 days, then 100 mcg IM once weekly for 4 weeks, then 100 mcg IM once monthly until recovery has been recommended and used in children.    The adult dosage (1,000 mcg IM once daily or every other day for 1 week, then once weekly for 4 to 8 weeks, then monthly) has also been used in children. 100 mcg IM once daily over a period of 2 or more weeks (total of 1 to 5 mg) then 30 to 50 mcg IM every 4 weeks is the FDA-approved dosage.

Infants

Dosing is not well established in pediatric patients; guide by clinical response and laboratory measurements. 250 to 1,000 mcg IM once daily for 4 to 10 days then 100 to 1,000 mcg IM once weekly or monthly until recovery has been recommended and used in infants. 100 mcg IM once daily over a period of 2 or more weeks (total of 1 to 5 mg) then 30 to 50 mcg IM every 4 weeks is the FDA-approved dosage.

For the treatment of pernicious anemia. Intramuscular dosage Adults

1,000 mcg IM once daily or every other day for 1 week, then once weekly for 4 to 8 weeks, then monthly for life is the usual dosage. 30 mcg IM once daily for 5 to 10 days then 100 to 200 mcg IM once monthly is the FDA-approved dosage. Administer with folic acid, if needed.

Adolescents

1,000 mcg IM once daily or every other day for 1 week, then once weekly for 4 to 8 weeks, then monthly for life is the usual dosage. 100 mcg IM once daily over a period of 2 or more weeks (total of 1 to 5 mg) then 30 to 50 mcg IM every 4 weeks is the FDA-approved dosage. Administer with folic acid, if needed.

Children

Dosing is not well established in pediatric patients; guide by clinical response and laboratory measurements. 1,000 mcg IM once daily for 2 to 7 days, then 100 mcg IM once weekly for 4 weeks, then 100 mcg IM monthly has been recommended and used in children. The adult dosage (1,000 mcg IM once daily or every other day for 1 week, then once weekly for 4 to 8 weeks, then monthly) has also been used in children.  100 mcg IM once daily over a period of 2 or more weeks (total of 1 to 5 mg) then 30 to 50 mcg IM every 4 weeks is the FDA-approved dosage. Administer with folic acid, if needed.

Infants

Dosing is not well established in pediatric patients; guide by clinical response and laboratory measurements. 250 to 1,000 mcg IM once daily for 4 to 10 days then 100 to 1,000 mcg IM once weekly or monthly has been recommended and used in infants in case reports. 100 mcg IM once daily over a period of 2 or more weeks (total of 1 to 5 mg) then 30 to 50 mcg IM every 4 weeks is the FDA-approved dosage. Administer with folic acid, if needed.

For vitamin B12 deficiency diagnosis. Intramuscular dosage Adults

1,000 mcg IM once is the flushing dose for Schilling test/vitamin B12 absorption test.

For the adjunct treatment of primary homocystinuria† when a cobalamin cofactor metabolism (cbl) deficiency or defect is present. Intramuscular dosage Adults

1,000 to 2,000 mcg/day IM initially. Adjust dosage and frequency based on clinical and laboratory response.

Infants, Children, and Adolescents

1,000 to 2,000 mcg/day IM initially, with infants and children started at the lower end of the dosage range. Adjust dosage and frequency based on clinical and laboratory response.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Hydroxocobalamin and cyanocobalamin are excreted unchanged in the urine. In studies, oxalate crystals have been found in the urine of both healthy patients and those being treated for cyanide poisoning. Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
 
Hemodialysis
Specific guidelines are not available; it appears that no dosage adjustments are needed.

Drug Interactions

Bacillus Calmette-Guerin Vaccine, BCG: (Major) Medications known to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to hydroxocobalamin, vitamin B12 therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12. However, cancer patients usually benefit from vitamin B12 supplementation.
Colesevelam: (Moderate) It is not known if colesevelam can reduce the absorption of oral vitamin supplements including fat soluble vitamins A, D, E, and K. To minimize potential interactions, administer vitamins at least 4 hours before colesevelam.
Phenicol Derivatives: (Major) Chloramphenicol can antagonize the hematopoietic response to hydroxocobalamin, vitamin B12 through interference with erythrocyte maturation.

How Supplied

Cyanokit Intravenous Inj Pwd F/Sol: 5g
Cyanokit Intravenous Inj Pwd: 5g
Hydroxocobalamin/Primabalt-RP Intramuscular Inj Sol: 1ml, 1000mcg

Maximum Dosage
Adults

30 mcg/day IM, followed by 200 mcg/month IM is FDA-approved maximum; however, doses up to 2,000 mcg/day IM are used off-label; 10 g IV (total dose) for cyanide poisoning.

Geriatric

30 mcg/day IM, followed by 200 mcg/month IM is FDA-approved maximum; however, doses up to 2,000 mcg/day IM are used off-label; 10 g IV (total dose) for cyanide poisoning.

Adolescents

100 mcg/day IM, followed by 50 mcg/month IM is FDA-approved maximum; however, doses up to 2,000 mcg/day IM are used off-label; 140 mg/kg (Max: 10 g) IV total dose has been used off-label for cyanide poisoning.

Children

100 mcg/day IM, followed by 50 mcg/month IM is FDA-approved maximum; however, doses up to 2,000 mcg/day IM are used off-label; 140 mg/kg (Max: 10 g) IV total dose has been used off-label for cyanide poisoning.

Infants

100 mcg/day IM, followed by 50 mcg/month IM is FDA-approved maximum; however, doses up to 2,000 mcg/day IM are used off-label; 140 mg/kg (Max: 10 g) IV total dose has been used off-label for cyanide poisoning.

Mechanism Of Action

Hydroxocobalamin, vitamin B12 is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for vitamin B12. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which is also accompanied by the conversion of methyltetrahydrofolate to tetrahydrofolate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.
 
Cyanide binds to the ferric ion on the cytochrome oxidase enzyme, cytochrome a3; thus, inhibiting the function of the enzyme and preventing cellular use of oxygen. Secondary to the inhibition of cytochrome a3 and inability of the cell to utilize oxygen, it switches from aerobic to anaerobic production of adenosine triphosphate (ATP). Anaerobic metabolism favors lactate production over ATP leading to cellular hypoxia and metabolic acidosis. Hydroxocobalamin combines with cyanide to form cyanocobalamin, which is nontoxic and excreted in the urine. Specifically, the cyanide ion replaces the hydroxo ligand to form cyanocobalamin. Each hydroxocobalamin molecule binds one molecule of cyanocobalamin. Based on the molecular weight ratio of 50:1, 5 g hydroxocobalamin will bind 250 mg cyanide. Patients receiving hydroxocobalamin therapy for the treatment of known or suspected cyanide poisoning should also receive aggressive supportive care (ventilatory support, oxygen, and cardiovascular support).

Pharmacokinetics

Hydroxocobalamin is administered intravenously or intramuscularly. For the treatment of cyanide poisoning, hydroxocobalamin is administered as an intravenous infusion (IV). For the treatment of pernicious anemia, megaloblastic anemia, and vitamin B12 deficiencies and related syndromes, hydroxocobalamin is administered as an intramuscular injection (IM). Hydroxocobalamin significantly binds to plasma proteins.

Intravenous Route

Following IV administration, the mean volume of distribution was 0.19—0.3 L/kg in healthy volunteers and 0.45 L/kg in smoke inhalation victims. The mean half-life following IV administration was 1.6—5.4 hours in healthy volunteers compared to 26—31 hours in smoke inhalation victims. Following administration during in vitro studies, a 75% reduction of intracellular cyanide was observed along with the intracellular formation of cyanocobalamin; thus, hydroxocobalamin is thought to also work intracellularly. Hydroxocobalamin was found to cross the blood-brain barrier and enter the cerebrospinal fluid of animals utilized in an experimental study. Following IV infusion, the primary route of hydroxocobalamin excretion was found to be in the urine with 60% of the 5 g dose and 50% of the 10 g dose appearing in the urine within 72 hours of administration; urinary excretion accounts for a total of 60—70% of the administered dose. A majority of the urinary excretion occurs within the first 24 hours after administration.

Intramuscular Route

Following IM administration, approximately 50% of the dose remains at the injection site 2.5 hours after administration. Once absorbed, hydroxocobalamin (vitamin B12) is highly bound to transcobalamin II, a specific B-globulin carrier protein and is distributed and stored primarily in the liver as coenzyme B12. The bone marrow also stores a significant amount of the absorbed vitamin B12. This vitamin crosses the placenta and is distributed into breast milk. Enterohepatic recirculation conserves systemic stores. Hydroxocobalamin is excreted in both the bile and urine. Following the IM administration of 500—1000 mcg, 16—66% of the dose was excreted in the urine within 72 hours. Similar to IV administration, a majority of the urinary excretion occurs within the first 24 hours after IM administration.

Pregnancy And Lactation
Pregnancy

Adequate and well-controlled studies have not been conducted regarding the use of hydroxocobalamin during human pregnancy; data are insufficient to adequately assess the risk of birth defects, miscarriages, or adverse maternal or fetal outcomes. Hydroxocobalamin should only be administered during pregnancy when the benefit outweighs the potential for fetal risk.[33229] [33665] If an antidote is indicated for treatment of poisoning, the antidote should generally not be withheld because of pregnancy. Toxicity to the mother is a major determinant of fetal risk after cyanide exposure. For vitamin B12 supplementation, cyanocobalamin has been used within the recommended dietary intakes (RDIs) for pregnancy without harmful effects noted, and should be considered a preferred alternative for that indication. Vitamin B12 is an essential vitamin and requirements are increased during pregnancy. Amounts of vitamin B12 that are recommended by the Food and Nutrition Board, National Academy of Science-National Research Council for pregnant women should be consumed during pregnancy.[49235]

Hydroxocobalamin and cyanocobalamin are excreted in human breast milk. The manufacturer recommends mothers who receive hydroxocobalamin to treat cyanide poisoning avoid breast-feeding their infants. There are no data to determine when nursing can be reinitiated after administration of hydroxocobalamin.[33229] Cyanocobalamin is usually the preferred form of vitamin B12 supplementation if a patient is vitamin deficient; follow current recommendations for recommended dietary intakes (RDIs) during lactation for patients who are not deficient. There are no known harmful effects of vitamin B12 products during breast-feeding that have been reported.[27500] [49235]