Cyanokit: Indications, Dosage, Precautions, Adverse Effects
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Cyanokit - Product Information

Manufacture: EMD Serono, Inc
Country: Canada
Condition: Cyanide Poisoning, Schilling Test, Transcobalamin II Deficiency, Vitamin B12 Deficiency
Class: Antidotes, Vitamins
Form: Intravenous (IV), Powder
Ingredients: Hydroxocobalamin

Hydroxocobalamin

Powder for Solution for Infusion

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
intravenous Each vial contains:
2 × 2.5 g powder for
solution for infusion
Final concentration
after reconstitution is
25 mg/mL

Each vial contains:
1 × 5 g powder for
solution for infusion
Final concentration
after reconstitution is
25 mg/mL
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

Cyanokit contains hydroxocobalamin, an antidote indicated for the treatment of known or suspected cyanide poisoning.

Cyanokit is to be administered together with appropriate decontamination and supportive measures.

Identifying Patients With Cyanide Poisoning:

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogens, including cyanogenic plants, aliphatic nitriles, or prolonged exposure to sodium nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Cyanokit should be administered without delay.

Table 1 Common Signs and Symptoms of Cyanide Poisoning
Symptoms
•Headache
•Confusion
•Dyspnea
•Chest tightness
•Nausea
Signs
•Altered Mental Status (e.g., confusion, disorientation)
•Seizures or Coma
•Mydriasis
•Tachypnea / Hyperpnea (early)
•Bradypnea / Apnea (late)
•Hypertension (early) / Hypotension (late)
•Cardiovascular collapse
•Vomiting
•Plasma lactate concentration ≥8 mmol/L

In some settings, panic symptoms, including tachypnoea and vomiting, may mimic early cyanide poisoning signs. The presence of altered mental status (confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning, although these signs can occur with other toxic exposures as well.

Smoke Inhalation

Not all smoke inhalation victims will necessarily have cyanide poisoning, and may present with burns, trauma, and exposure to additional toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to the administration of Cyanokit, smoke-inhalation victims should be assessed for the following:

  • exposure to fire smoke in an enclosed area
  • soot present around mouth, nose and/or oropharynx
  • altered mental status

In this setting hypotension and/or a plasma lactate concentration ≥ 10 mmol/L (higher than the value mentioned under signs and symptoms due to the fact that carbon monoxide contributes to lactic acidaemia) are highly suggestive of cyanide poisoning. In the presence of the above signs, treatment with Cyanokit must not be delayed to obtain a plasma lactate concentration.

Use With Other Cyanide Antidotes

The safety of administering other cyanide antidotes simultaneously with Cyanokit has not been established. If the decision is made to administer another cyanide antidote with Cyanokit, these medicinal products must not be administered concurrently in the same intravenous line (see DOSAGE AND ADMINISTRATION).

Geriatrics (≥ 65 years of age)

Approximately 50 known or suspected cyanide victims aged 65 or older received hydroxocobalamin in clinical studies. In general, the safety and effectiveness of hydroxocobalamin in these patients was similar to that of younger patients. No adjustment of dose is required in elderly patients.

Pediatrics (< 18 years of age)

Limited safety and efficacy data are available for pediatric patients. In infants to adolescents, the dose of Cyanokit is 70 mg/kg (see DOSAGE AND ADMINISTRATION).

Contraindications

None.

Warnings and Precautions

General

Emergency Patient Management - In addition to Cyanokit, treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of oxygenation and hydration, cardiovascular support, and management of any seizure activity. Consideration should be given to decontamination measures based on the route of exposure.

Cyanokit does not substitute for oxygen therapy and must not delay the set up of the above measures.

Cardiovascular

Transient, generally asymptomatic, increase in blood pressure may occur in patients receiving hydroxocobalamin. The maximal increase in blood pressure has been observed toward the end of infusion.

Immune

Known hypersensitivity to hydroxocobalamin or vitamin B12 must be taken into benefit-risk consideration before administration of Cyanokit, since hypersensitivity reactions may occur in patients receiving hydroxocobalamin. Allergic reactions may include anaphylaxis, chest tightness, edema, urticaria, pruritus, dyspnea and rash.

Renal

Based on its vasopressor effect, hydroxocobalamin may cause vasoconstriction of the renal vasculature. Since no more than two injections of hydroxocobalamin are to be administered it is unlikely that this will have any effect in patients with normal renal function; the outcome in patients with impaired renal function is unknown

Sexual Function/Reproduction

No animal studies on male and female fertility and early embryonic development to implantation have been performed.

Developmental toxicity including teratogenicity was observed in animal studies at doses that correspond approximately to the maximum recommended human dose. See TOXICOLOGY.

Hydroxocobalamin levels were detected in urine for some patients up to 35 days following treatment with Cyanokit indicating that elimination of Cyanokit from the body may not be completed after 35 days.

Based on these data, it is recommended to practice adequate methods of contraception for 2 months following Cyanokit treatment.

Skin

Photosensitivity - Hydroxocobalamin absorbs visible light in the UV spectrum. It therefore has potential to cause photosensitivity. While it is not known if the skin redness predisposes to photosensitivity, patients should be advised to avoid direct sun while their skin remains discoloured.

Special Populations

Pregnant Women

Animal studies have shown teratogenic effects following daily exposurethroughout organogenesis. (See TOXICOLOGY) There are no adequate and well-controlled studies in pregnant women. However, treatment of maternal/fetal cyanide poisoning may be lifesaving.

In the case of known pregnancy at the time of treatment with Cyanokit or in the case that pregnancy becomes known after treatment with Cyanokit, health care professionals are requested to promptly report the exposure during pregnancy to the Sponsor and to carefully follow-up on the pregnancy and its outcome.

The extent of exposure in pregnancy with Cyanokit in clinical trials is very limited. In a clinical study of the safety of Cyanokit in healthy volunteers, a pregnant subject was inadvertently enrolled and administered 5 g of hydroxocobalamin IV during her fourth week of gestation. Her pregnancy was uneventful and she reported the birth of a normal healthy baby at term.

In a retrospective study of cyanide ingestion/inhalation, a female subject, 4-months pregnant, ingested an undetermined amount of potassium cyanide. She received 10 g of hydroxocobalamin in addition to sodium thiosulfate in the first 24 hours post-ingestion. The fetus suffered intrauterine death. The mother survived without sequelae.

The effect of Cyanokit on labour and delivery is unknown.

Nursing Women

It is not known whether hydroxocobalamin is excreted in human milk. Because of the unknown potential for adverse reactions in nursing infants, discontinue nursing after Cyanokit treatment.

Pediatrics (< 18 years of age)

Limited safety and efficacy data are available for pediatric patients.

Geriatrics (≥ 65 years of age)

In general, the safety of hydroxocobalamin in these patients is similar to that of younger patients. No adjustment of dose is required in elderly patients.

Renal Impairment

The safety and effectiveness of Cyanokit have not been studied in patients with renal impairment. Hydroxocobalamin and cyanocobalamin are eliminated unchanged by the kidneys. Oxalate crystals have been observed in the urine of both healthy subjects given hydroxocobalamin and patients treated with hydroxocobalamin following suspected cyanide poisoning.

Hepatic Impairment

The safety and effectiveness of Cyanokit have not been studied in patients with hepatic impairment.

Monitoring and Laboratory Tests

Effects on Blood Cyanide Assay

Hydroxocobalamin will lower blood cyanide concentrations. While determination of blood cyanide concentration is not required and must not delay treatment with hydroxocobalamin, it may be useful for documenting cyanide poisoning. If a cyanide blood level determination is planned, it is recommended to draw the blood sample before initiation of treatment with Cyanokit.

Interference With Burn Assessment

Because of its deep red colour, hydroxocobalamin has the potential to induce a red colouration of the skin and therefore may interfere with burn assessment. However, skin lesions, oedema, and pain are highly suggestive of burns.

Interference With Laboratory Tests

Because of its deep red colour, hydroxocobalamin has the potential to interfere with determination of laboratory parameters (e.g. clinical chemistry, haematology, coagulation, and urine parameters) (Table 2). In vitro tests indicate that the extent and duration of the interference is dependant on numerous factors such as the dose of hydroxocobalamin, analyte, analyte concentration, methodology, analyser, concentrations of cobalamins-(III) including cyanocobalamin and partially the time between sampling and measurement.

Based on in vitro studies and pharmacokinetic data obtained in healthy volunteers the following table describes interference with laboratory tests that may be observed following a 5 g dose of hydroxocobalamin. Interference following a 10 g dose can be expected to last up to an additional 24 hours. The extent and duration of interference in cyanide-poisoned patients may differ according to the severity of intoxication. Results may vary considerably from one analyser to another, therefore, caution is required when reporting and interpreting laboratory results.

Table 2 Laboratory Interference Observed with in vitro Samples of Hydroxocobalamin
Laboratory
Parameter
No Interference
Observed
Artificially
Increaseda
Artificially
Decreaseda
Unpredictablec Duration of
Interference
Clinical
Chemistry
Calcium
Sodium
Potassium
Chloride
Urea
Gamma glutamyl
transferase (GGT)
Creatinine
Total and
conjugate
bilirubinb
Triglycerides
Cholesterol
Total protein
Glucose
Albumin
Albumin
phosphatase
Alanine
aminotransferase
(ALT)
Amylase
Phosphate
Uric Acid
Aspartate
aminotransferase
(AST)
Creatine Kinase
(CK)
Creatine Kinase
isoenzyme MB
(CKMB)
Lactate
dehydrogenase
(LDH)
24 hours with the
exception of
bilirubin (up to 4
days)
Hematology Erythrocytes
Hematocrit
Mean corpuscular
volume (MCV)
Leukocytes
Lymphocytes
Monocytes
Eosinophils
Neutrophils
Platelets
Hemoglobin (Hb)
Mean corpuscular
hemoglobin
(MCH)
Mean corpuscular
hemoglobin
concentration
(MCHC)
Basophils
12 - 16 hours
Coagulation Activated partial
thromoplastin
time (aPTT)
Prothrombin time
(PT)
Quick or INR
24 – 48 hours
Urinalysis pH (with doses ≥5
g)
Glucose
Protein
Erythrocytes
Leukocytes
Ketones
Bilirubin
Urobilinogen
Nitrite
pH (with
equivalent doses
of <5 g)
48 hours up to 8
days; color
changes may
persist up to 28
days

a ≥10% interference observed on at least 1 analyzer

b Artificially decreased using the diazo method

c Inconsistent results

Analyzers used: ACL Futura (Instrumentation Laboratory), AxSYM/Architect (Abbott), BM Coasys110 (Boehringer Mannheim), CellDyn 3700 (Abbott), Clinitek 500 (Bayer), Cobas Integra 700, 400 (Roche), Gen-S Coultronics, Hitachi 917, STA Compact, Vitros 950 (Ortho Diagnostics).

Interference With haemodialysis machines

Because of its deep red color, hydroxocobalamin may cause haemodialysis machines to shut down due to an erroneous detection of a ‘blood leak’. This should be considered before haemodialysis is initiated in patients treated with hydroxocobalamin.

Adverse Reactions

Adverse Drug Reaction Overview

Serious adverse reactions with hydroxocobalamin include allergic reactions and increases in blood pressure [see WARNINGS AND PRECAUTIONS].

A total of 347 subjects were exposed to hydroxocobalamin in clinical studies. Of these 347 subjects, 245 patients had suspected exposure to cyanide at the time of hydroxocobalamin administration. The remaining 102 subjects were healthy volunteers who had not been exposed to cyanide at the time of hydroxocobalamin administration.

Most patients will experience a reversible red colouration of the skin and mucous membranes that may last up to 15 days after administration of Cyanokit. All patients will show a dark red colouration of the urine that is quite marked during the three days following administration. Urine colouration may last up to 35 days after administration of Cyanokit.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Experience in Healthy Subjects

A double-blind, randomized, placebo-controlled, singleascendingdose (2.5, 5, 7.5, and 10 g) study was conducted to assess the safety, tolerability, and pharmacokinetics of hydroxocobalamin in 136 healthy adult subjects. Because of the dark red color of hydroxocobalamin, the two most frequently occurring adverse reactions were chromaturia (red-coloured urine) which was reported in all subjects receiving a 5 g dose or greater; and erythema (skin redness), which occurred in most subjects receiving a 5 g dose or greater. Adverse reactions reported in at least 1% of the 5 g dose group and corresponding rates in the 10 g and placebo groups are shown in Table 3.

Table 3 Incidence of Adverse Reactions Occurring in ≥ 1% of Healthy Subjects in 5 g Dose Group and Corresponding Incidence in 10 g Dose Group and Placebo
Adverse Drug Reaction 5 g Dose Group 10 g Dose Group
Hydroxo-
cobalamin
N = 66
n (%)
Placebo

N = 22
n (%)
Hydroxo-
cobalamin
N = 18
n (%)
Placebo

N = 6
n (%)
Eye disorder
   Eye redness 2(3) 0 1(6) 0
Renal and Urinary Disorders
   Chromaturia (red colored urine) 66(100) 0 18(100) 0
   Pollakiuria (frequent urination) 1(2) 0 0 0
Skin and subcutaneous tissue
disorders
   Erythema 62(94) 0 18(100) 0
   Rash* 14(21) 0 3(17) 0
Immune Disorders
   Face edema 1(2) 0 0 0
   Pruritus 1(2) 0 3(17) 0
   Urticaria 1(2) 0 0 0
Investigations
   Blood amylase increased 1(2) 0 0 0
   Blood pressure increased 12(18) 0 5(28) 0
   Lymphocyte percent decreased 5(8) 0 3(17) 0
Gastrointestinal disorders
   Abdominal discomfort 2(3) 0 2(11) 0
   Flatulence 1(2) 0 0 0
   Loose stools 1(2) 0 0 0
   Nausea 4(6) 1(5) 2(11) 0
   Vomiting 2(3) 0 0 0
Nervous System Disorders
   Dizziness 2(3) 0 1(6) 0
   Headache 4(6) 1(5) 6(33) 0
General disorders and
administrative site conditions
   Chest discomfort 3(5) 0 2(11) 0
   Discomfort 1(2) 0 0 0
   Feeling hot and/or cold 2(3) 0 0 0
   Infusion site reaction 4(6) 0 7(39) 0
Musculoskeletal and connective
tissue disorders
   Joint/back pain 2(3) 0 0 0
Psychiatric disorders
   Restlessness 2(3) 0 0 0
Respiratory, thoracic and
mediastinal disorders
   Dyspnea 1(2) 0 0 0
   Sore or dry throat 3(5) 0 3(17) 0

* Rashes were predominately acneiform

Less Common Adverse Drug Reactions Occurring at a rate of less than 1%

Eye disorders: Swelling, irritation

Gastrointestinal disorders: Dyspepsia, diarrhoea, dysphagia, hematochezia

General disorders and administration site conditions: Peripheral oedema.

Immune system disorders: Allergic reactions including angioneurotic oedema and skin eruption (see WARNINGS AND PRECAUTIONS).

Nervous system disorders: Memory impairment

Respiratory, thoracic and mediastinal disorders: Pleural effusion.

Vascular disorders: hot flush.

Experience in Known and Suspected Poison Victims

Four open-label, uncontrolled, clinical studies (one of which was prospective and three of which were retrospective) were conducted in known or suspected cyanide-poisoning victims. A total of 245 patients received hydroxocobalamin treatment in these studies. Systematic collection of adverse events was not done in all of these studies and interpretation of causality is limited due to the lack of a control group and due to circumstances of administration (e.g., use in fire victims). Adverse reactions reported in these studies listed by system organ class included:

Cardiac disorders: Ventricular extrasystoles, an increase in heart rates, electrocardiogram repolarization abnormality.

Adverse reactions common to both the studies in known or suspected cyanide poisoning victims and the study in healthy volunteers are listed in the healthy volunteer section only and are not duplicated in this list.

Abnormal Hematologic and Clinical Chemistry Findings

Cyanokit may cause red discolouration of the plasma, which may cause artificial elevation or reduction in the levels of certain laboratory parameters (see WARNINGS AND PRECAUTIONS).

White blood cell counts (WBC) showed a slight and transient increase in mean values from baseline at 2 to 12 hours after treatment in healthy subjects, and small decreases in serum sodium levels were also observed. Changed values generally remained within normal ranges. Other minor and transient changes in hematology and clinical chemistry findings were considered due to interference by hydroxocobalamin or due to individual variation.

Post-Market Adverse Drug Reactions

The following adverse events have been reported in post-marketing surveillance. The relationship of these events to Cyanokit use is not known. Smoke inhalation and cyanide exposure may have contributed to these events:

  • Abnormal laboratory tests
  • Pulmonary edema
  • Cardiac arrest
  • Renal failure – in some cases requiring dialysis
  • Transient impairment of renal function

Drug Interactions

Overview

Due to its high molecular weight, hydroxocobalamin is unlikely to interact with or inhibit CYP450 enzymes at clinically relevant concentrations. It is therefore considered to have low potential to be involved in drug-drug interactions with drugs that are substrates of CYP450.

Physical incompatibility (particle formation) and chemical incompatibility were observed with the mixture of hydroxocobalamin in solution with selected drugs that are frequently used in resuscitation efforts. Hydroxocobalamin is also chemically incompatible with sodium thiosulfate and sodium nitrite and has been reported to be incompatible with ascorbic acid. Therefore, these and other drugs should not be administered simultaneously through the same IV line as hydroxocobalamin. (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

No formal drug-drug interaction studies with hydroxocobalamin have been done.

Drug-Food Interactions

No formal drug-food interaction studies with hydroxocobalamin have been done.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Because of its deep red color, hydroxocobalamin has been found to interfere with colorimetric determination of certain laboratory parameters (e.g., clinical chemistry, hematology, coagulation, and urine parameters). In vitro tests indicated that the extent and duration of the interference are dependent on numerous factors such as the dose of hydroxocobalamin, analyte, methodology, analyzer, hydroxocobalamin concentration, and partially on the time between sampling and measurement. Based on in-vitro studies and pharmacokinetic data obtained in healthy volunteers, Table 2 describes laboratory interference that may be observed following a 5 g dose of hydroxocobalamin (see WARNINGS AND PRECAUTIONS). Interference following a 10 g dose can be expected to last up to an additional 24 hours. The extent and duration of interference in cyanide-poisoned patients may differ. Results may vary substantially from one analyzer to another; therefore, caution should be used when reporting and interpreting laboratory results.

Dosage and Administration

Dosing Considerations

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Cyanokit should be administered in conjunction with appropriate airway, ventilatory and circulatory support.

The safety of administering other cyanide antidotes simultaneously with Cyanokit has not been established. If the decision is made to administer another cyanide antidote with Cyanokit, these medicinal products must not be administered simultaneously through the same intravenous line.

Recommended Dose and Dosage Adjustment

In adults, the initial dose of Cyanokit is 5 g administered as an IV infusion. Depending on the severity of the poisoning and the clinical response, a second dose may be administered by IV infusion. The maximum recommended total dose is 10 g.

In infants to adolescents, the initial dose of Cyanokit is 70 mg/kg body weight not exceeding 5 g. Depending on the severity of the poisoning and the clinical response, a second dose may be administered by IV infusion. The maximum recommended total dose is 140 mg/kg body weight not exceeding 10 g (Table 4).

Table 4 Initial Dosing Guidelines in Infants and Adolescents
Body weight in kg 5 10 20 30 40 50 60
Initial dose in g 0.35 0.70 1.40 2.1 2.80 3.50 4.20
Initial dose in mL 14 28 56 84 112 140 168

Use in Renal and Hepatic Impairment

Although the safety and efficacy of hydroxocobalamin has not been studied in patients with renal or hepatic impairment, Cyanokit is administered as emergency therapy in an acute, lifethreatening situation only, and no dosage adjustment is required in these patients.

Administration

The initial dose of hydroxocobalamin for adults is 5 g (i.e., two 2.5 g vials or one 5 g vial) administered as an intravenous (IV) infusion over 15 minutes (approximately 15 mL/min). Depending upon the severity of the poisoning and the clinical response, a second dose of 5 g may be administered by IV infusion for a total dose of 10 g. The rate of infusion for the second dose ranges from 15 minutes (for patients who are extremely unstable) to 2 hours depending on the patient’s condition.

Reconstitution

Dose per
Vial
Volume of Diluent to be
Added to Vial
Approximate
Available Volume
Nominal Concentration per mL
2.5 g 100 mL Approx. 100 mL 25 mg/mL
5 g 200 mL Approx. 200 mL 25 mg/mL

2.5g Vial: Each 2.5 g vial is to be reconstituted with 100 ml of diluent using the supplied sterile transfer device. Sodium chloride 9 mg/ml (0.9%) solution for injection is the recommended diluent. Only when sodium chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or 5% glucose can also be used.

The Cyanokit 2.5g vial is to be rocked or inverted for at least 30 seconds to mix the solution. It must not be shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy.

5 g Vial: Each 5 g vial is to be reconstituted with 200 ml of diluent using the supplied sterile transfer device. Sodium chloride 9 mg/ml (0.9%) solution for injection is the recommended diluent. Only when sodium chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or 5% glucose can also be used.

The Cyanokit 5 g vial is to be rocked or inverted for at 60 seconds to mix the solution. It must not be shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy.

Because the reconstituted solution is a dark red solution, some insoluble particles may not be seen. The intravenous infusion set provided in the kit must therefore be used as it includes an appropriate filter and is to be primed with the reconstituted solution. Repeat this procedure if necessary with the second vial.

Incompatibility Information

Physical incompatibility (particle formation) and chemical incompatibility were observed with the mixture of hydroxocobalamin in solution with selected drugs that are frequently used in resuscitation efforts. Hydroxocobalamin is also chemically incompatible with sodium thiosulfate and sodium nitrite and has been reported to be incompatible with ascorbic acid. Therefore, these and other drugs must not be administered simultaneously through the same IV line as hydroxocobalamin.

Simultaneous administration of hydroxocobalamin and blood products (whole blood, packed red cells, platelet concentrate and/or fresh frozen plasma) through the same IV line is not recommended. However, blood products and hydroxocobalamin can be administered simultaneously using separate IV lines (preferably on contralateral extremities, if peripheral lines are being used).

Storage of Reconstituted Drug Product

Once reconstituted, hydroxocobalamin is stable for up to 6 hours at a temperature between 2°C and 40°C (35.6°F and 104°F). Do not freeze. Any reconstituted product not used by 6 hours should be discarded.

Overdosage

For management of a suspected drug overdose, contact your Regional Poison Control Center

Limited data are available about overdose with Cyanokit. Doses as high as 15 g have been administered without reported specific dose related adverse reactions. If overdose occurs, treatment is directed to the management of symptoms. Haemodialysis may be effective in such a circumstance, but is only indicated in the event of significant hydroxocobalamin-related toxicity. Because of its deep red color, hydroxocobalamin may interfere with the performance of haemodialysis machines (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Action and Clinical Pharmacology

Mechanism of Action

Cyanide is an extremely toxic poison. In the absence of rapid and adequate treatment, exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well. Signs and symptoms of acute systemic cyanide poisoning may develop rapidly within minutes, depending on the route and extent of cyanide exposure.

The action of hydroxocobalamin in the treatment of cyanide poisoning is based on its ability to tightly bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide ion by substituting the hydroxo ligand linked to the trivalent cobalt to form cyanocobalamin. Cyanocobalamin is a stable, non-toxic compound that is excreted in the urine.

Pharmacodynamics

Administration of Cyanokit to cyanide-poisoned patients with the attendant formation of cyanocobalamin resulted in increases in blood pressure and variable changes in heart rate upon initiation of hydroxocobalamin infusions. Preclinical studies suggest that increase in blood pressure may be related to nitric oxide scavenging property of hydroxocobalamin (see DETAILED PHARMACOLOGY).

Pharmacokinetics

Table 5 Summary of Hydroxocobalamin’s Pharmacokinetic Parameters in Healthy Subjects (i.e. total cobalamins-(III))
Cmax
(μg eq/mL)
t½
(h)
AUC0-t
(μg eq/mL*h)
Clearance
(L/h)
Volume of
distribution
(L)
5.0 g Single
Dose
Mean (SD)
579.0 (112.6) 31.0 (2.8) 8453.7 (2639.8) 0.566 (0.148) 21.8 (5.0)
10.0 g Single
Dose
Mean (SD)
995.3 (149.1) 29.6 (4.7) 14271.5
(2166.5)
0.645 (0.103) 23.0 (2.7)

Notes: All calculations for pharmacokinetic parameters are based on the sum of all cobalamin-(III) complexes and are for total cobalamins-(III).

Absorption and Distribution

Following IV administration of hydroxocobalamin significant binding to plasma proteins and low molecular weight physiological compounds occurs, to form various cobalamin-(III) complexes by replacing the hydroxo ligand. The low molecular weight cobalamins-(III) formed, including hydroxocobalamin, are termed “free cobalamins-(III)”; the sum of free and protein-bound cobalamins is termed “total cobalamins-(III)”. In order to reflect the exposure to the sum of all derivatives, pharmacokinetics of cobalamins-(III) were investigated instead of hydroxocobalamin alone, using the concentration unit μg eq/mL.

Dose-proportional pharmacokinetics were observed following single dose IV administration of 2.5 to 10 g of hydroxocobalamin in healthy volunteers. Mean free and total cobalamins-(III) Cmax values of 113 and 579 μg eq/mL, respectively, were determined following a dose of 5 g of Hydroxocobalamin. Similarly, mean free and total cobalamins-(III) Cmax values of 197 and 995 μg eq/mL, respectively, were determined following the dose of 10 g of hydroxocobalamin.

Metabolism

Hydroxocobalamin reacts with plasma constituents to form various cobalamin-(III) complexes. The exact structure of these metabolites of hydroxocobalamin has not been investigated. In cyanide-poisoned individuals, hydroxocobalamin binds cyanide to form cyanocobalamin.

Excretion

The predominant mean half-life of free and total cobalamins-(III) was found to be approximately 26 to 31 hours at both the 5 g and 10 g dose level. The mean total amount of cobalamins-(III) excreted in urine during the collection period of 72 hours was about 60% of a 5 g dose and about 50% of a 10 g dose of hydroxocobalamin. Overall, the total urinary excretion was calculated to be at least 60 to 70% of the administered dose. The majority of the urinary excretion occurred during the first 24 hours, but red-coloured urine was observed for up to 35 days following the IV infusion.

In cyanide-poisoned patients, hydroxocobalamin is expected to bind cyanide to form cyanocobalamin, which is excreted in urine. The pharmacokinetics of total cobalamins-(III) in this population may be affected by the body’s cyanide load, since cyanocobalamin was reported to exhibit a 2-3 times shorter half-life than total cobalamins-(III) in healthy volunteers.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of hydroxocobalamin have not been studied in pediatric patients.

Geriatrics

The pharmacokinetics of hydroxocobalamin have not been studied in geriatric patients.

Gender

When normalized for body weight, male and female subjects revealed no major differences in pharmacokinetic parameters of free and total cobalamins-(III) following the administration of 5 and 10 g of hydroxocobalamin.

Hepatic Insufficiency

The pharmacokinetics of hydroxocobalamin have not been studied in patients with hepatic impairment.

Renal Insufficiency

The pharmacokinetics of hydroxocobalamin have not been studied in patients with renal impairment. Hydroxocobalamin and cyanocobalamin are eliminated unchanged by the kidneys. Oxalate crystals have been observed in the urine of both healthy subjects given hydroxocobalamin and patients treated with hydroxocobalamin following suspected cyanide poisoning.

Storage and Stability

Storage of Lyophilized Form

Store at 25°C (77°F); excursions permitted to 15-30°C (59 to 86°F) [see USP Controlled Room Temperature].

Cyanokit may be exposed during short periods to the temperature variations of usual transport (15 days submitted to temperatures ranging from 5 to 40°C (41 to 104°F), transport in the desert (4 days submitted to temperatures ranging from 5 to 60°C (41 to 140°F)) and freezing/defrosting cycles (15 days submitted to temperatures ranging from -20 to 40°C (-4 to104°F)).

Storage of Reconstituted Solution

Store up to 6 hours at a temperature between 2°C and 40°C (35.6°F and 104°F). Do not freeze. Discard any unused portion after 6 hours.

Special Handling Instructions

Please see DOSAGE AND ADMINISTRATION section.

Dosage Forms, Composition and Packaging

Availability of Dosage Forms

Cyanokit 2.5 g Powder for Solution for Infusion consists of two Type II colourless 250 mL glass vials closed with a bromobutyl rubber stopper and an aluminum cap with a plastic lid.

Cyanokit 5 g Powder for Solution for Infusion consists of one Type I colourless 250 mL glass vial closed with a bromobutyl rubber stopper and an aluminum cap with a plastic lid.

Composition

Each vial contains lyophilized hydroxocobalamin dark red crystalline powder for infusion. Excipients include hydrochloric acid.

Each 2.5 g Cyanokit carton contains two glass vials (each glass vial packed in one cardboard box), two sterile transfer devices, one sterile intravenous infusion set and one sterile short catheter for administration to children. Diluent is not included.

Each 5 g Cyanokit carton contains one glass vial packed in a cardboard box, one sterile transfer device, one sterile intravenous infusion set and one sterile short catheter for administration to children. Diluent is not included.