NDC 50633-310 Cyanokit

Hydroxocobalamin

NDC Product Code 50633-310

NDC CODE: 50633-310

Proprietary Name: Cyanokit What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Hydroxocobalamin What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Hydroxocobalamin is a man-made injectable form of vitamin B12 used to treat low levels (deficiency) of this vitamin. Vitamin B12 helps your body use fat and carbohydrates for energy and make new protein. It is also important for normal blood, cells, and nerves. Most people get enough vitamin B12 in their diet, but a deficiency may occur in certain health conditions (e.g., poor nutrition, stomach/intestinal problems, infection, cancer). Serious vitamin B12 deficiency may result in anemia, stomach problems, and nerve damage.

NDC Code Structure

  • 50633 - Btg International Inc.

NDC 50633-310-11

Package Description: 1 VIAL, GLASS in 1 CARTON > 250 mL in 1 VIAL, GLASS

NDC Product Information

Cyanokit with NDC 50633-310 is a a human prescription drug product labeled by Btg International Inc.. The generic name of Cyanokit is hydroxocobalamin. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 700496 and 700499.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Cyanokit Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • HYDROCHLORIC ACID (UNII: QTT17582CB)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Antidote - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Btg International Inc.
Labeler Code: 50633
FDA Application Number: NDA022041 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-15-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Cyanokit Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

CYANOKIT is indicated for the treatment of known or suspected cyanide poisoning.

2.1 Important Dosage And Administration Instructions

  • If clinical suspicion of cyanide poisoning is high, administer CYANOKIT without delay.
  • Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Airway, ventilatory and circulatory support, oxygen administration, and management of seizures should not be delayed to administer CYANOKIT [see Warnings and Precautions (5.1)].
  • The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Other

  • Identifying Patients with Cyanide PoisoningCyanide 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, cyanogenic plants, aliphatic nitriles, and 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.
  • Table 1 Common Signs and Symptoms of Cyanide Poisoning
  • Symptoms Headache
  • Confusion
  • Dyspnea
  • Chest tightness
  • Nausea
  • SignsAltered 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 tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

  • Smoke InhalationNot all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of CYANOKIT, smoke-inhalation victims should be assessed for the following:
  • Exposure to fire or smoke in an enclosed area
  • Presence of soot around the mouth, nose or oropharynx
  • Altered mental status
  • Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration ≥10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

Use with Other Cyanide AntidotesThe safety of administering other cyanide antidotes simultaneously with CYANOKIT has not been established. If a decision is made to administer another cyanide antidote with CYANOKIT, these drugs should not be administered concurrently in the same intravenous line [see Dosage and Administration (2.4)].

Clinical Laboratory EvaluationsBecause 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.
The data presented in Table 2 is collected from in vitro studies and pharmacokinetic data in healthy volunteers and describes laboratory interference 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. In addition, results may vary substantially from one analyzer to another. Be aware of this when reporting and interpreting laboratory results.
Table 2 Laboratory Interference Observed with in vitro Samples of Hydroxocobalamin
Laboratory Parameter
No Interference Observed
Artificially Increased *
Artificially Decreased *
Un-predictable
Duration of Interference
* ≥10% interference observed on at least 1 analyzer
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)
Clinical ChemistryCalciumSodiumPotassiumChlorideUreaGGT
CreatinineBilirubinTriglyceridesCholesterolTotal proteinGlucoseAlbuminAlkaline phosphatase
ALTAmylase
PhosphateUric AcidASTCKCKMBLDH
24 hours with the exception of bilirubin (up to 4 days)
HematologyErythrocytesHematocritMCVLeukocytesLymphocytesMonocytesEosinophilsNeutrophilsPlatelets
HemoglobinMCHMCHCBasophils
12 - 16 hours
CoagulationaPTTPT (Quick or INR)
24 - 48 hours
UrinalysispH (with all doses)GlucoseProteinErythrocytesLeukocytesKetonesBilirubinUrobilinogenNitrite
pH (with equivalent doses of <5 g)
48 hours up to 8 days; color changes may persist up to 28 days

Clinical MethodsBecause of its deep red color, hydroxocobalamin may cause hemodialysis machines to shut down due to an erroneous detection of a “blood leak”. This should be considered before hemodialysis is initiated in patients treated with hydroxocobalamin.

  • Experience in Healthy SubjectsBecause clinical trials were conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.
  • A double-blind, randomized, placebo-controlled, single-ascending-dose (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-colored 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 5% 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 >5% of Subjects in 5 g Dose Group and Corresponding Incidence in 10 g Dose Group and Placebo
  • * Rashes were predominantly acneiform
  • ADR5 g Dose Group10 g Dose GroupHydroxocobalaminN=66n (%)PlaceboN=22n (%)HydroxocobalaminN=18n (%)PlaceboN=6n (%)Chromaturia (red colored urine)
  • 66 (100)
  • 0
  • 18 (100)
  • 0
  • Erythema
  • 62 (94)
  • 0
  • 18 (100)
  • 0
  • Oxalate crystals in urine
  • 40 (61)
  • 1 (5)
  • 10 (56)
  • 0
  • Rash*
  • 13 (20)
  • 0
  • 8 (44)
  • 0
  • Blood pressure increased
  • 12 (18)
  • 0
  • 5 (28)
  • 0
  • Nausea
  • 4 (6)
  • 1 (5)
  • 2 (11)
  • 0
  • Headache
  • 4 (6)
  • 1 (5)
  • 6 (33)
  • 0
  • Lymphocyte percent decreased
  • 5 (8)
  • 0
  • 3 (17)
  • 0
  • Infusion site reaction
  • 4 (6)
  • 0
  • 7 (39)
  • 0
  • In this study, the following adverse reactions were reported to have occurred in a dose-dependent fashion and with greater frequency than observed in placebo-treated cohorts: increased blood pressure (particularly diastolic blood pressure), rash, nausea, headache and infusion site reactions. All were mild to moderate in severity and resolved spontaneously when the infusion was terminated or with standard supportive therapies.
  • Other adverse reactions reported in this study and considered clinically relevant were:
  • Eye disorders: swelling, irritation, redness
  • Gastrointestinal disorders: dysphagia, abdominal discomfort, vomiting, diarrhea, dyspepsia, hematochezia
  • General disorders and administration site conditions: peripheral edema, chest discomfort
  • Immune system disorders: allergic reaction
  • Nervous system disorders: memory impairment, dizziness
  • Psychiatric disorders: restlessness
  • Respiratory, thoracic and mediastinal disorders: dyspnea, throat tightness, dry throat
  • Skin and subcutaneous tissue disorders: urticaria, pruritus
  • Vascular disorders: hot flush

  • Experience in Known or Suspected Cyanide Poisoning VictimsFour 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
  • Investigations: electrocardiogram repolarization abnormality, heart rate increased
  • Respiratory, thoracic, and mediastinal disorders: pleural effusion
  • 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.

Interference with Laboratory TestsBecause 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). Be aware of this when reporting and interpreting laboratory results [see Warnings and Precautions (5.5)].

Risk SummaryAvailable data from cases reported in the published literature and postmarketing surveillance with CYANOKIT use in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal and fetal outcomes. There are risks to the pregnant woman and fetus associated with untreated cyanide poisoning (see Clinical Considerations). In animal studies, hydroxocobalamin administered to pregnant rats and rabbits during the period of organogenesis caused skeletal and soft tissue abnormalities, including alterations in the central nervous system, at exposures similar to human exposures at the therapeutic dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal riskCyanide readily crosses the placenta. Cyanide poisoning is a medical emergency in pregnancy which can be fatal for the pregnant woman and fetus if left untreated. Life-sustaining therapy should not be withheld due to pregnancy.

Data

Animal DataIn animal studies, pregnant rats and rabbits received CYANOKIT (75, 150, or 300 mg/kg/d) during the period of organogenesis. Following intraperitoneal dosing in rats and intravenous dosing in rabbits, maternal exposures were equivalent to 0.5, 1, or 2 times the human exposure at the therapeutic dose (based on AUC). In the high dose groups for both species, maternal toxicity occurred, and there was a reduced number of live fetuses due to embryofetal resorptions. In addition, decreased live fetal weight occurred in high dose rats, but not in rabbits. Incomplete skeletal ossification occurred in both rats and rabbits. In rats, two fetuses of the high dose group and two fetuses of the mid dose group (each from a different litter) had short, rudimentary or small front or hind legs. Rabbit litters and fetuses exhibited a dose-dependent increase in various gross soft tissue and skeletal anomalies. The main findings in rabbits were flexed, rigid flexor or medially rotated forelimbs or hindlimbs and domed heads at external examination; enlarged anterior or posterior fontanelles of the ventricles of the brain and flat, bowed or large ribs at skeletal examination; and dilated ventricles of the brain, and thick wall of the stomach at visceral examination. It is unknown if similar findings would be observed in rats and rabbits if CYANOKIT was administered as a single dose during any critical period of development.

Risk SummaryBreastfeeding is not recommended during treatment with CYANOKIT. There are no data to determine when breastfeeding may be safely restarted following administration of CYANOKIT. Hydroxocobalamin and Vitamin B12 (which is formed when hydroxocobalamin combines with cyanide) are present in human milk. There are no data on the effects of hydroxocobalamin on the breastfed infant or the effects on milk production.

DistributionThe volume of distribution at steady state (Vss) for both free and total cobalamins-(III) showed no apparent relationship to dose. The Vss ranged from 280.7 to 349.5 L for free cobalamins-(III), and from 21.8 to 25.6 L for total cobalamins-(III). The comparatively high values for Vss of free cobalamins-(III) are due to the high protein binding of hydroxocobalamin as it reacts in the blood with plasma constituents to form cobalamins-(III) complexes and the rapid distribution of free cobalamins-(III) into tissues.

EliminationThe 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-colored urine was observed for up to 35 days following the intravenous infusion. The 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.

MetabolismHydroxocobalamin does not undergo metabolism.

ExcretionHydroxocobalamin is mainly excreted in urine.
In cyanide poisoning victims, hydroxocobalamin binds to cyanide to form cyanocobalamin, which is mainly excreted in urine.

CarcinogenesisLong-term animal studies have not been performed to evaluate the carcinogenic potential of hydroxocobalamin.

MutagenesisHydroxocobalamin was negative in the following mutagenicity assays: in vitro bacterial reverse mutation assay using Salmonella typhimurium and Escherichia coli strains, an in vitro assay of the tk locus in mouse lymphoma cells, and an in vivo rat micronucleus assay.

Impairment of FertilityThe effect of hydroxocobalamin on fertility has not been evaluated.

Effects on Blood PressureInitiation of hydroxocobalamin infusion as part of the therapeutic interventions generally resulted in increases in blood pressure and variable changes in heart rate (often normalization).

Survival of Patients Presenting in Cardiac ArrestOf the 245 patients across all four studies, 68 (28%) presented in cardiac arrest. While blood pressure and heart rate may have been restored in many of these 68 patients, only five (7%) survived.

Erythema and ChromaturiaAdvise patients that skin redness may last up to 2 weeks and urine coloration may last for up to 5 weeks after administration of CYANOKIT. While it is not known if the skin redness predisposes to photosensitivity, patients should be advised to avoid direct sun while their skin remains discolored.

RashInform patients that an acneiform rash may appear anywhere from 7 to 28 days following hydroxocobalamin treatment. This rash will usually resolve without treatment within a few weeks.

Renal Function MonitoringAdvise patients that renal function will be monitored for 7 days following treatment with CYANOKIT or, in the event of renal impairment, until renal function returns to normal.

PregnancyAdvise pregnant women that maternal cyanide poisoning results in fetal cyanide poisoning. Treatment for cyanide poisoning may be lifesaving for both the pregnant woman and fetus. Advise females of reproductive potential to notify their provider if they were pregnant during therapy with CYANOKIT [see USE IN SPECIFIC POPULATIONS (8.1)].

LactationAdvise women that breastfeeding is not recommended during treatment with CYANOKIT [see USE IN SPECIFIC POPULATIONS (8.2)].

The starting dose of hydroxocobalamin for adults is 5 g administered as an intravenous infusion over 15 minutes (approximately 15 mL/min). Administration of the entire vial constitutes a complete starting dose. Depending upon the severity of the poisoning and the clinical response, a second dose of 5 g may be administered by intravenous infusion for a total dose of 10 g. The rate of infusion for the second dose may range from 15 minutes (for patients in extremis) to two hours, as clinically indicated.

2.3 Preparation Of Solution For Infusion

Reconstitute the 5 g vial of hydroxocobalamin with 200 mL of diluent (not provided with CYANOKIT) using the supplied sterile transfer spike. The recommended diluent is 0.9% Sodium Chloride injection (0.9% NaCl). Lactated Ringers injection and 5% Dextrose injection (D5W) have also been found to be compatible with hydroxocobalamin and may be used if 0.9% NaCl is not readily available. The line on the vial label represents 200 mL volume of diluent. Following the addition of diluent to the lyophilized powder, the vial should be repeatedly inverted or rocked, not shaken, for at least 60 seconds prior to infusion.
Visually inspect hydroxocobalamin solutions for particulate matter and color prior to administration. If the reconstituted solution is not dark red or if particulate matter is observed after the solution has been appropriately mixed, the solution should be discarded.

2.4 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 should not be administered simultaneously through the same intravenous 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 intravenous line is not recommended. However, blood products and hydroxocobalamin can be administered simultaneously using separate intravenous lines (preferably on contralateral extremities, if peripheral lines are being used).

2.5 Storage Of Reconstituted Drug Product

Once reconstituted, hydroxocobalamin is stable for up to 6 hours at temperatures not exceeding 40°C (104°F). Do not freeze. Any reconstituted product not used by 6 hours should be discarded.

3 Dosage Forms And Strengths

CYANOKIT (hydroxocobalamin for injection) for intravenous infusion consists of 1 vial, containing 5 g lyophilized hydroxocobalamin dark red crystalline powder for injection. After reconstitution, the vial contains hydroxocobalamin for injection, 25 mg/mL [see How Supplied/Storage and Handling (16) for full kit description].

4 Contraindications

None

5.1 Emergency Patient Management

In conjunction with CYANOKIT, treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of oxygenation and hydration, cardiovascular support, and management of seizures. Consideration should be given to decontamination measures based on the route of exposure.

5.2 Risk Of Anaphylactic And Other Hypersensitivity Reactions

Use caution in the management of patients with known anaphylactic reactions to hydroxocobalamin or cyanocobalamin. Consider alternative therapies, if available.
Allergic reactions may include: anaphylaxis, chest tightness, edema, urticaria, pruritus, dyspnea, and rash.
Allergic reactions including angioneurotic edema have also been reported in postmarketing experience.

5.3 Risk Of Renal Injury

Cases of acute renal failure with acute tubular necrosis, renal impairment, and urine calcium oxalate crystals have been reported. In some situations, hemodialysis was required to achieve recovery. Regular monitoring of renal function, including but not limited to blood urea nitrogen (BUN) and serum creatinine, should be performed for 7 days following CYANOKIT therapy.

5.4 Risk Of Increased Blood Pressure

Many patients with cyanide poisoning will be hypotensive; however, elevations in blood pressure have also been observed in known or suspected cyanide poisoning victims.
Elevations in blood pressure (≥180 mmHg systolic or ≥110 mmHg diastolic) were observed in approximately 18% of healthy subjects (not exposed to cyanide) receiving hydroxocobalamin 5 g and 28% of subjects receiving 10 g. Increases in blood pressure were noted shortly after the infusions were started; the maximal increase in blood pressure was observed toward the end of the infusion. These elevations were generally transient and returned to baseline levels within 4 hours of dosing. Monitor blood pressure during treatment with CYANOKIT.

5.6 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 discolored.

5.7 Use Of Blood Cyanide Assay

While determination of blood cyanide concentration is not required for management of cyanide poisoning and should not delay treatment with CYANOKIT, collecting a pretreatment blood sample may be useful for documenting cyanide poisoning as sampling post-CYANOKIT use may be inaccurate.

6 Adverse Reactions

Serious adverse reactions with hydroxocobalamin include allergic reactions, renal injury, and increases in blood pressure [see Warnings and Precautions (5.2, 5.3, 5.4)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of CYANOKIT. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Cases of acute renal failure with acute tubular necrosis, renal impairment, and urine calcium oxalate crystals have been reported in patients treated with CYANOKIT.

7 Drug Interactions

Formal drug interaction studies have not been conducted with CYANOKIT.

8.4 Pediatric Use

Safety and effectiveness of CYANOKIT have not been established in this population. In non-US marketing experience, a dose of 70 mg/kg has been used to treat pediatric patients.

8.5 Geriatric Use

Approximately 50 known or suspected cyanide poisoning 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.

8.6 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.

8.7 Hepatic Impairment

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

10 Overdosage

No data are available about overdose with CYANOKIT in adults. Should overdose occur, treatment should be directed to the management of symptoms. Hemodialysis 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 hemodialysis machines [see Warnings and Precautions (5.5)].

11 Description

Hydroxocobalamin, the active ingredient in CYANOKIT, is cobinamide dihydroxide dihydrogen phosphate (ester), mono (inner salt), 3'-ester with 5,6-dimethyl-1-α-D-ribofuranosyl-1H-benzimidazole, an antidote. The drug substance is the hydroxylated active form of vitamin B12 and is a large molecule in which a trivalent cobalt ion is coordinated in four positions by a tetrapyrol (or corrin) ring. It is a hygroscopic, odorless, dark red, crystalline powder that is freely soluble in water and ethanol, and practically insoluble in acetone and diethyl ether. Hydroxocobalamin has a molecular weight of 1346.36 atomic mass units, an empirical formula of C62H89CoN13O15P and the following structural formula:
CYANOKIT (hydroxocobalamin for injection) for intravenous infusion is a cyanide antidote package which contains one colorless 250 mL glass vial, containing 5 g dark red lyophilized hydroxocobalamin, pH adjusted with hydrochloric acid, one transfer spike, one intravenous administration set, one quick use reference guide and one package insert.
The 5 g vial of hydroxocobalamin for injection is to be reconstituted with 200 mL of 0.9% NaCl, to give a dark red injectable solution (25 mg/mL). If 0.9% NaCl is not readily available, 200 mL of either Lactated Ringers injection or 5% Dextrose injection (D5W) may be used as the diluent. Diluent is not included in the CYANOKIT. The pH of the reconstituted product ranges from 3.5 to 6.0.

12.1 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 CYANOKIT in the treatment of cyanide poisoning is based on its ability to bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide ion by substituting it for the hydroxo ligand linked to the trivalent cobalt ion, to form cyanocobalamin, which is then excreted in the urine.

12.2 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 [see Warnings and Precautions (5.4)].

12.3 Pharmacokinetics

Following intravenous administration of hydroxocobalamin significant binding to plasma proteins and low molecular weight physiological compounds occurs, forming 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) (i.e., cobalamin-(III) entity without specific ligand) were investigated instead of hydroxocobalamin alone, using the concentration unit μg eq/mL.
Dose-proportional pharmacokinetics was observed following single dose intravenous 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.
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.

14.1 Animal Efficacy (Dog) Study Of Cyanokit For Cyanide Poisoning

The effectiveness of CYANOKIT for treatment of cyanide poisoning has not been determined in humans because inducing cyanide poisoning in humans to study the drug's efficacy is not ethical. Therefore, the effectiveness of CYANOKIT for cyanide poisoning was established based on the results of the adequate and well-controlled animal efficacy study described below. While the results of this animal study cannot be extrapolated to humans with certainty, the extrapolation is supported by the understanding of the pathophysiologic mechanisms of the toxicity of cyanide and the mechanisms of the protective effect of hydroxocobalamin as examined in dogs. In addition, the results of uncontrolled human studies and the animal study establish that hydroxocobalamin is likely to produce clinical benefit in humans.
The effectiveness of hydroxocobalamin was examined in a randomized, placebo-controlled, blinded study in cyanide-poisoned adult dogs assigned to treatment with vehicle (0.9% saline), or 75 or 150 mg/kg hydroxocobalamin. Anesthetized dogs were poisoned by intravenous administration of a lethal dose of potassium cyanide. Dogs then received vehicle or 75 or 150 mg/kg hydroxocobalamin, administered intravenously over 7.5 minutes. The 75 and 150 mg/kg doses are approximately equivalent to 5 and 10 g of hydroxocobalamin (respectively) in humans based on both body weight and the Cmax of hydroxocobalamin (total cobalamins-(III)). Survival at 4 hours and at 14 days was significantly greater in low-and high-dose groups compared with dogs receiving vehicle alone (Table 4). Hydroxocobalamin reduced whole blood cyanide concentrations by approximately 50% by the end of the infusion compared with vehicle.
Table 4 Survival of Cyanide-Poisoned Dogs
ParameterTreatmentVehicleN=17CYANOKIT75 mg/kg N=19150 mg/kgN=18Survival at Hour 4, n (%)
7 (41)
18 (95)
18 (100)
Survival at Day 14, n (%)
3 (18)
15 (79)
18 (100)
Histopathology revealed brain lesions that were consistent with cyanide-induced hypoxia. The incidence of brain lesions was markedly lower in hydroxocobalamin treated animals compared to vehicle treated groups.

14.2 Smoke Inhalation Victims

A prospective, uncontrolled, open-label study was carried out in 69 subjects who had been exposed to smoke inhalation from fires. Subjects had to be over 15 years of age, present with soot in the mouth and expectoration (to indicate significant smoke exposure), and have altered neurological status. The median hydroxocobalamin dose was 5 g with a range from 4 to 15 g.
Fifty of 69 subjects (73%) survived following treatment with hydroxocobalamin. Nineteen subjects treated with hydroxocobalamin did not survive. Fifteen patients treated with hydroxocobalamin were in cardiac arrest initially at the scene; 13 of these subjects died and 2 survived.
Of the 42 subjects with pretreatment cyanide levels considered to be potentially toxic, 28 (67%) survived. Of the 19 subjects whose pretreatment cyanide levels were considered potentially lethal, 11 (58%) survived. Of the 50 subjects who survived, 9 subjects (18%) had neurological sequelae at hospital discharge. These included dementia, confusion, psychomotor retardation, anterograde amnesia, intellectual deterioration moderate cerebellar syndrome, aphasia, and memory impairment.
Two additional retrospective, uncontrolled studies were carried out in subjects who had been exposed to cyanide from fire or smoke inhalation. Subjects were treated with up to 15 g of hydroxocobalamin. Survival in these two studies was 34 of 61 (56%) for one study, and 30 of 72 (42%) for the second.

14.3 Cyanide Poisoning By Ingestion Or Inhalation

A retrospective, uncontrolled study was carried out in 14 subjects who had been exposed to cyanide from sources other than from fire or smoke (i.e., ingestion or inhalation). Subjects were treated with 5 to 20 g of hydroxocobalamin. Eleven of 12 subjects whose blood cyanide concentration was known had initial blood cyanide levels considered to be above the lethal threshold.
Ten of 14 subjects (71%) survived, following administration of hydroxocobalamin. One of the four subjects who died had presented in cardiac arrest. Of the 10 subjects who survived, only 1 subject had neurological sequelae at hospital discharge. This subject had post-anoxic encephalopathy, with memory impairment, considered to be due to cyanide poisoning.

14.4 Cross-Study Findings

Experience with Dosing Greater than 10 g of HydroxocobalaminAcross all four uncontrolled studies, 10 patients who did not demonstrate a full response to 5 or 10 g-doses of hydroxocobalamin were treated with more than 10 g of hydroxocobalamin. One of these 10 patients survived with unspecified neurological sequelae.

16 How Supplied/Storage And Handling

  • Each CYANOKIT carton (NDC 50633-310-11) consists of the following:
  • One 250 mL glass vial, containing lyophilized hydroxocobalamin for injection, 5 g
  • One sterile transfer spike
  • One sterile intravenous infusion set
  • One quick use reference guide
  • One package insert
  • Diluent is not included.

Storage And Handling

StorageLyophilized formStore 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 to 104°F)).
Reconstituted solutionStore up to 6 hours at a temperature not exceeding 40ºC (104°F). Do not freeze. Discard any unused portion after 6 hours.

17 Patient Counseling Information

CYANOKIT is indicated for cyanide poisoning and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

* Please review the disclaimer below.