Label: CYANOKIT- hydroxocobalamin injection, powder, lyophilized, for solution

  • NDC Code(s): 11704-370-01
  • Packager: Meridian Medical Technologies, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated December 13, 2017

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use Cyanokit safely and effectively. See full prescribing information for Cyanokit.
    Cyanokit ® (hydroxocobalamin for injection) 5 g for intravenous infusion Initial U.S. Approval: 1975

    RECENT MAJOR CHANGES

    Warnings and Precautions, Renal Disorders (5.3) 06/2017

    INDICATIONS AND USAGE

    Cyanokit contains hydroxocobalamin, an antidote indicated for the treatment of known or suspected cyanide poisoning. (1.1)

    • If clinical suspicion of cyanide poisoning is high, Cyanokit should be administered without delay. (1.2)
    • The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222. (1.2)

    DOSAGE AND ADMINISTRATION

    • The starting dose of Cyanokit for adults is 5 g, administered by intravenous infusion over 15 minutes. One 5 g vial is a complete starting dose. (2.1)
    • 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. (2.1)
    • The rate of infusion for the second 5 g dose may range from 15 minutes (for patients in extremis) to 2 hours based on patient condition. (2.1)
    • The recommended diluent is 0.9% Sodium Chloride injection. (2.2)
    • Diluent is not included with Cyanokit. (2.2)
    • There are a number of drugs and blood products that are incompatible with Cyanokit, thus Cyanokit requires a separate intravenous line for administration. (2.3)

    DOSAGE FORMS AND STRENGTHS

    Cyanokit (hydroxocobalamin for injection) 5 g for intravenous infusion consists of 1 vial, containing 5 g lyophilized hydroxocobalamin dark red crystalline powder for injection. (3) After reconstitution, the vial contains hydroxocobalamin for injection, 25 mg/mL. One 5 g vial is a complete starting dose. (3)

    CONTRAINDICATIONS

    None (4)

    WARNINGS AND PRECAUTIONS

    • Use caution in the management of patients with known anaphylactic reactions to hydroxocobalamin or cyanocobalamin. Consideration should be given to use of alternative therapies, if available. (5.2)
    • Allergic reactions may include: anaphylaxis, chest tightness, edema, urticaria, pruritus, dyspnea, and rash. (5.2)
    • Acute renal failure with acute tubular necrosis, renal impairment and urine calcium oxalate crystals have been reported following Cyanokit therapy. Monitor renal function for 7 days following Cyanokit therapy. (5.3)
    • Blood pressure increase: Substantial increases in blood pressure may occur following Cyanokit therapy. (5.4)

    ADVERSE REACTIONS

    Most common adverse reactions (>5%) include transient chromaturia, erythema, oxalate crystals in urine, rash, increased blood pressure, nausea, headache, and injection site reactions. (6.1)

    To report SUSPECTED ADVERSE REACTIONS contact Meridian Medical Technologies®, Inc. at 1-800-438-1985, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    USE IN SPECIFIC POPULATIONS

    • Pregnancy: Based on animal studies, may cause fetal harm; however, treatment of maternal/fetal cyanide poisoning may be lifesaving. (8.1)
    • Nursing mothers: Because of the unknown potential for adverse reactions in nursing infants, discontinue nursing after Cyanokit treatment.
    • No safety and efficacy studies have been performed in pediatric patients. (8.4)

    See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

    Revised: 6/2017

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  • FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Indication

    1.2 Identifying Patients with Cyanide Poisoning

    1.3 Use with Other Cyanide Antidotes

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    2.2 Preparation of Solution for Infusion

    2.3 Incompatibility Information

    2.4 Storage of Reconstituted Drug Product

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Emergency Patient Management

    5.2 Allergic Reactions

    5.3 Renal Disorders

    5.4 Blood Pressure Increase

    5.5 Use of Blood Cyanide Assay

    5.6 Interference with Clinical Laboratory Evaluations and Clinical Methods

    5.7 Photosensitivity

    6 ADVERSE REACTIONS

    6.1 Clinical Studies Experience

    6.2 Postapproval Experience

    7 DRUG INTERACTIONS

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Labor and Delivery

    8.3 Nursing Mothers

    8.4 Pediatric Use

    8.5 Geriatric Use

    8.6 Renal Impairment

    8.7 Hepatic Impairment

    10 OVERDOSAGE

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.2 Pharmacodynamics

    12.3 Pharmacokinetics

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    13.2 Animal Pharmacology

    14 CLINICAL STUDIES

    14.1 Smoke Inhalation Victims

    14.2 Cyanide Poisoning by Ingestion or Inhalation

    14.3 Cross-Study Findings

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    17.1 Erythema and Chromaturia

    17.2 Rash

    17.3 Renal Disorders

    17.4 Pregnancy and Breast Feeding

    FDA-Approved Patient Labeling

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1 INDICATIONS AND USAGE

    1.1 Indication

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

    1.2 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, 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. 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 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.

    The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

    Smoke Inhalation

    Not 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.

    1.3 Use with Other Cyanide Antidotes

    Caution should be exercised when administering other cyanide antidotes simultaneously with Cyanokit, as the safety of co-administration 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 (2.3).]

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  • 2 DOSAGE AND ADMINISTRATION

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

    2.1 Recommended Dosing

    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.

    2.2 Preparation of Solution for Infusion

    The 5 g vial of hydroxocobalamin for injection is to be reconstituted 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.

    Hydroxocobalamin solutions should be visually inspected for particulate matter and color prior to administration. If the reconstituted solution is not dark red or if particulate matter is seen after the solution has been appropriately mixed, the solution should be discarded.

    2.3 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).

    2.4 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.

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  • 3 DOSAGE FORMS AND STRENGTHS

    Cyanokit (hydroxocobalamin for injection) 5 g 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. Administration of the entire 5 g vial constitutes a complete starting dose. [See How Supplied/Storage and Handling (16) for full kit description.]

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  • 4 CONTRAINDICATIONS

    None

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 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.

    5.2 Allergic Reactions

    Use caution in the management of patients with known anaphylactic reactions to hydroxocobalamin or cyanocobalamin. Consideration should be given to use of 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 Renal Disorders

    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 Blood Pressure Increase

    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.

    5.5 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.

    5.6 Interference with Clinical Laboratory Evaluations and Clinical Methods

    Clinical Laboratory Evaluations

    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, the following table (Table 2) 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. Results may vary substantially from one analyzer to another; therefore, caution should be used when reporting and interpreting laboratory results.

    Table 2 Laboratory Interference Observed with In-Vitro Samples of Hydroxocobalamin

    * ≥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)

    Laboratory Parameter No
    Interference
    Observed
    Artificially Increased * Artificially Decreased * Un-
    predictable
    Duration of Interference
    Clinical
    Chemistry
    Calcium
    Sodium
    Potassium
    Chloride
    Urea
    GGT
    Creatinine
    Bilirubin
    Triglycerides
    Cholesterol
    Total protein
    Glucose
    Albumin
    Alkaline phosphatase
    ALT
    Amylase
    Phosphate
    Uric Acid
    AST
    CK
    CKMB
    LDH
    24 hours with the exception of bilirubin (up to 4 days)
    Hematology Erythrocytes
    Hematocrit
    MCV
    Leukocytes
    Lymphocytes
    Monocytes
    Eosinophils
    Neutrophils
    Platelets
    Hemoglobin
    MCH
    MCHC
    Basophils
    12 - 16 hours
    Coagulation aPTT
    PT (Quick or INR)
    24 - 48 hours
    Urinalysis pH (with all doses)
    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

    Clinical Methods

    Because 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.

    5.7 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.

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  • 6 ADVERSE REACTIONS

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

    6.1 Clinical Studies Experience

    Because clinical trials were conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.

    Experience in Healthy Subjects

    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

    ADR 5 g Dose Group 10 g Dose Group
    Hydroxocobalamin
    N=66 n (%)
    Placebo N=22 n (%) Hydroxocobalamin
    N=18 n (%)
    Placebo N=6 n (%)
    Chromaturia (red colored urine) 66 (100) 0 18 (100) 0
    Erythema 62 (94) 0 18 (100) 0
    Oxalate crystals in urine 40 (61) 1 (4) 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 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
    • 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.

    6.2 Postapproval 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.

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  • 7 DRUG INTERACTIONS

    No formal drug interaction studies have been conducted with Cyanokit.

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C. There are no adequate and well controlled studies of Cyanokit in pregnant women. In animal studies, hydroxocobalamin caused skeletal and visceral (soft tissue) abnormalities at exposures (based on AUC) similar to human exposures at the therapeutic dose. Cyanokit should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because cyanide readily crosses the placenta, maternal cyanide poisoning results in fetal cyanide poisoning. Timely treatment of the pregnant mother may be lifesaving for both mother and fetus.

    In 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 dependant 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.

    8.2 Labor and Delivery

    The effect of Cyanokit on labor and delivery is unknown.

    8.3 Nursing Mothers

    It is not known whether hydroxocobalamin is excreted in human milk. Cyanokit may be administered in life-threatening situations, and therefore, breast-feeding is not a contraindication to its use. Because of the unknown potential for adverse reactions in nursing infants, the patient should discontinue nursing after receiving 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.

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  • 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 (5.6)].

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  • 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. 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:

    Structural Formula

    Cyanokit (hydroxocobalamin for injection) 5 g 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.

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  • 12 CLINICAL PHARMACOLOGY

    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.

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

    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.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

    The effect of hydroxocobalamin on fertility has not been evaluated.

    13.2 Animal Pharmacology

    Evidence of the effectiveness of hydroxocobalamin for treatment of cyanide poisoning was obtained primarily from studies in animals due to the ethical considerations of performing such controlled studies in humans. While the results of these animal studies 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
    Parameter
    Treatment
    Vehicle N=17 Cyanokit
    75 mg/kg N=19 150 mg/kg N=18
    Survival 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.

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  • 14 CLINICAL STUDIES

    Due to ethical considerations, no controlled human efficacy studies have been performed. A controlled animal study demonstrated efficacy in cyanide-poisoned adult dogs [see Animal Pharmacology (13.2)].

    14.1 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.

    14.2 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.

    14.3 Cross-Study Findings

    Experience with Dosing Greater than 10 g of Hydroxocobalamin

    Across 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.

    Effects on Blood Pressure

    Initiation 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 Arrest

    Of 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.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Each Cyanokit carton (NDC 11704-370-01) 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

    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 to 104°F)).

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

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  • 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.

    17.1 Erythema and Chromaturia

    Patients should be advised 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.

    17.2 Rash

    In some patients 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.

    17.3 Renal Disorders

    Patients should be advised 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.

    17.4 Pregnancy and Breast Feeding

    Patients should be advised that maternal cyanide poisoning results in fetal cyanide poisoning. Treatment for cyanide poisoning may be lifesaving for both mother and fetus. Patients should notify their physician if they were pregnant during therapy with Cyanokit [see USE IN SPECIFIC POPULATIONS (8.1)]. It is not known whether hydroxocobalamin is excreted in human milk.

    FDA-Approved Patient Labeling

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  • PATIENT PACKAGE INSERT

    Patient Information

    Cyanokit (hydroxocobalamin for injection) 5 g for intravenous infusion

    Treatment for known or suspected cyanide poisoning

    What is Cyanokit?

    Cyanokit is an emergency treatment (antidote) used in patients with known or suspected cyanide poisoning. Cyanide is a chemical poison. Cyanide poisoning can happen from:

    • breathing smoke from household and industrial fires
    • breathing or swallowing cyanide
    • having your skin exposed to cyanide

    Cyanide poisoning is a life-threatening condition because cyanide stops your body from being able to use oxygen. You can die if your body does not have enough oxygen.

    Cyanokit was approved for the treatment of known or suspected cyanide poisoning based on testing:

    • how well it worked in animals (It is not ethical to poison people with cyanide in order to test a treatment.)
    • its safety in people with cyanide poisoning

    How is Cyanokit used?

    Cyanokit is given through a vein (intravenous) over 15 minutes by an emergency care provider or doctor. A second dose may be given to you if needed.

    What are possible side effects with Cyanokit?

    Serious side effects may include:

    • allergic reactions: Signs of a serious allergic reaction include chest tightness, trouble breathing, swelling, hives, itching, and a rash.
    • kidney injury: Signs of kidney injury include kidney impairment and urine crystals.
    • increased blood pressure

    Other side effects may include:

    • red colored urine
    • red colored skin and mucous membranes, acne-like rash
    • nausea, vomiting, diarrhea, bloody stools, trouble swallowing, stomach pain
    • throat tightness, dry throat
    • headache, dizziness, memory problems, restlessness
    • infusion site reaction
    • eye swelling, irritation, or redness
    • swelling of feet and ankles
    • irregular heart beat, increased heart rate
    • fluid in lungs

    These are not all the side effects with Cyanokit.

    After treatment with Cyanokit:

    • Skin and urine redness. Skin redness may last up to 2 weeks. Avoid sun exposure while your skin is red. Urine redness may last up to 5 weeks.
    • Acne-like rash. An acne-like rash may appear 7 to 28 days after treatment with Cyanokit. This rash usually goes away without any treatment.
    • Pregnancy. Be sure to tell your doctor immediately if you were pregnant or think you may have been pregnant during treatment with Cyanokit. Treatment for cyanide poisoning may save your life and the life of your unborn baby.
    • Breastfeeding. Talk to your doctor if you breastfeed your child. The ingredient in Cyanokit may pass into your breast milk.

    Talk to your doctor about any side effect that bothers you or that does not go away.

    Manufactured by:
    Merck Santé s.a.s.,
    Semoy, France

    Distributed by
    Meridian Medical Technologies®, Inc.
    Columbia, MD 21046
    1-800-438-1985

    180_US_20171_NO

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL – 5 g VIAL LABEL

    CYANOKIT®

    (hydroxocobalamin for Injection)

    5 g per vial

    For Intravenous Use

    To be reconstituted with 200 mL of 0.9% Sodium Chloride Injection

    Diluent Not Included

    Rx Only

    Manufactured by:

    Merck Santé s.a.s.

    Semoy, France

    Distributed by

    Meridian Medical Technologies®, Inc.

    Columbia, MD 21046

    1-800-438-1985

    MERIDIAN

    MEDICAL TECHNOLOGIES®

    PRINCIPAL DISPLAY PANEL – 5 g VIAL LABEL
    Close
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL – 5 g INNER CARTON

    CYANOKIT®

    (hydroxocobalamin for injection)

    5 g per vial

    For Intravenous Use

    Rx Only

    Manufactured by:

    Merck Santé s.a.s.

    Semoy, France

    Distributed by

    Meridian Medical

    Technologies®, Inc.

    Columbia, MD 21046

    1-800-438-1985

    MERIDIAN

    MEDICAL TECHNOLOGIES®

    PRINCIPAL DISPLAY PANEL – 5 g INNER CARTON
    Close
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL – 5 g OUTER CARTON

    NDC 11704-370-01

    CYANOKIT®

    (hydroxocobalamin for injection)

    5 g per vial

    For Intravenous Use

    To be reconstituted with 200 mL of Sodium Chloride Injection

    Diluent Not Included

    Kit Contains:

    1 Vial, containing Hydroxocobalamin for Injection, 5 g

    1 Intravenous administration set

    1 Transfer spike

    1 Quick Use Reference Guide

    1 Package Insert

    MERIDIAN

    MEDICAL TECHNOLOGIES®

    PRINCIPAL DISPLAY PANEL – 5 g OUTER CARTON
    Close
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL – 5 g PATIENT INSTRUCTION CARD Front Side

    CYANOKIT®

    (hydroxocobalamin for injection)

    5 g per vial

    For Intravenous Use

    To be reconstituted with 200 mL of 0.9% Sodium Chloride Injection

    Diluent Not Included

    PRINCIPAL DISPLAY PANEL – 5 g PATIENT INSTRUCTION CARD Front Side
    Close
  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL – 5 g PATIENT INSTRUCTION CARD Back SidePRINCIPAL DISPLAY PANEL – 5 g PATIENT INSTRUCTION CARD Back Side

    Close
  • INGREDIENTS AND APPEARANCE
    CYANOKIT 
    hydroxocobalamin injection, powder, lyophilized, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:11704-370
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Hydroxocobalamin (UNII: Q40X8H422O) (Hydroxocobalamin - UNII:Q40X8H422O) Hydroxocobalamin 5 g  in 250 mL
    Inactive Ingredients
    Ingredient Name Strength
    hydrochloric acid (UNII: QTT17582CB)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:11704-370-01 1 in 1 CARTON 10/01/2011
    1 250 mL in 1 VIAL, GLASS; Type 1: Convenience Kit of Co-Package
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022041 10/01/2011
    Labeler - Meridian Medical Technologies, Inc. (167671341)
    Registrant - Merck Santé s.a.s (384668112)
    Establishment
    Name Address ID/FEI Business Operations
    Merck Sante 384668112 ANALYSIS(11704-370) , LABEL(11704-370) , MANUFACTURE(11704-370) , PACK(11704-370) , STERILIZE(11704-370)
    Establishment
    Name Address ID/FEI Business Operations
    Meridian Medical Technologies, Inc. 167671341 LABEL(11704-370)
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