Cyanokit Drug Information
Generic name: HYDROXOCOBALAMIN
Antidote [EPC]
Uses of Cyanokit
is indicated for the treatment of known or suspected cyanide poisoning. CYANOKIT is indicated for the treatment of known or suspected cyanide poisoning.
Dosage & Administration of Cyanokit
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Side Effects of Cyanokit
Clinical Studies Experience Experience in Healthy Subjects
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. 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 0 18 0 Erythema 62 0 18 0 Oxalate crystals in urine 40 1 10 0 Rash* 13 0 8 0 Blood pressure increased 12 0 5 0 Nausea 4 1 2 0 Headache 4 1 6 0 Lymphocyte percent decreased 5 0 3 0 Infusion site reaction 4 0 7 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.
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.
Warnings & Cautions for Cyanokit
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.
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.
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.
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.
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. 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 Coasys 110 (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 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.
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.
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.
Drug Interactions with Cyanokit
Formal drug interaction studies have not been conducted with CYANOKIT. Interference with Laboratory Tests 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). Be aware of this when reporting and interpreting laboratory results.
Pregnancy Safety for Cyanokit
Pregnancy Risk Summary Available 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 risk Cyanide 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 Data 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-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.
Pediatric Use of Cyanokit
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.
Overdosage Information for Cyanokit
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.
Clinical Studies of Cyanokit
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 C max 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 18 18 Survival at Day 14, n (%) 3 15 18 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.
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.
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.
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.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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