was determined [5:5% 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 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. Drug Interactions No formal drug interaction studies have been conducted with Cyanokit. USE IN SPECIFIC POPULATIONS 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. Labor and Delivery The effect of Cyanokit on labor and delivery is unknown. 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. 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. 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. Renal Impairment The safety and effectiveness of Cyanokit have not been studied in patients with renal impairment. Hydroxocobalamin and cyanocobalamin are eliminated unchanged by the kidneys. Oxalate crystals have been observed in the urine of both healthy subjects given hydroxocobalamin and patients treated with hydroxocobalamin following suspected cyanide poisoning. Hepatic Impairment The safety and effectiveness of Cyanokit have not been studied in patients with hepatic impairment. 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 )]. Cyanokit 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 B 12 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 C 62 H 89 CoN 13 O 15 P and the following 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. Cyanokit - Clinical Pharmacology Mechanism of Action Cyanide is an extremely toxic poison. In the absence of rapid and adequate treatment, exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well. Signs and symptoms of acute systemic cyanide poisoning may develop rapidly within minutes, depending on the route and extent of cyanide exposure. The action of 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. 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. 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) C max 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) C max 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. Nonclinical Toxicology 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. 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 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 (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. 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 )] . 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. 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. 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. 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. 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. 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 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. increased blood pressure Other side effects may include: red colored urine red colored skin and mucous membranes, acnelike 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 NO180_US 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 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 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 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 Back Side Cyanokit hydroxocobalamin injection, powder, lyophilized, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:11704-370 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Hydroxocobalamin (Hydroxocobalamin) Hydroxocobalamin 5 g in 250 mL Inactive Ingredients Ingredient Name Strength hydrochloric acid Packaging # Item Code Package Description 1 NDC:11704-370-01 1 VIAL, GLASS in 1 CARTON 1 250 mL in 1 VIAL, GLASS 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 (384953134) Establishment Name Address ID/FEI Operations Merck Santé s.a.s 384953134 MANUFACTURE(11704-370), ANALYSIS(11704-370), PACK(11704-370), LABEL(11704-370) Establishment Name Address ID/FEI Operations Meridian Medical Technologies, Inc. 167671341 LABEL(11704-370) Revised: 03/2017 Meridian Medical Technologies, Inc. Next Interactions Print this page Add to My Med List More about Cyanokit (hydroxocobalamin) Side Effects During Pregnancy Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: vitamins Consumer resources Cyanokit Cyanokit injection Cyanokit (Advanced Reading) Professional resources Hydroxocobalamin (FDA) Related treatment guides Cyanide Poisoning Schilling Test Transcobalamin II Deficiency Vitamin B12 Deficiency]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Vitamins Related Drugs vitamins cholecalciferol , cyanocobalamin , folic acid , ergocalciferol , Vitamin D3 , biotin Vitamin B12 Deficiency cyanocobalamin , Vitamin B12 , B-12 , hydroxocobalamin , Nascobal , More... Schilling Test cyanocobalamin , Vitamin B12 , B-12 , hydroxocobalamin , Nascobal , More... Cyanide Poisoning hydroxocobalamin , amyl nitrite , sodium thiosulfate , Nithiodote , More... 1 more conditions... Cyanokit Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first!} } growing older
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