This information is not for clinical use. These highlights do not include all the information needed to use Cyanokit safely and effectively. Before taking Cyanokit please consult with your doctor. See full prescribing information for Cyanokit.

Recent 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) 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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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.] 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 None (4)

Warning and Cautions

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) 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.

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)]. 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 SUSPECTEDcontact Meridian Medical Technologies ® , Inc. at 1-800-438-1985 , or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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.

Drug Interactions

No formal drug interaction studies have been conducted with Cyanokit.

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) 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.