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BRIEF SUMMARY: Consult full Prescribing Information for complete product information 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. 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). WARNINGS AND PRECAUTIONS 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. 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. 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. 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 or greater systolic or 110 mmHg or greater 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. 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. 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 LABORATORY PARAMETER Clinical Chemistry Hematology Coagulation Urinalysis No Interference Observed Calcium Sodium Potassium Chloride Urea GGT Erythrocytes Hematocrit MCV Leukocytes Lymphocytes Monocytes Eosinophils Neutrophils Platelets Artificially Increased* Creatinine Bilirubin Triglycerides Cholesterol Total protein Glucose Albumin Alkaline phosphatase Hemoglobin MCH MCHC Basophils pH (with all doses) Glucose Protein Erythrocytes Leukocytes Ketones Bilirubin Urobilinogen Nitrite Artificially Decreased* ALT Amylase pH (with equivalent doses of <5 g) Unpredictable Phosphate Uric Acid AST CK CKMB LDH aPTT PT (Quick or INR) Duration of Interference 24 hours with the exception of bilirubin (up to 4 days) 12-16 hours 24-48 hours 48 hours up to 8 days; color changes may persist up to 28 days *10% or greater 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 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. ADVERSE REACTIONS Serious adverse reactions with hydroxocobalamin include allergic reactions, renal disorders and increases in blood pressure. 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 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 *Rashes were predominantly acneiform 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