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warnings and cautions
5 WARNINGS AND PRECAUTIONS Risk of Anaphylaxis and Other Hypersensitivity Reactions : Consider alternative therapies, if available, in patients with known anaphylactic reactions to hydroxocobalamin or cyanocobalamin. ( 5.2 ) Risk of Renal Injury : 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 ) Risk of Increased Blood Pressure : Substantial increases in blood pressure may occur following CYANOKIT therapy. Monitor blood pressure during treatment. ( 5.4 ) 5.1 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. 5.2 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. 5.3 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. 5.4 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. 5.5 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. 5.6 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. 5.7 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.
6 ADVERSE REACTIONS Serious adverse reactions with hydroxocobalamin include allergic reactions, renal injury, 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 infusion site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS contact BTG at 1-877-377-3784, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 (100) 0 18 (100) 0 Erythema 62 (94) 0 18 (100) 0 Oxalate crystals in urine 40 (61) 1 (5) 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 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.