Cyanokit (Page 2 of 5)

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 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)
Clinical Chemistry	CalciumSodiumPotassiumChlorideUreaGGT	CreatinineBilirubinTriglyceridesCholesterolTotal proteinGlucoseAlbuminAlkaline phosphatase	ALTAmylase	PhosphateUric AcidASTCKCKMBLDH	24 hours with the exception of bilirubin (up to 4 days)
Hematology	ErythrocytesHematocritMCVLeukocytesLymphocytesMonocytesEosinophilsNeutrophilsPlatelets	HemoglobinMCHMCHCBasophils			12 — 16 hours
Coagulation				aPTTPT (Quick or INR)	24 — 48 hours
Urinalysis		pH (with all doses)GlucoseProteinErythrocytesLeukocytesKetonesBilirubinUrobilinogenNitrite	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)].

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
	HydroxocobalaminN=66n (%)	PlaceboN=22n (%)	HydroxocobalaminN=18n (%)	PlaceboN=6n (%)
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.