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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. 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 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 dependent 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. 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. 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. 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. Renal Disorders Patients should be advised that renal function will be monitored for 7 days following treatment with Cyanokit or, in the event of renal impairment, until renal function returns to normal. 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. It is not known whether hydroxocobalamin is excreted in human milk. This brief summary is based on CYANOKIT ® (hydroxocobalamin for injection) Prescribing Information Version 180_US_20171_NO, Issued: June 2017. For current package insert and further product information, please visit www.cyanokit.com or call Pfizer Medical Information toll-free at 1-800-438-1985. CYANOKIT is a registered trademark of SERB Sarl, licensed by Meridian Medical Technologies, Inc., a Pfizer company. © 2017 Meridian Medical Technologies, Inc., a Pfizer company. All rights reserved. PP-CYA-USA-0053 Printed in USA/November 2017