Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: SERB S.A., Avenue Louise 480, 1050 Brussels, Belgium
Pharmacotherapeutic group: Antidotes
ATC code: V03AB33
The action of hydroxocobalamin in the treatment of cyanide poisoning is based on its ability to tightly bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide ion by substituting the hydroxo ligand linked to the trivalent cobalt ion to form cyanocobalamin. Cyanocobalamin is a stable, non-toxic compound that is excreted in the urine.
Due to ethical considerations, no controlled human efficacy studies have been performed.
The effectiveness of hydroxocobalamin was examined in a controlled study in cyanide-poisoned adult dogs. Dogs were poisoned by intravenous administration of a lethal dose of potassium cyanide. Dogs then received sodium chloride 9 mg/mL, 75 mg/kg or 150 mg/kg hydroxocobalamin, administered intravenously over 7.5 minutes. The 75 mg/kg and 150 mg/kg doses are approximately equivalent to 5 g and 10 g of hydroxocobalamin, respectively, in humans, not only on a body weight basis but also on Cmax basis of hydroxocobalamin [total cobalamins-(III), see section 5.2]. Survival at hour 4 and at day 14 was significantly greater in 75 mg/kg and 150 mg/kg hydroxocobalamin dose groups compared with dogs receiving sodium chloride 9 mg/mL alone:
Survival of cyanide-poisoned dogs:
| Parameter | Treatment | ||
|---|---|---|---|
| Sodium chloride 9 mg/mL (N=17) | Hydroxocobalamin | ||
| 75 mg/kg (N=19) | 150 mg/kg (N=18) | ||
| Survival at Hour 4, N (%) | 7 (41) | 18 (95)* | 18 (100)* |
| Survival at Day 14, N (%) | 3 (18) | 15 (79)* | 18 (100)* |
* p<0.025
Histopathology revealed brain lesions that were consistent with cyanide-induced hypoxia. The incidence of brain lesions was markedly lower in dogs having received 150 mg/kg hydroxocobalamin than in dogs having received 75 mg/kg hydroxocobalamin or sodium chloride 9 mg/mL.
The rapid and complete recovery of haemodynamics and subsequently of blood gases, pH, and lactate after cyanide poisoning likely contributed to the better outcome of the hydroxocobalamin-treated animals. Hydroxocobalamin reduced whole blood cyanide concentrations from about 120 nmol/mL to 30-40 nmol/mL by the end of the infusion compared with 70 nmol/mL in dogs receiving sodium chloride 9 mg/mL alone.
A total of 245 patients with suspected or known cyanide-poisoning were included in the clinical studies of the efficacy of hydroxocobalamin as an antidote. Of the 213 patients in whom the outcome was known the survival was 58%. Of the 89 patients who died, 63 were initially found in cardiac arrest, suggesting that many of these patients had almost certainly suffered irreparable brain injury prior to administration of hydroxocobalamin. Among 144 patients not in initial cardiac arrest whose outcomes were known, 118 (82%) survived. Furthermore, in 34 patients with known cyanide concentrations above the lethal threshold (≥100 μmol/L), 21 (62%) survived following treatment with hydroxocobalamin.
Administration of hydroxocobalamin was generally associated with a normalisation of blood pressure (systolic blood pressure >90 mmHg) in 17 of 21 patients (81%) who had low blood pressure (systolic blood pressure >0 and ≤90 mmHg) after exposure to cyanide. Where neurological assessment over time was possible, (96 patients of the 171 patients who presented with neurological symptoms prior to hydroxocobalamin administration), 51 (53%) patients receiving hydroxocobalamin showed improvement or a complete restoration.
Approximately 50 known or suspected cyanide victims aged 65 or older received hydroxocobalamin in clinical studies. In general, the effectiveness of hydroxocobalamin in these patients was similar to that of younger patients.
Documentation on efficacy is available for 54 paediatric patients. The mean age of the paediatric patients was about six years and the mean dose of hydroxocobalamin was about 120 mg/kg body weight. The survival rate of 41% depended very much on the clinical situation. Out of the 20 paediatric patients without initial cardiac arrest, 18 (90%) survived, of whom 4 with sequelae. In general, the effectiveness of hydroxocobalamin in paediatric patients was similar to that of adults.
Following intravenous administration of Cyanokit, significant binding to plasma proteins and low molecular weight physiological compounds occurs, to form various cobalamin-(III) complexes by replacing the hydroxo ligand. The low molecular weight cobalamins-(III) formed including hydroxocobalamin are termed free cobalamins-(III); the sum of free and protein-bound cobalamins is termed total cobalamins-(III). In order to reflect the exposure to the sum of all derivatives, pharmacokinetics of cobalamins-(III) were investigated instead of hydroxocobalamin, requiring the concentration unit μg eq/mL (i.e. cobalamin-(III) entity without specific ligand).
Dose-proportional pharmacokinetics were observed following single dose intravenous administration of 2.5 to 10 g of Cyanokit in healthy volunteers. Mean free and total cobalamins-(III) Cmax values of 113 and 579 μg eq/mL, respectively, were determined following a dose of 5 g Cyanokit (the recommended initial dose). Similarly, mean free and total cobalamins-(III) Cmax values of 197 and 995 μg eq/mL, respectively, were determined following the dose of 10 g Cyanokit. The predominant mean half-life of free and total cobalamins-(III) was approximately 26 to 31 hours at the 5 and 10 g dose level.
The mean total amount of cobalamins-(III) excreted in urine during the collection period of 72 hours was approximately 60% of a 5 g dose and approximately 50% of a 10 g dose of Cyanokit. Overall, the total urinary excretion was calculated to be at least 60 to 70% of the administered dose. The majority of the urinary excretion occurred during the first 24 hours, but red coloured urine was observed for up to 35 days following the intravenous infusion.
When normalized for body weight, male and female subjects revealed no major differences in plasma and urinary pharmacokinetic parameters of free and total cobalamins-(III) following the administration of 5 g or 10 g Cyanokit.
In cyanide-poisoned patients, hydroxocobalamin is expected to bind cyanide to form cyanocobalamin, which is excreted in the urine. The pharmacokinetics of total cobalamins-(III) in this population may be affected by the body's cyanide load, since cyanocobalamin was reported to exhibit a 2-3 times lower half-life than total cobalamins-(III) in healthy volunteers.
In anaesthetised rabbits, hydroxocobalamin exerted haemodynamic effects (increased mean arterial blood pressure and total peripheral resistance, decreased cardiac output) related to its nitric oxide-scavenging property.
No special hazard for humans was identified based on conventional studies of single and repeated dose toxicity and genotoxicity. The liver and kidney were found to be the major target organs. However findings were only seen at exposure levels considered being higher than the maximum human exposure, indicating limited relevance to clinical use. In particular, liver fibrosis was observed in dogs after administration of hydroxocobalamin for 4 weeks at 300 mg/kg. The relevance of this finding to humans is unlikely since it was not reported in short-term studies conducted with hydroxocobalamin.
Developmental toxicity, including teratogenicity, was observed in rats and rabbits at dose levels of 150 mg/kg and higher administered daily throughout organogenesis. The dose of 150 mg/kg approximately corresponds to the maximum recommended human dose.
No data are available on male and female fertility as well as on peri- and postnatal development. Hydroxocobalamin has not been evaluated for carcinogenic potential.
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