There is limited information about the effects of large doses of Натрия тиосульфат пентагидрат in humans. Oral administration of 3 g Натрия тиосульфат пентагидрат per day for 1-2 weeks in humans resulted in reductions in room air arterial oxygen saturation to as low as 75%, which was due to a rightward shift in the oxygen hemoglobin dissociation curve. The subjects returned to baseline oxygen saturations 1 week after discontinuation of Натрия тиосульфат пентагидрат. A single intravenous administration of 20 mL of 10% Натрия тиосульфат пентагидрат reportedly did not change oxygen saturations.
Chemical incompatibility has been reported between Натрия тиосульфат пентагидрат and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Натрия тиосульфат пентагидрат and sodium nitrite, when administered sequentially through the same IV line.
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Натрия тиосульфат пентагидрат.
The medical literature has reported the following adverse events in association with Натрия тиосульфат пентагидрат administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
| System organ class | Frequency | Undesirable effect |
| Cardiac and vascular disorders | Not known | Hypotension |
| Nervous system disorders | Not known | Headache, disorientation |
| Gastrointestinal disorders | Not known | Nausea*, vomiting* |
| Blood and lymphatic system disorders | Not known | Prolonged bleeding time* |
| General disorders and administration site conditions | Not known | Salty taste in mouth, warm sensation over body |
*Description of selected adverse reactions
Nausea and vomiting
In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and administration of large doses of Натрия тиосульфат пентагидрат have been associated with a higher incidence of nausea and vomiting. However, administration of 0.045 g Натрия тиосульфат пентагидрат per kilogram up to a maximum of 15 g in a 10-15% solution over 10-15 minutes was associated with nausea and vomiting in 7 of 26 patients without concomitant cyanide intoxication.
Prolonged bleeding time
In a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% Натрия тиосульфат пентагидрат was associated with increases in clotting time 1-3 days after administration. However, no significant changes were observed in other hematological parameters.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme - Website: www.mhra.gov.uk/yellowcard.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use and development.
Натрия тиосульфат пентагидрат is indicated for sequential use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Натрия тиосульфат пентагидрат should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
Pharmacotherapeutic group: antidotes, ATC code: V03AB06 (Натрия тиосульфат пентагидрат)
Mechanism of action
Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration.
Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and Натрия тиосульфат пентагидрат is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Pharmacodynamic effects
Sodium Nitrite
Sodium nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
NaNO2 + Hemoglobin → Methemoglobin
HCN + Methemoglobin → Cyanomethemoglobin
Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite. It has been suggested that sodium nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, sodium nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Натрия тиосульфат пентагидрат
The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Натрия тиосульфат пентагидрат is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
Clinical efficacy and safety
There have been no controlled clinical trials conducted to systematically assess the clinical efficacy and safety of Натрия тиосульфат пентагидрат.
Absorption
Натрия тиосульфат пентагидрат taken orally is not systemically absorbed. Intravenous injection of Натрия тиосульфат пентагидрат is 100% bioavailability.
Distribution
Натрия тиосульфат пентагидрат is rapidly distributed throughout extracellular fluid after IV administration. The volume of distribution of Натрия тиосульфат пентагидрат is 150 mL/kg.
Biotransformation and elimination
Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys.
Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. After an intravenous injection of 1 g Натрия тиосульфат пентагидрат in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of Натрия тиосульфат пентагидрат (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported elimination half-life was 182 minutes.
Натрия тиосульфат пентагидрат drug product may contain trace impurities of sodium sulfite. The presence of a trace amount of sulfites in this product should not deter administration of the drug for treatment of emergency situations, even if the patient is sulfite- sensitive.
Not relevant.
Posology
For intravenous use. For single use only.
Adults
10 mL of sodium nitrite (rate of 2.5 to 5 mL/minute) should be administered intravenously, immediately followed by 50 mL of Натрия тиосульфат пентагидрат (rate of 5 mL/minute).
Special populations
Older people
No specific dose adjustment is required in elderly patients (aged > 65 years).
Paediatric population
0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of sodium nitrite (rate of 2.5 to 5 mL/minute) not to exceed 10 mL should be administered intravenously, immediately followed by 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) (rate of 2.5 to 5 mL/minute) not to exceed 50 mL total dose of Натрия тиосульфат пентагидрат.
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and Натрия тиосульфат пентагидрат.
In adult and paediatric patients with known anaemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration.
Method of administration
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Administration of sodium nitrite, followed by Натрия тиосульфат пентагидрат, should be considered adjunctive to appropriate supportive therapies such as airway, ventilatory, and circulatory support. Supportive therapies, including oxygen administration, should not be delayed to administer sodium nitrite and Натрия тиосульфат пентагидрат.
Sodium nitrite injection and Натрия тиосульфат пентагидрат injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium nitrite should be administered first, followed immediately by Натрия тиосульфат пентагидрат. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
All parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
No special requirements for disposal.
