Summary of Product Characteristics Updated 16-Aug-2016 | Hope Pharmaceuticals Ltd
PosologyFor intravenous use. For single use only.
Adults10 mL of sodium nitrite (rate of 2.5 to 5 mL/minute) should be administered intravenously, immediately followed by 50 mL of sodium thiosulfate (rate of 5 mL/minute).Special populationsOlder peopleNo specific dose adjustment is required in elderly patients (aged ≥ 65 years).
Paediatric population0.2 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 sodium thiosulfate.NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.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 (see section 4.4).
Method of administrationComprehensive 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 sodium thiosulfate, 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 sodium thiosulfate.Sodium nitrite injection and sodium thiosulfate 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 sodium thiosulfate. 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.
|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|
Prolonged bleeding timeIn a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% sodium thiosulfate 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 reactionsReporting 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.
Sodium NitriteSodium 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 → MethemoglobinHCN + Methemoglobin → CyanomethemoglobinVasodilation 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.
Sodium ThiosulfateThe primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Sodium thiosulfate 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 safetyThere have been no controlled clinical trials conducted to systematically assess the clinical efficacy and safety of sodium thiosulfate.
AbsorptionSodium thiosulfate taken orally is not systemically absorbed. Intravenous injection of sodium thiosulfate is 100% bioavailability.
DistributionSodium thiosulfate is rapidly distributed throughout extracellular fluid after IV administration. The volume of distribution of sodium thiosulfate is 150 mL/kg.
Biotransformation and eliminationMost 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 sodium thiosulfate in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported elimination half-life was 182 minutes.