Sodium Thiosulfate Solution for Injection

Solution for Injection The solution for injection is a clear and colourless solution.

4.1 Therapeutic indications Sodium thiosulfate is indicated for sequential use with hydroxocobalamin or 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 sodium thiosulfate should be carefully weighed against the potential benefits, especially if the patient is not in extremis. Sodium thiosulfate is to be administered together with appropriate decontamination and supportive measures (see section 4.4).4.2 Posology and method of administration **Posology** For intravenous use. For single use only. ***Adults*** Initial dose: 10 mL (300 mg) of sodium nitrite (rate of 2.5 to 5 mL/minute) should be administered intravenously, immediately followed by 50 mL (12.5 g) of sodium thiosulfate (rate of 5 mL/minute). Alternatively, an initial dose of 5 g hydroxocobalamin administered as an intravenous infusion over 15 minutes followed by 50 mL (12.5 g) of sodium thiosulfate (rate of 5 mL/minute). ***Special populations*** *Older people* No specific dose adjustment is required in elderly patients (aged > 65 years). ***Paediatric population*** In infants to adolescents (0 to 18 years old), 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 sodium thiosulfate. Alternatively, in infants to adolescents (0 to 18 years old), the initial dose of hydroxocobalamin is 70 mg/kg body weight not exceeding 5 g 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 no treatment response is observed within 30 to 60 minutes or if signs of poisoning reappear, repeat treatment after 30 minutes of initial administration 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 Sodium Nitrite SmPC section 4.4). ***Renal and hepatic impairment*** Although the safety and efficacy of sodium thiosulfate have not been studied in patients with renal and hepatic impairments, sodium thiosulfate is administered as emergency therapy in an acute, life-threatening situation only and no dose adjustment is required in these patients. **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 cyanide antidotes 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 cyanide antidotes. Sodium nitrite injection and sodium thiosulfate injection are administered by slow intravenous injection. Cyanide antidotes should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium thiosulfate may be administered soon after prior treatment with a fast-acting cyanide antidote such as sodium nitrite or hydroxocobalamin. 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.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use Treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of oxygenation and hydration, cardiovascular support, and management of seizures. Consideration must be given to decontamination measures based on the route of exposure. Sodium thiosulfate does not substitute oxygen therapy and must not delay the set up of the above measures. The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and/or signs and symptoms of cyanide intoxication. Cyanide poisoning may result from exposure to smoke from closed space fires, inhalation, ingestion, or dermal exposure. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogens, including cyanogenic plants, aliphatic nitriles, or prolonged exposure to sodium nitroprusside. *Signs and symptoms of cyanide poisoning* Common signs and symptoms of cyanide poisoning include: nausea, vomiting, headache, altered mental status (e.g. confusion, disorientation), chest tightness, dyspnoea, tachypnoea or hyperpnoea (early), bradypnoea or apnoea (late), hypertension (early) or hypotension (late), cardiovascular collapse, seizures or coma, mydriasis, and plasma lactate concentration > 8 mmol/L. In the setting of multiple casualties such as terrorism or chemical disaster, panic symptoms including tachypnoea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning. *Smoke inhalation* Not all smoke inhalation victims necessarily will have cyanide poisoning, but may present with burns, trauma, and exposure to additional toxic substances aggravating the clinical picture. Before sodium thiosulfate is administered, it is recommended to check affected persons for the presence of the following: • exposure to fire smoke in an enclosed area • soot present around mouth, nose and/or oropharynx • altered mental status In this setting hypotension and/or a plasma lactate concentration ≥ 10 mmol/L (higher than the one mentioned under signs and symptoms due to the fact that carbon monoxide contributes to lactic acidaemia) are highly suggestive of cyanide poisoning. In the presence of the above signs, treatment with sodium thiosulfate must not be delayed to obtain a plasma lactate concentration. Sodium thiosulfate 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. Each 12.5 g dose of sodium thiosulfate contains approximately 3.6 g of sodium which is equivalent to 180% of the WHO recommended maximal daily intake of 2 g sodium for an adult. Each 12.5 g dose of sodium thiosulfate also contains 115 mg of potassium and 140 mg of boric acid.4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. Possible interaction may occur with hydroxocobalamin. Sodium thiosulfate should not be co-administered with hydroxocobalamin in the same injection line.4.6 Fertility, pregnancy and lactation **Pregnancy** There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sodium thiosulfate in pregnant women. Animals studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of sodium thiosulfate during pregnancy. **Breastfeeding** It is unknown whether sodium thiosulfate is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with sodium thiosulfate. **Fertility** There are no fertility data from the use of sodium thiosulfate in animals.4.7 Effects on ability to drive and use machines Not relevant.4.8 Undesirable effects There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium thiosulfate. The medical literature has reported the following adverse events in association with sodium thiosulfate 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 sodium thiosulfate have been associated with a higher incidence of nausea and vomiting. However, administration of 0.045 g sodium thiosulfate 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% 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 reactions** Reporting suspected adverse reactions after authorisation of the medicinal product directly to www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.4.9 Overdose There is limited information about the effects of large doses of sodium thiosulfate in humans. Oral administration of 3 g sodium thiosulfate 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 sodium thiosulfate. A single intravenous administration of 20 mL of 10% sodium thiosulfate reportedly did not change oxygen saturations.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: antidotes, ATC code: V03AB06 (sodium thiosulfate) **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 sodium thiosulfate 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. *Sodium Thiosulfate* The 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: Rhodanese Na2S2O3 + CN- → SCN- + Na2SO3 **Clinical efficacy and safety** There have been no controlled clinical trials conducted to systematically assess the clinical efficacy and safety of sodium thiosulfate.5.2 Pharmacokinetic properties **Absorption** Sodium thiosulfate taken orally is not systemically absorbed. Intravenous injection of sodium thiosulfate is 100% bioavailability. **Distribution** Sodium thiosulfate is rapidly distributed throughout extracellular fluid after IV administration. The volume of distribution of sodium thiosulfate 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 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.5.3 Preclinical safety data 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.

6.1 List of excipients Boric Acid Potassium Chloride Water for Injections Sodium Hydroxide and/or boric acid for pH Adjustment6.2 Incompatibilities Chemical incompatibility has been reported between sodium thiosulfate and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between sodium thiosulfate and sodium nitrite, when administered sequentially through the same IV line.6.3 Shelf life 5 years From a microbiological point of view, Sodium Thiosulfate Solution for Injection should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.6.4 Special precautions for storage Do not store above 25°C. For storage conditions after first opening of the medicinal product, see Section 6.3.6.5 Nature and contents of container Each carton of Sodium Thiosulfate Solution for Injection contains one 50 mL single use glass vial of sodium thiosulfate 250 mg/mL solution for injection (containing 12.5 g of sodium thiosulfate). Each glass vial includes a chlorobutyl stopper and an aluminum cap with a plastic lid.6.6 Special precautions for disposal and other handling No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.