2.1 Important Dosage and Administration Instructions

• If clinical suspicion of cyanide poisoning is high, administer Sodium Thiosulfate Injection without delay.
• Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of sodium nitrite and sodium thiosulfate should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed in order to administer sodium nitrite and sodium thiosulfate [see Warnings and Precautions (5.1)].
• The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

2.2 Recommended Dosing

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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration.

Visually inspect all parenteral drug products for particulate matter and discoloration prior to administration.

2.3 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Sodium Thiosulfate Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, obtain hemoglobin/hematocrit when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.

2.4 Incompatibility Information

Chemical incompatibility has been reported between Sodium Thiosulfate Injection 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 as described in Dosage and Administration.

Simultaneous administration of Sodium Thiosulfate Injection and blood products (whole blood, packed red cells, platelet concentrate and/or fresh frozen plasma) through the same intravenous line is not recommended. However, blood products and Sodium Thiosulfate Injection can be administered simultaneously using separate intravenous lines (preferably on contralateral extremities, if peripheral lines are being used).

5.1 Sulfites

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

There are case reports in the medical literature of sodium nitrite in conjunction with sodium thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of sodium thiosulfate in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

8.5 Geriatric Use

Sodium thiosulfate is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Sodium thiosulfate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

12.1 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.

12. 2 Pharmacodynamics

In dogs, pretreatment with sodium thiosulfate to achieve a steady state level of 2 μmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Human Data

The human data supporting the use of sodium thiosulfate for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of sodium thiosulfate report its use in conjunction with sodium nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of sodium thiosulfate or sodium nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

Animal Data (Cyanide Poisoning)

THE EFFECTIVENESS OF SODIUM THIOSULFATE AND SODIUM NITRITE FOR THE TREATMENT OF ACUTE CYANIDE POISONING HAS NOT BEEN STUDIED IN HUMANS IN ADEQUATE AND WELL-CONTROLLED CLINICAL TRIALS BECAUSE INDUCING THE CONDITION IN HUMANS TO STUDY THE DRUG'S EFFICACY IS NOT ETHICAL.

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of sodium thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of sodium nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of sodium nitrite and sodium thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) sodium nitrite or 1 g/kg sodium thiosulfate alone or in sequence immediately after subcutaneous injection of sodium cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg sodium nitrite and/or 0.5 g/kg sodium thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of sodium cyanide required to cause death, and when administered together, sodium nitrite and sodium thiosulfate resulted in a synergistic effect in raising the lethal dose of sodium cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous sodium nitrite and sodium thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of sodium nitrite and sodium thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of sodium nitrite, with or without sodium thiosulfate, was found not to be effective in the same setting.

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F).

Protect from direct light. Do not freeze.

(Note: Sodium Nitrite must be obtained separately.)

Hypotension

When feasible, patients should be informed of the possibility of hypotension.

Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Lactation

Advise women that breastfeeding is not recommended during treatment with Sodium Thiosulfate Injection [see Use in Specific Populations (8.2)].