sodium thiosulfate

Sodium thiosulfate is a medication used as an antidote to cyanide poisoning. Sodium thiosulfate is sequentially administered as an intravenous (IV) injection after sodium nitrite IV injection and both drugs are typically used together to reverse the effects of cyanide. Pedmark brand of sodium thiosulfate is used to reduce toxicity to the ear (ototoxicity) in pediatric patients, caused by the cancer chemotherapy drug cisplatin.

Cyanide poisoning can result from inhalation, ingestion, or skin exposure to cyanide-containing compounds, including smoke from closed-space fires. Cyanide binds to cytochrome a3, a component of the cytochrome oxidase, an enzyme essential for cellular respiration. Cyanide inhibits cytochrome oxidase which prevents cells from using oxygen, resulting in low tissue oxygen (hypoxia), high acidity (metabolic acidosis), and eventually, cellular death.

Sodium thiosulfate serves as a sulfur donor for the enzyme rhodanese, also known as thiosulfate sulfurtransferase. Rhodanese is a key enzyme naturally produced in the body for detoxification of environmental toxins. Sodium thiosulfate facilitates the conversion of cyanide by rhodanese into a relatively less toxic thiocyanate that is eliminated in the urine.

The chemotherapy drug cisplatin can cause irreversible damage to the hair cells in the cochlea in the inner ear, leading to loss of hearing. Cisplatin causes production of reactive oxygen species (ROS), also known as free radicals, a type of unstable oxygen molecules that cause oxidative stress. Oxidative stress damages the DNA and leads to cellular death.

Sodium thiosulfate interacts with cisplatin to produce an inactive platinum species, reducing the risk of ototoxicity. Sodium thiosulfate also increases the level of glutathione, the natural antioxidant in the body that neutralizes free radicals.

The uses of sodium thiosulfate include the following:

FDA-approved

• Acute cyanide in adults and children that is judged to be life-threatening, in combination with sodium nitrite
• Cisplatin-induced ototoxicity in pediatric patients one month and older (Pedmark only)

Off-label

• Cisplatin toxicity to the kidneys (nephrotoxicity)
• Leakage of medication from the veins into the surrounding tissue (extravasation) including:
  • Cisplatin extravasation
  • Delayed calcium extravasation
  • Bendamustine extravasation

Orphan designation

• Calciphylaxis, a condition in which calcium accumulates in the small blood vessels of skin and fat tissues
• Mechlorethamine extravasation
• Sulfur mustard poisoning
• Dermatomyositis, an inflammatory muscle disease with skin rash

• Do not use Pedmark brand of sodium thiosulfate in patients younger than 1 month.
• Do not use Pedmark in patients with a history of severe hypersensitivity to sodium thiosulfate or any of its components.
• Monitor patients treated with Pedmark for hypersensitivity reactions. If a hypersensitivity reaction occurs, discontinue Pedmark and institute appropriate care. Administer glucocorticoids and antihistamines before each subsequent administration.
• Sodium thiosulfate products may contain trace impurities of sodium sulfite. Sodium thiosulfate treatment should not be withheld even if the patient is sulfite-sensitive, because it is used for emergency, life-threatening situations. Sulfite sensitivity is relatively more common in people with asthma.
• Pedmark can increase blood sodium levels and reduce potassium levels. Monitor patients for hypernatremia and hypokalemia. Discontinue in patients with serum sodium greater than 145 mmol/L and institute supportive care and appropriate supplementation.
• Sodium thiosulfate can cause nausea and vomiting. Administer antiemetics prior to each administration and provide additional antiemetics and supportive therapy as appropriate.

Common side effects of sodium thiosulfate (generic) include:

• Nausea
• Vomiting
• Headache
• Low blood pressure (hypotension), infusion rate-dependent
• Salty taste in the mouth
• Warm sensation over the body
• Prolonged bleeding time
• Hypersensitivity reactions
• Local irritation
• Contact dermatitis

Common side effects of sodium thiosulfate (Pedmark) administered with cisplatin for cisplatin-induced toxicity include:

• Vomiting
• Nausea
• Decreased hemoglobin
• High blood sodium levels (hypernatremia)
• Low blood potassium (hypokalemia)
• Low phosphate level in blood (hypophosphatemia)
• High magnesium level in blood (hypermagnesemia)
• High temperature (pyrexia)
• Oral inflammation (stomatitis)
• Hypersensitivity reactions including severe allergic reaction (anaphylaxis)
• Low blood pressure (hypotension)
• High blood pressure (hypertension)
• Excessive acidity of body fluids (metabolic acidosis)
• Low blood calcium levels (hypocalcemia)

Serious side effects of Pedmark include:

• Infection
• Decrease in blood count of neutrophil immune cells (neutropenia)
• Febrile neutropenia
• Decrease in platelet count (thrombocytopenia)
• Decrease in white blood cell count
• Decrease in lymphocyte count
• Low red blood cell count (anemia)
• Increase in liver enzyme alanine aminotransferase (ALT)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injection Solution

• 250 mg/mL (25%)

Injectable Solution

• 12.5 g/100 mL (single-dose vial; Pedmark)

Cyanide Poisoning

Adult:

• 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
• Sodium Nitrite: 10 mL of sodium nitrite at the rate of 2.5 to 5 mL/minute
• Sodium thiosulfate: 50 mL of sodium thiosulfate immediately following administration of sodium nitrite
• Airway, ventilatory and circulatory support, and oxygen administration should not be delayed in order to administer sodium nitrite and sodium thiosulfate
• If signs of poisoning reappear, repeat treatment using one-half original dose of both sodium nitrite and sodium thiosulfate
• Expert advice from a regional poison control center may be obtained by calling 1-800-222-1222

Pediatric:

• 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
• Sodium Nitrite: 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 body surface are [BSA]) of sodium nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL  
• Sodium Thiosulfate: 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of sodium nitrite
• Airway, ventilatory and circulatory support, and oxygen administration should not be delayed in order to administer sodium nitrite and sodium thiosulfate
• If signs of poisoning reappear, repeat treatment using one-half original dose of both sodium nitrite and sodium thiosulfate
• Expert advice from a regional poison control center may be obtained by calling 1-800-222-1222

Dosing considerations

• The safety of administering other cyanide antidotes simultaneously with sodium thiosulfate injection has not been established; if a decision is made to administer another cyanide antidote with sodium thiosulfate injection, these drugs should not be administered concurrently in the same intravenous (IV) line
• If clinical suspicion of cyanide poisoning is high, administer sodium thiosulfate injection without delay
• Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires
• Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to sodium nitroprusside
• 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 basis of clinical history and signs and symptoms of cyanide intoxication
• Symptoms of cyanate poisoning include headache, confusion, dyspnea, chest tightness, nausea
• Signs of cyanide poisoning include altered mental status (e.g., confusion, disorientation), seizures or coma, mydriasis, tachypnea/hyperpnea, bradypnea/apnea (late), hypertension (early)/hypotension (late), cardiovascular collapse, vomiting, plasma lactate concentration greater than 8 mmol/L
• In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs; the presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well
• Smoke inhalation
  • Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult
  • Prior to administration of sodium thiosulfate injection, smoke-inhalation victims should be assessed for exposure to fire or smoke in an enclosed area, presence of soot around the mouth, nose, or oropharynx; altered mental status, although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims
  • Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia); if cyanide poisoning is suspected, treatment should not be delayed in order to obtain a plasma lactate concentration

Adult:

Cisplatin Extravasation (Off-label)

• 2 mL 1/6 molar solution through IV cannula for every 100 mg cisplatin; remove needle, then inject 0.1 mL injections clockwise around extravasation area up to 1 mL; repeat several times within the 3-4 hours of extravasation incident
• Preparation of 1/6 molar solution: 1.6 mL of 25% solution plus 8.4 mL sterile water for injection

Cisplatin Nephrotoxicity (Off-label)

• 4 g/m² IV bolus followed by 12 g/m² IV infusion over 6 hours

Pediatric:

Cisplatin-Induced Ototoxicity

Pedmark only

• Indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients aged 1 month and older with localized, non-metastatic solid tumors
• Administer as IV infusion over 15 minutes starting 6 hours after completing cisplatin infusion
• For multiday cisplatin regimens, administer 6 hours after each cisplatin infusion but at least 10 hours before the next cisplatin infusion
• Do not start if it is under 10 hours before starting next cisplatin infusion
• Dose is based on surface area according to actual body weight (ABW)
• ABW under 5 kg: 10 g/m2
• ABW 5-10 kg: 15 g/m2
• ABW above 10 kg: 20 g/m2

Dosage Modifications

Pedmark

• Grade 3 or 4 hypersensitivity reactions: Permanently discontinue
• Hypernatremia (sodium above 145 mmol/L): Withhold until sodium normalizes; resume at same dose
• Grade 3 or 4 hypokalemia: Withhold until potassium normalizes; resume at the same dose
• Grade 3 other adverse reactions: Withhold until Grade 1 or lower; resume at same dose
• Grade 4 other adverse reactions: Permanently discontinue

Renal impairment

• Sodium thiosulfate is substantially excreted by the kidney
• Mild-to-severe or end-stage renal disease: No dose adjustment necessary
• If GFR decreased to below 60 mL/min/1.73 m2, monitor for signs and symptoms of hypernatremia and hypokalemia more closely

Dosing Considerations

• Not substitutable with other sodium thiosulfate products

Limitations of use

• Safety and efficacy not established when administered following cisplatin infusions later than 6 hours
• May not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred

• There is insufficient information about sodium thiosulfate overdose. Limited studies in humans indicate sodium thiosulfate may decrease arterial oxygen saturation.
• Overdose of sodium thiosulfate during treatment of cyanide poisoning can lead to excessive levels of thiocyanate and lead to thiocyanate toxicity. Thiocyanate toxicity can cause symptoms that include joint pain (arthralgia), muscle cramps, nausea, vomiting, blurred vision, ringing in ears (tinnitus), and psychotic behavior.
• Overdose treatment includes enhancing the elimination of thiocyanate with hemodialysis, as well as providing supportive and symptomatic treatment.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Sodium thiosulfate has no known interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies on use of sodium thiosulfate injections in pregnant women, and the drug should be used during pregnancy if clearly needed.
• Untreated cyanide poisoning can be fatal to the mother and fetus. Sodium thiosulfate is a life-saving antidote and should not be withheld during pregnancy. Animal studies and available human reports do not indicate fetal harm from sodium thiosulfate.
• It is not known if sodium thiosulfate is present in breast milk and no data are available on its effects on milk production or the breastfed infant.
• Sodium thiosulfate is administered in life-threatening situations and nursing is not a contraindication, however, it should be administered with caution in nursing mothers because many drugs are excreted in milk.
• There are no data to determine when breastfeeding may be safely restarted following administration of sodium thiosulfate.