Sodium Thiosulfate (Systemic)


VA CLASSIFICATION
Primary: AD200
Secondary: AD900



Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidote (to cyanide poisoning)—

antineoplastic adjunct—

Indications

Accepted

Toxicity, cyanide (treatment adjunct)—Sodium thiosulfate, in conjunction with sodium nitrite, is indicated for use as an antidote in the treatment of cyanide poisoning. {01} {18}

Toxicity, cyanide, sodium nitroprusside–induced (prophylaxis)—Sodium thiosulfate may be used to prevent cyanide toxicity caused by rapid infusion of sodium nitroprusside. {04} {05} {07} {09} {10} Sodium nitroprusside infusion rates greater than 2 mcg per kg of body weight per minute generate cyanide ion faster than the body normally can eliminate it. The administration of sodium thiosulfate greatly increases the body's capacity for cyanide elimination. {10}

Nephrotoxicity, cisplatin-induced (prophylaxis)1—Sodium thiosulfate may be used with intraperitoneal cisplatin to reduce the toxicity associated with chemotherapy. {18} {29} Sodium thiosulfate, administered concurrently with cisplatin in the treatment of ovarian carcinoma, has been reported to reduce the dose-related nephrotoxicity of cisplatin, {20} {21} {24} {25} thereby allowing the dose of cisplatin to be increased. {23} {25}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    248.17 {16}


pH
    6 to 9.5. {18} {19}

Mechanism of action/Effect:

Antidote (to cyanide poisoning)—Sodium thiosulfate acts as a sulfur donor for the endogenous sulfur transferase enzyme, rhodanese. {02} {03} {04} {05} {11} {13} {14} Cyanide has a very high affinity for iron in the ferric state. It reacts readily with the trivalent (ferric) iron of mitochondrial cytochrome oxidase, thereby inhibiting cellular respiration, resulting in lactic acidosis and cytotoxic hypoxia. {02} {10} {15} Sodium nitrite reacts with hemoglobin to form methemoglobin, {01} {08} which competes with cytochrome oxidase for the cyanide ion. Cyanide preferentially binds to methemoglobin {02} {11} {15} to form cyanmethemoglobin {01} {02} {11} {15} and restore the activity of cytochrome oxidase. {02} {15} As cyanide dissociates from methemoglobin, sodium thiosulfate facilitates its conversion by rhodanese to thiocyanate, a less toxic ion. {01} {03} {08} {10} {11} {13} {14} {15} {26}

Antineoplastic adjunct—The mechanism by which sodium thiosulfate reduces the nephrotoxicity caused by cisplatin is not fully understood. {20} {21} {23} {24} However, it is believed that sodium thiosulfate reacts covalently with cisplatin to form a non-toxic complex {20} {21} {23} {24} {25} that is more efficiently eliminated than non–protein bound cisplatin. {20} It is also believed that sodium thiosulfate protects against nephrotoxicity by reducing delivery of cisplatin to the kidneys and by neutralizing cisplatin in the kidneys where sodium thiosulfate is highly concentrated. {21} {24} {25}

Distribution:

Distributed throughout the cellular fluid. {18}

Half-life:

Thiocyanate—3 to 7 days. {08} {10} May be doubled or tripled in the presence of renal failure. {10}

Thiosulfate—15 to 20 minutes. {06} {07} {10} {11}

Elimination:


Renal—
        Antidote (to cyanide poisoning): Primarily as thiocyanate. {02} {03} {06} {10} {11} {15} {24}
        Antineoplastic adjunct: As a nontoxic sodium thiosulfate/cisplatin complex. {20} {24}



In dialysis—
        Dialysis is of no value in removing cyanide, {08} {10} {13} but may be used to increase elimination of thiocyanate. {08} {10}



Precautions to Consider

Pregnancy/Reproduction

Problems in humans have not been documented.

Breast-feeding

It is not known whether sodium thiosulfate is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of sodium thiosulfate have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.


Geriatrics


Appropriate studies on the relationship of age to the effects of sodium thiosulfate have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Edematous sodium-retaining conditions such as:{30}{31}
Cirrhosis of liver
Congestive heart failure
Renal function impairment
Toxemia of pregnancy
» Hypertension    (may be exacerbated)


Sensitivity to sodium thiosulfate


Overdose
For more information on the management of thiocyanate toxicity, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Symptoms of thiocyanate toxicity
    
Arthralgias (pain in the joints){13}
    
blurred vision {10}
    
hyperreflexia {10}
    
muscle cramps {13}
    
nausea and vomiting {05}{11}{13}
    
psychotic behavior (agitation; delusions; hallucinations){13}
    
tinnitus (ringing in the ears){10}

Note: Symptoms of thiocyanate toxicity may be seen at serum thiocyanate concentrations above 10 mg per 100 mL (1.72 mmol/L). {13} Thiocyanate toxicity becomes life-threatening at serum concentrations of 20 mg per 100 mL (3.44 mmol/L). {10} {17}



Treatment of overdose
To enhance elimination—Hemodialysis; {08} {10} clearance rates during dialysis can approach the blood flow rate of the dialyzer. {10}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sodium Thiosulfate (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Sensitivity to sodium thiosulfate
Other medical problems, especially edema or hypertension

Proper use of this medication

» Proper dosing


General Dosing Information

For treatment of cyanide toxicity
Cyanide poisoning is rapidly fatal. Inhalation of cyanide gas produces symptoms of cyanide toxicity within seconds, followed by death within minutes. Oral ingestion of cyanide produces symptoms of toxicity within minutes, followed by death within minutes or hours. {13} Blood cyanide concentrations often are not available for several hours. {02} {13} Therefore, therapy should be instituted immediately based upon reasonable suspicion of cyanide toxicity. {01} {10} {13}

Supportive therapy includes moving the patient to an uncontaminated area {01} {17} and/or removing contaminated clothing; {01} {13} administering 100% oxygen; {01} {02} {13} {17} controlling seizures with anticonvulsants; {02} correcting metabolic acidosis with bicarbonate; {02} {13} and supporting pulse and blood pressure with fluids, atropine, or vasopressors. These measures alone may allow survival in relatively mild cases of cyanide toxicity. {02}

In more severe cases of cyanide toxicity, chances of survival are increased by specific antidote administration. {02} Antidotal therapy should be started by breaking an amyl nitrite inhalant, holding it in front of the patient's mouth, and allowing the patient to inhale for 15 seconds. The inhalant should then be taken away for 15 seconds. This procedure may be repeated until an intravenous line is established and sodium nitrite is prepared. {01} {12} {13} Amyl nitrite should not be administered if an intravenous line already has been established and the sodium nitrite is readily available. {10} {13} {26} Amyl nitrite, if given, should then be discontinued and sodium nitrite administered intravenously in a dose of 300 mg (for adults) and 180 to 240 mg (6 to 8 mL) per square meter of body surface area (approximately 6 mg [0.2 mL] per kg of body weight) (for children), at a rate of 75 to 150 mg (2.5 to 5 mL) per minute. {01} {02} {10} {11} {12} {13} {17} The pediatric dose should not exceed 300 mg (10 mL). {01} Blood pressure and methemoglobin concentrations should be monitored closely, {02} {11} and the administration of sodium nitrite discontinued if the systolic blood pressure goes below 80 mm Hg. The methemoglobin concentration should not exceed 40% in adults {02} {11} {12} or 30% in children. {12}

Sodium thiosulfate should be administered intravenously, immediately following the infusion of sodium nitrite. {01} {02} {10} {11} {12} {13} {17}

If signs of cyanide toxicity are still present 2 hours following administration of sodium nitrite and sodium thiosulfate, administration of both may be repeated at one-half the original dose. {01} {10} {11} {18}

If cyanide was ingested, gastric lavage should follow antidotal therapy. {15} {17}


Parenteral Dosage Forms

SODIUM THIOSULFATE INJECTION USP

Usual adult and adolescent dose
Cyanide toxicity
Intravenous, 12.5 grams (50 mL of a 25% solution) {01} {02} {03} {10} {11} {12} {13} {15} {17} {18} administered at a rate of 0.625 to 1.25 grams (2.5 to 5 mL) per minute. {13} {17} {18}

Cyanide toxicity, sodium nitroprusside–induced
Intravenous, administered concurrently with sodium nitroprusside at 5 to 10 times the rate of sodium nitroprusside. {10}

Nephrotoxicity, cisplatin-induced1
Intravenous, no standard dosing regimen has been established; however, experts recommend an initial loading dose of 4 grams per square meter of body surface area administered just before administration of cisplatin, followed by an intravenous infusion of 12 grams per square meter of body surface area administered over six hours beginning at the same time as cisplatin instillation. {21} {22} {27} {28}


Usual pediatric dose
Cyanide toxicity
Intravenous, 412.5 mg per kg of body weight {13} or 7 grams per square meter of body surface area, {01} administered at a rate of 0.625 to 1.25 grams (2.5 to 5 mL) per minute. {13} {17} {18}


Usual pediatric prescribing limits
Cyanide toxicity
12.5 grams (50 mL). {01} {13}


Strength(s) usually available
U.S.—


12.5 grams per 50 mL (Rx)[Generic](boric acid)(potassium chloride)(sodium hydroxide and/or sulfuric acid)

Canada—


12.5 grams per 50 mL (Rx)[Generic](boric acid)(potassium chloride)(sodium hydroxide and/or sulfuric acid)

Note: Sodium thiosulfate is a component of the Cyanide Antidote Package. Also contained in the kit are: amyl nitrite inhalants (0.3 mL) and sodium nitrite injection, (300 mg per 10 mL). {01}


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), {18} unless otherwise specified by manufacturer.

Stability:
Sodium thiosulfate contains no preservative; therefore, unused portions should be discarded. {18}



Developed: 03/30/1994



References
  1. Cyanide antidote package package insert (Lilly—US and Canada), Rev 8/30/90, Rec 3/8/93.
  1. Hall AH, Rumack BH. Clinical toxicology of cyanide. Ann Emerg Med 1986; 15: 1067-74.
  1. Marrs TC. Antidotal treatment of acute cyanide poisoning. Adverse Drug React Acute Poisoning Rev 1988; 4: 179-206.
  1. Cole PV, Vesey CJ. Sodium thiosulfate decreases blood cyanide concentrations after the infusion of sodium nitroprusside. Br J Anaesth 1987; 59: 531-5.
  1. Ivankovich AD, Braverman B, Stephens TS, Shulman M, Heyman HJ. Sodium thiosulfate disposition in humans: relation to sodium nitroprusside toxicity. Anesthesiology 1983; 58: 11-7.
  1. Schulz V. Clinical pharmacokinetics of nitroprusside, cyanide, thiosulfate and thiocyanate. Clin Pharmacokinet 1984; 9: 239-51.
  1. Pasch T, Schulz V, Hoppelshäuser G. Nitroprusside-induced formation of cyanide and its detoxication with thiosulfate during deliberate hypotension. J Cardiovasc Pharmacol 1983; 5: 77-85.
  1. Marbury TC, Sheppard JE, Gibbons K, Lee C-SC. Combined antidotal and hemodialysis treatments for nitroprusside-induced cyanide toxicity. J Toxicol Clin Toxicol 1982; 19: 475-82.
  1. Lundquist P, Rosling H, Tydén H. Cyanide release from sodium nitroprusside during coronary bypass in hypothermia. Acta Anaesthesiol Scand 1989; 33: 686-8.
  1. Nipride package insert (Roche—US), Rev 10/90, Rec 12/12/90.
  1. Baskin SI, Horowitz AM, Nealley EW. The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning. J Clin Pharmacol 1992; 32: 368-75.
  1. Drug evaluations subscription. Chicago: American Medical Association, Spring 1990: 4:14-4:15.
  1. Ellenhorn MJ, Barceloux DG, editors. Medical toxicology diagnosis and treatment of human poisoning. New York: Elsevier, 1988: 829-35.
  1. Scolnick B, Hamel D, Woolf AD. Successful treatment of life-threatening proprionitrile exposure with sodium nitrite/sodium thiosulfate followed by hyperbaric oxygen. J Occup Med 1993; 35: 577-80.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 1630-1.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993: 610.
  1. Dreisbach RH, Robertson WO, editors. Handbook of poisoning: prevention, diagnosis & treatment. 12th ed. Norwalk, CT: Appleton & Lange, 1987: 253-5, 382-3.
  1. Sodium thiosulfate package insert (Lyphomed—US), Rev 7/91, Rec 7/28/92.
  1. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1, 1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: 1270.
  1. Hirosawa A, Niitani H, Hayashibara K, Tsuboi E. Effects of sodium thiosulfate in combination therapy of cis-dichlorodiammineplatinum and vindesine. Cancer Chemother Pharmacol 1989; 23: 255-8.
  1. Goel R, Cleary SM, Horton C, Kirmani S, Abramson I, Kelly C, et al. Effect of sodium thiosulfate on the pharmacokinetics and toxicity of cisplatin. J Natl Cancer Inst 1989; 81: 1552-60.
  1. Markman M, Cleary S, Pfeifle CE, Howell SB. High dose intracavitary cisplatin with intravenous thiosulfate. Cancer 1985; 56: 2364-8.
  1. Pfeifle CE, Howell SB, Felthouse RD, Woliver TBS, Andrews PA, Markman M, et al. High-dose cisplatin with sodium thiosulfate protection. J Clin Oncol 1985; 3: 237-44.
  1. Howell SB, Pfeifle CE, Wung WE, Olshen RA. Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 1983; 43: 1426-31.
  1. Howell SB, Pfeifle CL, Wung WE, Olshen RA, Lucas WE, Yon JL, et al. Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 1982; 97: 845-51.
  1. Panel comment, 11/93.
  1. Howell SB, Kirmani S, Lucas WE, Zimm S. A phase II trial of intraperitoneal cisplatin and etoposide for primary treatment of ovarian epithelial cancer. J Clin Oncol 1990; 8: 137-45.
  1. Kim S, Howell SB, McClay E, Kirmani S. Dose intensification of cisplatin chemotherapy through biweekly administration. Ann Oncol 1993; 4: 221-7.
  1. Panel comment, 11/93.
  1. Panel comment, 11/93.
  1. Reviewer comment, 12/93.
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