A Comprehensive Monograph on Sodium Thiosulfate: From Chemical Commodity to Targeted Therapeutic Agent

I. Introduction and Executive Summary

Overview

Sodium Thiosulfate, with the chemical formula Na2​S2​O3​, is an inorganic salt that has traversed a remarkable path from a widely used industrial and chemical commodity to a critical, life-saving medication and a targeted therapeutic agent in modern medicine.[1] Historically known to photographers as "hypo" for its role in fixing photographic film, its applications have expanded into diverse fields, including water treatment as a dechlorinating agent and analytical chemistry as a titrant.[1] However, its most profound impact lies in its medical applications. For nearly a century, it has been a cornerstone in the treatment of acute cyanide poisoning, a role that cemented its place in emergency medicine.[3] More recently, rigorous clinical investigation has led to its approval by major global regulatory bodies for a highly specific and novel indication: the prevention of permanent, debilitating hearing loss (ototoxicity) in pediatric cancer patients undergoing cisplatin chemotherapy.[5] This evolution from a bulk chemical to a precision supportive care drug highlights a sophisticated understanding of its unique chemical reactivity and its translation into distinct, context-dependent pharmacological effects.

Executive Summary

This report provides a definitive and exhaustive monograph on Sodium Thiosulfate, synthesizing comprehensive data on its physicochemical properties, pharmacological profile, clinical applications, and regulatory status. It begins by detailing the fundamental chemical and physical characteristics that directly influence its pharmaceutical formulation and route of administration. The analysis then elucidates its distinct mechanisms of action, explaining how the same molecule can function as a sulfur donor for cyanide detoxification, a direct chemical inactivator and antioxidant for preventing cisplatin-induced ototoxicity, and a potent calcium-solubilizing agent in the management of calciphylaxis.

The report critically evaluates the pivotal clinical trial evidence that underpins its modern indications, particularly the landmark studies that established its efficacy in preventing hearing loss in children with cancer. A detailed examination of its pharmacokinetic profile reveals the basis for its requisite intravenous administration and provides a rationale for dose adjustments and timing in special populations, such as patients undergoing hemodialysis. The comprehensive safety profile, including common adverse effects like electrolyte disturbances and rare but serious hypersensitivity reactions, is thoroughly reviewed.

Furthermore, the report chronicles the complex and lengthy regulatory journey of its branded formulation, Pedmark®/Pedmarqsi™, offering a compelling case study in the repurposing of an established compound for a novel therapeutic use. Key findings underscore the critical importance of pharmaceutical formulation, precise administration timing, and careful patient selection in achieving optimal therapeutic outcomes. This analysis demonstrates the transformation of Sodium Thiosulfate from a simple inorganic salt into a sophisticated tool of modern medicine, reflecting a significant advancement in targeted, preventative supportive care.

II. Physicochemical Properties and Pharmaceutical Formulations

Chemical Identity and Structure

Sodium Thiosulfate is an inorganic sodium salt with the chemical formula Na2​S2​O3​.[7] The molecule consists of two sodium cations (

Na+) ionically bonded to a single thiosulfate anion (S2​O32−​).[7] It is commercially available in two primary forms: the anhydrous salt (

Na2​S2​O3​), which has a molar mass of 158.11 g/mol, and the more common and stable pentahydrate form (Na2​S2​O3​⋅5H2​O), which has a molecular weight of 248.18 g/mol.[1] The pentahydrate is often referred to by its historical names, "soda" or "hypo".[1] The distinction between these two forms is of paramount importance in pharmaceutical manufacturing and compounding to ensure accurate calculations for dosing and solution preparation.

Physical Properties

Sodium Thiosulfate pentahydrate presents as a colorless, odorless, monoclinic crystalline solid or a white crystalline powder.[8] It possesses a distinct saline taste.[1] One of its most significant physical properties is its high solubility in water; at 100°C, 231 grams will dissolve in 100 mL of water.[1] In stark contrast, it is insoluble in alcohol.[1] This high aqueous solubility is fundamental to its use in medicine, as it allows for the preparation of concentrated solutions for intravenous administration.

The thermal properties of the pentahydrate are well-defined. It has a low melting point of approximately 48.3°C.[1] Upon heating to 100°C, it undergoes dehydration, losing all five of its water molecules of crystallization.[1] Further heating leads to decomposition; at 310°C it decomposes to form sulfur and sodium sulfite, while at higher temperatures it can yield sodium sulfate and sodium polysulfide (

4Na2​S2​O3​→3Na2​SO4​+Na2​S5​).[1] The compound is also described as hygroscopic and can be deliquescent (absorb moisture from the air to dissolve) in a hot, humid environment, necessitating storage in well-sealed containers.[1]

Chemical Properties and Reactivity

The chemical behavior of Sodium Thiosulfate is defined by the reactivity of the thiosulfate anion. It is stable in neutral and alkaline aqueous solutions, but it readily decomposes in the presence of acid. This reaction liberates sulfur dioxide gas and precipitates elemental sulfur, as shown in the following reaction: Na2​S2​O3​+2HCl→2NaCl+H2​O+SO2​+S.[1] This instability in acidic environments is not merely a chemical curiosity; it is the primary reason for the drug's extremely poor and erratic absorption when administered orally, as it is rapidly degraded by gastric acid. This fundamental chemical property dictates the clinical necessity for intravenous administration to achieve reliable and therapeutic systemic drug levels.[10]

Sodium Thiosulfate is a potent reducing agent. It famously reacts with oxidizing agents such as iodine, reducing it to iodide while the thiosulfate is oxidized to tetrathionate (2S2​O32−​+I2​→S4​O62−​+2I−).[8] This specific reaction forms the basis of iodometric titrations in analytical chemistry.[2] Its reducing properties are also harnessed in industrial applications, such as the dechlorination of water, where it neutralizes residual chlorine.[1]

Furthermore, the thiosulfate ion is an effective complexing agent, or ligand. It can form stable, soluble complexes with various metal ions. Its most well-known application in this regard is in photography, where it dissolves unexposed silver halide crystals (e.g., silver bromide) from film by forming the soluble complex ion 3−, thereby "fixing" the image.[1] This ability to form soluble complexes with metals is also central to some of its therapeutic effects.

Table 1: Summary of Physicochemical Properties of Sodium Thiosulfate

Property	Anhydrous Form (Na2​S2​O3​)	Pentahydrate Form (Na2​S2​O3​⋅5H2​O)	Source(s)
Molecular Formula	Na2​S2​O3​	Na2​S2​O3​⋅5H2​O	1
Molar Mass	158.11 g/mol	248.18 g/mol	1
Appearance	Opaque crystalline powder	Colorless, odorless monoclinic crystals or white crystalline powder	1
Melting Point	N/A (Decomposes)	48 - 48.3°C	1
Boiling Point	N/A (Decomposes)	100°C (Loses water of crystallization)	1
Density	1.667 g/cm³	1.685 g/cm³	1
Water Solubility	Soluble	Highly Soluble (231 g/100 mL at 100°C)	1
Alcohol Solubility	Insoluble	Insoluble	1
pH of Solution	6.0 - 8.5 (50 mg/mL in H2​O)	6.0 - 8.5 (50 mg/mL in H2​O)	1
Stability	Hygroscopic; Decomposes in acid	Weathers in dry air; Deliquescent in humid air; Decomposes in acid	1

Pharmaceutical Formulations

A critical aspect of modern Sodium Thiosulfate therapy is the distinction between pharmaceutical formulations. While it has long been available as a generic chemical, its recent approval for a specific pediatric oncology indication has introduced a highly specialized product.

• Pedmark® (U.S.) / Pedmarqsi™ (E.U.): This is a unique, sterile, single-dose, ready-to-use formulation supplied in vials containing 12.5 grams of Sodium Thiosulfate in 100 mL of solution (125 mg/mL).[11] This specific product was rigorously tested in the pivotal clinical trials that established its safety and efficacy for preventing cisplatin-induced ototoxicity in children.[13] It is formulated to be free of certain impurities, such as potassium chloride, and contains low, controlled levels of boron.[5]
• Other Formulations: Sodium Thiosulfate is also available in other forms, such as part of cyanide antidote kits (often co-packaged with sodium nitrite) or as a bulk chemical substance.[14] These formulations have not been approved for otoprotection. The U.S. Food and Drug Administration (FDA) has issued a specific warning that these other products are not substitutable for Pedmark®.[5] The rationale is that they may contain impurities at levels that were not evaluated for safety in the context of repeated administration to pediatric patients, posing potential risks of cardiac events (from potassium) or other toxicities (from boron).[5] This underscores that for this targeted therapy, the specific drug product—not just the active ingredient—is essential for safe and effective use.

III. Comprehensive Pharmacological Profile

A. Mechanisms of Action

The therapeutic versatility of Sodium Thiosulfate is remarkable, stemming from the multifaceted reactivity of the thiosulfate anion. This single chemical entity can participate in distinct biochemical pathways depending on the specific pathological environment, allowing it to function as a biochemical cofactor, an antioxidant and chemical inactivator, and a solubilizing agent.

1. Cyanide Detoxification

The classical and life-saving role of Sodium Thiosulfate is as an antidote to cyanide poisoning.[16] Cyanide exerts its profound toxicity by binding to the ferric ion (

Fe3+) within cytochrome c oxidase in the mitochondrial electron transport chain, effectively halting aerobic respiration and leading to cellular hypoxia and rapid death.[18] The body has a natural, but limited, capacity to detoxify cyanide via the mitochondrial enzyme rhodanese (thiosulfate cyanide sulfurtransferase).[14] This enzyme catalyzes the conversion of the highly toxic cyanide ion (

CN−) into the much less toxic and readily excretable thiocyanate ion (SCN−).[2]

The primary mechanism of action of Sodium Thiosulfate in this context is to serve as an exogenous sulfur donor.[14] In a severe cyanide exposure, the endogenous supply of sulfur donors becomes the rate-limiting factor for the rhodanese-catalyzed detoxification pathway.[19] By providing a vast surplus of sulfur in the form of thiosulfate, intravenous administration of the drug dramatically accelerates this natural detoxification process, allowing for the rapid conversion and subsequent renal clearance of the cyanide burden.[2]

In clinical practice for severe poisoning, Sodium Thiosulfate is often part of a two-step therapy administered sequentially after sodium nitrite.[3] Sodium nitrite works by a different mechanism: it oxidizes hemoglobin to methemoglobin, which has a high affinity for cyanide. This creates a systemic "sink," pulling cyanide out of the mitochondria and binding it in the circulation as non-toxic cyanomethemoglobin. Sodium Thiosulfate then provides the sulfur substrate needed to permanently detoxify the cyanide as it is slowly released from the cyanomethemoglobin complex.[3]

2. Prevention of Cisplatin-Induced Ototoxicity

The most significant modern application of Sodium Thiosulfate is in preventing the irreversible, bilateral sensorineural hearing loss caused by the chemotherapeutic agent cisplatin, particularly in children.[3] Cisplatin's ototoxicity is primarily mediated by the generation of excessive reactive oxygen species (ROS) within the delicate structures of the cochlea (inner ear).[23] This intense oxidative stress triggers a cascade of events leading to the apoptosis (programmed cell death) of the cochlear outer hair cells, which are essential for hearing, especially at high frequencies.[23]

The otoprotective mechanism of Sodium Thiosulfate in this setting is understood to be multifactorial, addressing both the cause and the effect of the cochlear damage:

1. Direct Cisplatin Inactivation: Sodium Thiosulfate can circulate in the plasma and directly interact with cisplatin and its electrophilic aquated species. It forms inactive and non-toxic platinum-thiosulfate complexes, which are then excreted from the body. This action effectively reduces the concentration of active cisplatin that can penetrate the blood-perilymph barrier and reach the inner ear, thereby lowering the toxic insult to the cochlear cells.[23]
2. Antioxidant Activity: Sodium Thiosulfate also functions as a potent antioxidant. It can directly scavenge the harmful ROS generated by cisplatin within the cochlea, neutralizing them before they can inflict damage on cellular components like lipids, proteins, and DNA. This mitigates the oxidative stress that is the primary trigger for the apoptotic cell death of the outer hair cells.[23]

The clinical success of this intervention hinges critically on its administration timing. Sodium Thiosulfate is given as a 15-minute infusion precisely 6 hours after the completion of the cisplatin infusion.[23] This delay is a carefully calculated therapeutic window. It allows the cisplatin to distribute to tumor tissues and exert its desired cytotoxic, anti-cancer effects. Administering Sodium Thiosulfate concurrently with or too soon after cisplatin would risk systemic neutralization of the chemotherapy drug, potentially compromising its efficacy and leading to treatment failure.[23] This timed, sequential administration is a sophisticated strategy that separates the therapeutic effect of cisplatin from its toxic side effect.

3. Management of Calcific Uremic Arteriolopathy (Calciphylaxis)

In the context of end-stage renal disease, Sodium Thiosulfate is used off-label to treat calciphylaxis, a devastating and often fatal condition characterized by the progressive calcification of small and medium-sized blood vessels in the skin and subcutaneous fat.[3] This leads to vessel thrombosis, severe tissue ischemia, and the development of intensely painful, non-healing necrotic ulcers.[29]

While the exact mechanism is not fully elucidated, its efficacy is believed to derive from two primary properties:

1. Calcium Solubilization and Chelation: The core pathology of calciphylaxis is the deposition of insoluble calcium salts, primarily calcium phosphate, in the vessel walls. Sodium Thiosulfate intervenes by reacting with these deposits to form calcium thiosulfate (CaS2​O3​). Calcium thiosulfate is vastly more soluble in water than calcium phosphate—by a factor of 250 to 100,000.[30] This chemical transformation allows the deposited calcium to be mobilized from the tissues back into the circulation, from where it can be effectively removed from the body by hemodialysis.[2]
2. Antioxidant and Vasodilatory Effects: Endothelial dysfunction and oxidative stress are also implicated in the pathogenesis of calciphylaxis. Sodium Thiosulfate is a potent antioxidant that can donate electrons to neutralize free radicals.[2] This may help to reduce inflammation and restore the function of the vascular endothelium. There is also evidence to suggest it may promote vasodilation, possibly by enhancing the production of endothelial nitric oxide (eNO), which could improve blood flow to ischemic tissues.[29]

B. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Sodium Thiosulfate has been formally investigated, revealing key characteristics that govern its clinical use, particularly the necessity of intravenous administration and the impact of renal function on its clearance.

Absorption

Oral administration of Sodium Thiosulfate is clinically ineffective due to extremely poor and highly variable absorption. A pharmacokinetic study in healthy volunteers found that the mean oral bioavailability was only 7.6%, with a wide range from 0.8% to 26%.[10] This was corroborated by the finding that only 4% of an orally administered dose was recovered in the urine over 24 hours.[10] This poor absorption profile is a direct consequence of its chemical instability in the highly acidic environment of the stomach, where it is rapidly degraded.[1] Consequently, to achieve predictable and therapeutic systemic concentrations, intravenous administration is the only viable route.[10]

Distribution

Following intravenous administration, Sodium Thiosulfate is distributed in the body according to a one-compartment model, with an estimated mean volume of distribution of 0.226 L/kg.[10] The serum half-life in individuals with normal renal function is relatively short, reported to be between 15 and 50 minutes.[28]

Metabolism

A substantial portion of thiosulfate elimination occurs through nonrenal pathways, which are presumed to be metabolic. In healthy individuals, this nonrenal clearance accounts for approximately half of the total body clearance.[10] The primary metabolic pathway is believed to be the oxidation of thiosulfate to sulfate, a process that likely occurs predominantly in the liver but also in other tissues.[10]

A crucial finding from pharmacokinetic studies is that this metabolic clearance pathway remains intact even in patients with severe renal failure. The nonrenal clearance rate was not significantly different between healthy volunteers (mean 2.25 ml/min/kg) and anuric patients on hemodialysis (mean 2.04 ml/min/kg).[10] This demonstrates that while the kidneys are a major route of elimination for the unchanged drug, the body's ability to metabolize thiosulfate is not compromised by the loss of renal function.

Excretion

The excretion of Sodium Thiosulfate and its metabolites is highly dependent on renal function.

• Renal Excretion: In individuals with normal kidney function, renal clearance is a major elimination pathway, with a mean rate of 1.86 ml/min/kg, which closely mirrors the glomerular filtration rate (GFR).[10] This pathway accounts for roughly 50% of the total body clearance.[10] The primary metabolite from cyanide detoxification, thiocyanate, is also cleared by the kidneys. However, thiocyanate has a much longer half-life of approximately 3 days, which can be prolonged to as long as 9 days in patients with renal impairment, creating a risk of accumulation and toxicity.[28]
• Hemodialysis Clearance: Sodium Thiosulfate is a small molecule that is effectively removed by hemodialysis. Studies have measured a high hemodialysis clearance rate of 2.62 ml/min/kg.[10] This efficient removal by dialysis has significant implications for its use in patients with end-stage renal disease (ESRD). The drug's handling in this population is dichotomous: its metabolism is normal, but its primary route of excretion is absent. Hemodialysis serves as an artificial replacement for this lost renal clearance. This understanding directly informs clinical strategy: if the primary goal is to mobilize and remove calcium-thiosulfate complexes in calciphylaxis treatment, the drug should be administered shortly before or during the dialysis session to maximize clearance. Conversely, if the goal is to maintain sustained tissue concentrations for antioxidant effects, dosing on non-dialysis days may be more appropriate.[10]

Table 2: Comparative Pharmacokinetic Parameters of Intravenous Sodium Thiosulfate

Parameter	Healthy Volunteers	Hemodialysis Patients (Off-Dialysis)	Hemodialysis Patients (On-Dialysis)	Source(s)
Total Body Clearance (ml/min/kg)	4.11 ± 0.77	2.04 ± 0.72	4.53 ± 1.40	10
Renal Clearance (ml/min/kg)	1.86 ± 0.45	N/A (Anuric)	N/A (Anuric)	10
Nonrenal Clearance (ml/min/kg)	2.25 ± 0.42	2.04 ± 0.72	2.04 ± 0.72 (Estimated)	10
Hemodialysis Clearance (ml/min/kg)	N/A	N/A	2.62 ± 1.01	10
Half-life	~15-50 min	Prolonged	Reduced during dialysis	28
Volume of Distribution (L/kg)	~0.226	~0.226	~0.226	10
Oral Bioavailability	7.6% (0.8% to 26%)	Not studied	Not studied	10

IV. Therapeutic Indications and Clinical Efficacy

A. Cyanide Poisoning: The Classical Antidote

Sodium Thiosulfate is a cornerstone antidote for acute cyanide poisoning, an indication for which it has been used since the 1930s.[3] It is indicated for life-threatening toxicity resulting from various exposures, including inhalation of hydrogen cyanide gas in industrial accidents or fires, ingestion of cyanide salts, or exposure to cyanogenic compounds.[3]

In clinical practice, it is a key component of the traditional cyanide antidote kit and is typically administered intravenously immediately after sodium nitrite in severe cases.[17] The combination therapy is considered more effective than either agent alone.[4] However, in specific scenarios such as smoke inhalation victims who may have concurrent carbon monoxide poisoning, Sodium Thiosulfate alone is recommended.[3] This is because sodium nitrite induces methemoglobinemia, which would further compromise the already impaired oxygen-carrying capacity of the blood in a patient with carboxyhemoglobinemia.[3] While its efficacy is well-established through decades of clinical use, there are some concerns regarding its onset of action, which relies on an enzymatic process and may be slower than that of direct binding agents like hydroxocobalamin.[3]

B. Prevention of Cisplatin-Induced Ototoxicity in Pediatric Oncology

The most significant recent development in the therapeutic use of Sodium Thiosulfate is its approval for the prevention of cisplatin-induced ototoxicity. It is specifically indicated, under the brand names Pedmark® (U.S.) and Pedmarqsi™ (E.U.), to reduce the risk of permanent hearing loss in pediatric patients, from one month to less than 18 years of age, who are receiving cisplatin for localized, non-metastatic solid tumors.[3]

This indication is supported by high-level evidence from two pivotal, international, randomized, open-label Phase 3 clinical trials. The success of these trials represents a major paradigm shift in supportive care for oncology, moving beyond the management of side effects after they occur to the proactive, mechanism-based prevention of an irreversible toxicity. Historically, supportive care has focused on treating reversible side effects like nausea or myelosuppression. However, because cisplatin-induced hearing loss is permanent, prevention is the only effective strategy. By identifying the underlying mechanism (ROS-mediated damage) and a counteracting agent (Sodium Thiosulfate), and by designing a clinical protocol with carefully timed administration to avoid interfering with anti-tumor efficacy, researchers established a new model of targeted "chemoprotection."

The key clinical evidence is summarized below:

• SIOPEL 6 (NCT00652132): This trial enrolled 114 children with standard-risk hepatoblastoma. Patients were randomized to receive cisplatin-based chemotherapy either alone or with sequential Sodium Thiosulfate. The results were compelling: the incidence of hearing loss (defined as Brock Grade ≥1) was significantly lower in the group receiving Sodium Thiosulfate (39%) compared to the group receiving cisplatin alone (68%). This corresponded to an unadjusted relative risk of 0.58, indicating a 42% reduction in the risk of developing hearing loss.[5]
• COG ACCL0431 (NCT00716976): This trial included a broader population of 125 pediatric patients with various solid tumors. In the evaluable primary analysis population, the incidence of hearing loss (per American Speech-Language-Hearing Association criteria) was 28.6% in the Sodium Thiosulfate arm versus 56.4% in the control arm, a statistically significant difference.[23] The odds of developing hearing loss were approximately 70% lower for patients receiving Sodium Thiosulfate (odds ratio 0.31).[23] A secondary analysis of this trial provided further valuable information, showing that the protective effect was most pronounced in the patients at highest risk for ototoxicity, particularly children younger than 5 years and those with diagnoses such as neuroblastoma, hepatoblastoma, or medulloblastoma.[37]

A key limitation of use noted in the approved labeling is that the efficacy of Sodium Thiosulfate has not been established when administered following cisplatin infusions that last longer than 6 hours. This is because irreversible damage to the cochlear hair cells may have already occurred during a prolonged infusion, rendering a post-treatment protective agent ineffective.[11]

Table 3: Summary of Pivotal Clinical Trials for Cisplatin-Induced Ototoxicity Prevention

Trial Name	NCT Number	Patient Population	Intervention Arms	Primary Endpoint	Key Efficacy Results	Source(s)
SIOPEL 6	NCT00652132	114 pediatric patients with standard-risk hepatoblastoma	1. Cisplatin-based chemotherapy 2. Cisplatin-based chemotherapy + Sodium Thiosulfate	Incidence of hearing loss (Brock Grade ≥1)	Hearing Loss Incidence: • 39% with STS • 68% with Cisplatin alone Relative Risk: 0.58 (95% CI: 0.40, 0.83)	5
COG ACCL0431	NCT00716976	125 pediatric patients with various localized solid tumors	1. Cisplatin-based chemotherapy (Observation) 2. Cisplatin-based chemotherapy + Sodium Thiosulfate	Incidence of hearing loss (ASHA criteria) 4 weeks post-treatment	Hearing Loss Incidence: • 28.6% with STS • 56.4% with Observation alone Odds Ratio: 0.31 (95% CI: 0.13, 0.73); p=0.0036	5

C. Management of Calcific Uremic Arteriolopathy (Calciphylaxis)

Sodium Thiosulfate has emerged as a primary off-label therapy for calciphylaxis, a condition for which it has received Orphan Drug designation.[3] Although large-scale randomized controlled trials are still lacking, a substantial body of evidence from case series and observational studies supports its use.[29] Clinicians report that intravenous administration of Sodium Thiosulfate, typically at doses of 12.5 to 25 grams three times per week following hemodialysis, can lead to a rapid and dramatic reduction in the excruciating pain associated with the condition's ischemic lesions.[28] Furthermore, many reports document significant improvement and healing of the necrotic skin ulcers over weeks to months of therapy.[30] Despite these positive outcomes, the overall mortality rate for calciphylaxis remains very high, and Sodium Thiosulfate is used as part of a multi-faceted treatment approach that also includes meticulous wound care and management of underlying mineral bone disease.[30]

D. Dermatological and Other Uses

• Topical Antifungal: Sodium Thiosulfate has a long history of use as a topical antifungal agent. It is effective in the treatment of tinea versicolor (pityriasis versicolor), a superficial fungal infection of the skin, and is sometimes compounded with salicylic acid for this purpose.[3] It has also been used in foot baths for the prophylaxis of ringworm (tinea pedis).[3]
• Extravasation Antidote: In oncology, it is employed as an off-label antidote for the extravasation (accidental leakage of a drug from a vein into surrounding tissue) of certain vesicant chemotherapeutic agents, including cisplatin, nitrogen mustard, and bendamustine.[14] When injected locally into the affected area, it is believed to neutralize the reactive chemical species of the extravasated drug, thereby reducing severe local tissue damage, pain, and necrosis.[14]

V. Dosing, Administration, and Clinical Practice Guidelines

The dosing and administration of Sodium Thiosulfate are highly specific to the indication, patient population, and, in the case of ototoxicity prevention, the specific pharmaceutical product used. Adherence to established protocols is critical for both safety and efficacy.

1. Cyanide Poisoning

• Adults: The standard adult dose is 12.5 grams of Sodium Thiosulfate (equivalent to 50 mL of a 25% w/v solution). This is administered via slow intravenous injection over approximately 10 minutes. It should be given immediately after the administration of sodium nitrite. If signs and symptoms of cyanide toxicity persist or recur, a second dose of 6.25 grams (half the original dose) may be administered after 30 minutes.[33]
• Pediatrics: The pediatric dose is calculated based on body weight: 250 mg/kg (equivalent to 1 mL/kg of a 25% solution). This is also given by slow intravenous injection following sodium nitrite. The maximum initial dose should not exceed 12.5 grams. A repeat dose of 125 mg/kg (half the original dose) can be considered if needed.[28]

2. Prevention of Cisplatin-Induced Ototoxicity (Pedmark®/Pedmarqsi™ only)

This indication requires strict adherence to dosing based on body surface area and precise administration timing. Only the approved Pedmark®/Pedmarqsi™ formulation should be used.

• Administration Timing: The infusion must begin exactly 6 hours after the completion of the cisplatin infusion. This timing is non-negotiable to ensure anti-tumor efficacy is not compromised. The Sodium Thiosulfate is administered as an intravenous infusion over 15 minutes. For multi-day cisplatin regimens, it is critical that the Sodium Thiosulfate infusion is completed at least 10 hours before the next cisplatin dose is scheduled to begin.[11]
• Dosing (Based on Actual Body Weight and Surface Area):
• Actual Body Weight (ABW) <5 kg: 10 g/m²
• Actual Body Weight (ABW) 5-10 kg: 15 g/m²
• Actual Body Weight (ABW) >10 kg: 20 g/m².[11]

3. Calciphylaxis (Off-Label)

While no universally standardized protocol exists, the most widely reported and empirically successful regimen involves the intravenous administration of 25 grams of Sodium Thiosulfate three times per week.[29] It is typically infused over 30 to 60 minutes, either during the last hour of a hemodialysis session or immediately following the session to leverage the drug's dialyzability for clearing mobilized calcium complexes.[28] Doses may be adjusted downward (e.g., to 12.5 grams) based on patient tolerance, particularly if side effects like nausea or metabolic acidosis occur.[30]

Administration and Monitoring

• Intravenous Administration: For all indications, Sodium Thiosulfate is administered intravenously. During infusion, especially when co-administered with sodium nitrite, the patient's blood pressure must be closely monitored, as hypotension can occur.[28]
• Monitoring for Ototoxicity Prevention: When used with cisplatin, serum electrolytes, particularly sodium and potassium, must be monitored due to the high risk of hypernatremia and hypokalemia.[3]
• Incompatibilities: A significant chemical incompatibility exists between Sodium Thiosulfate and hydroxocobalamin (another cyanide antidote). These two drugs must never be administered simultaneously through the same intravenous line.[28] No incompatibility has been reported with sodium nitrite when given sequentially through the same line.[28]

Table 4: Recommended Dosing Regimens for Key Indications

Indication	Patient Population	Dose	Route of Administration	Critical Administration Notes	Source(s)
Cyanide Poisoning	Adult	12.5 g	Slow IV injection (~10 min)	Administer immediately after sodium nitrite. May repeat with half-dose if symptoms recur.	33
	Pediatric	250 mg/kg (Max: 12.5 g)	Slow IV injection	Administer immediately after sodium nitrite. May repeat with half-dose if symptoms recur.	28
Cisplatin Ototoxicity Prevention	Pediatric (1 mo to <18 yr)	Based on Actual Body Weight (ABW): • <5 kg: 10 g/m² • 5-10 kg: 15 g/m² • >10 kg: 20 g/m²	IV infusion over 15 min	Use Pedmark®/Pedmarqsi™ only. Start exactly 6 hours after cisplatin infusion ends. Must be given ≥10 hours before next cisplatin dose.	11
Calciphylaxis (Off-Label)	Adult (typically ESRD)	12.5 - 25 g, 3 times/week	IV infusion over 30-60 min	Typically administered after or during the last hour of hemodialysis. Monitor for metabolic acidosis.	28

VI. Safety, Tolerability, and Risk Management

While Sodium Thiosulfate is generally considered to have low toxicity, its use in high doses and in specific patient populations is associated with a distinct profile of adverse effects that require careful monitoring and management.[41]

A. Adverse Drug Reactions and Side Effects

• Common Adverse Effects: The most frequently reported side effects, particularly with the high doses used in ototoxicity prevention, are gastrointestinal. Nausea and vomiting are very common.[3] Other common, generally transient effects include a salty taste in the mouth and a diffuse sensation of warmth throughout the body during infusion.[29]
• Metabolic and Electrolyte Disturbances: These are among the most clinically significant adverse effects, especially in the pediatric oncology setting.
• Hypernatremia: The drug itself is a sodium salt and delivers a substantial sodium load. Clinically significant hypernatremia (high serum sodium) occurred in 12% to 26% of patients in the pediatric trials and requires monitoring.[3]
• Hypokalemia: Low serum potassium is a common finding and may require supplementation.[3]
• Hypophosphatemia: Low serum phosphate has also been observed.[3]
• Metabolic Acidosis: This can be a serious complication, particularly in patients with pre-existing renal impairment being treated for calciphylaxis.[3]
• Serious and Less Common Adverse Effects:
• Hypotension: A drop in blood pressure can occur, which may be related to the rate of infusion. The risk is significantly higher when Sodium Thiosulfate is administered in conjunction with sodium nitrite, which is a potent vasodilator.[33]
• Hypersensitivity Reactions: Serious allergic reactions, including life-threatening anaphylaxis, have been reported. Symptoms can include hives, rash, chest tightness, difficulty breathing, and angioedema.[42]
• Thiocyanate Toxicity: In cases of overdose or in patients with severe renal impairment who cannot clear the thiocyanate metabolite, accumulation can lead to a specific toxicity syndrome. Symptoms include blurred vision, tinnitus, muscle cramps, hyperreflexia, arthralgia, and central nervous system effects like disorientation, agitation, and psychotic behavior.[41]

B. Warnings, Precautions, and Contraindications

• Contraindications: The only absolute contraindication is a history of a severe hypersensitivity reaction to Sodium Thiosulfate or any of its components.[12]
• Warnings and Precautions:
• Sulfite Sensitivity: Pharmaceutical preparations of Sodium Thiosulfate may contain trace amounts of sodium sulfite as an impurity.[38] While this does not preclude its use in sulfite-sensitive individuals, particularly in a life-threatening emergency like cyanide poisoning, caution should be exercised. Sulfite sensitivity is more prevalent in patients with a history of asthma.[38]
• Conditions Exacerbated by Sodium/Fluid Load: Due to its high sodium content, Sodium Thiosulfate should be used with caution in patients with conditions that are sensitive to fluid and sodium retention. These include hypertension, congestive heart failure, edematous states, cirrhosis of the liver, and toxemia of pregnancy, as the drug may exacerbate these conditions.[41]
• Renal Impairment: Patients with impaired renal function are at a greater risk for adverse reactions due to the decreased ability to excrete the drug and its thiocyanate metabolite. Close monitoring is essential in this population.[33]

C. Drug-Drug and Disease-State Interactions

Formal drug-drug interaction studies with Sodium Thiosulfate are limited.[35] The most clinically relevant interactions are pharmacodynamic rather than pharmacokinetic.

• Sodium Nitrite: The co-administration of sodium nitrite and Sodium Thiosulfate for cyanide poisoning presents a significant risk for additive and severe hypotension. Blood pressure must be monitored vigilantly throughout administration.[33]
• Antihypertensive Agents: While data is specific to the co-packaged cyanide antidote, there is a theoretical increased risk of hypotension when Sodium Thiosulfate is given to patients already taking antihypertensive medications, diuretics, or phosphodiesterase-5 (PDE5) inhibitors. This is primarily a concern related to the vasodilatory effects of concurrently administered nitrites.[35]
• Disease Interactions: The primary disease-state interactions relate to renal impairment, which increases the risk of accumulation and toxicity, and the sodium-retaining conditions mentioned previously.[43]

VII. Regulatory Landscape and Development History

The regulatory history of Sodium Thiosulfate is a compelling narrative of how an old, unpatented chemical can be navigated through the rigorous modern drug approval process for a novel, specific indication. This journey highlights the importance of high-quality clinical evidence and precisely controlled pharmaceutical manufacturing.

A. U.S. Food and Drug Administration (FDA) Trajectory

For decades, Sodium Thiosulfate was used medically in the U.S. primarily as part of the cyanide antidote kit, which existed in a state of being medically accepted but not formally approved under modern standards. The development of Pedmark® for ototoxicity prevention represented a completely new regulatory endeavor.

The path to approval was notably long and arduous. Fennec Pharmaceuticals initiated a rolling New Drug Application (NDA) in December 2018.[46] The application was granted Priority Review in March 2020, signaling that the FDA considered it a potential significant advance in therapy.[46] However, the company subsequently received a Complete Response Letter (CRL) in August 2020, indicating the agency's refusal to approve the application in its current form.[46] Following resubmissions, another CRL was anticipated in late 2021.[46] Finally, after a further resubmission, Pedmark® was granted FDA approval on September 20, 2022.[5] This challenging process underscores the high bar set by the FDA for manufacturing controls, purity, and clinical data, even for a known substance. The application benefited from Fast Track and Orphan Drug designations, which are intended to facilitate the development of drugs for serious conditions and rare diseases.[5]

A crucial post-approval development occurred in early 2024 when the FDA issued a safety communication explicitly warning healthcare providers that Pedmark® is not substitutable with other Sodium Thiosulfate products.[5] This warning was based on the fact that the safety and efficacy demonstrated in the pivotal pediatric trials were specific to the Pedmark® formulation. Other generic or compounded formulations, which have not been tested for this indication, may contain impurities like potassium chloride or higher levels of boric acid, posing unevaluated risks to pediatric patients undergoing repeated infusions.[5] This regulatory action firmly establishes that the "drug product" (the final formulated medicine) is distinct from the "drug substance" (the active ingredient). The safety and efficacy are tied to the entire product, including its purity and excipients, a critical lesson for modern precision medicine.

B. European Medicines Agency (EMA) Authorisation

The regulatory process in Europe followed a similar, evidence-based path. Sodium Thiosulfate, under the brand name Pedmarqsi™, was reviewed by the EMA's Committee for Medicinal Products for Human Use (CHMP). The CHMP issued a positive opinion in March 2023, recommending the drug for approval.[36] The European Commission (EC) granted the formal marketing authorisation in June 2023.[6]

The approval was granted under the Paediatric-Use Marketing Authorisation (PUMA) framework.[6] This is a specific regulatory pathway in the E.U. designed to encourage the development of medicines specifically for children by providing incentives, such as 10 years of data and market protection.[6] As with the FDA, the EMA's approval was based on the robust efficacy and safety data from the SIOPEL 6 and COG ACCL0431 clinical trials.[36] The successful approvals on both continents solidified Sodium Thiosulfate's new role as the first and only therapy authorized for preventing cisplatin-induced hearing loss in children.

VIII. Current Research and Future Directions

The recent success of Sodium Thiosulfate in pediatric oncology has spurred further research aimed at expanding its protective benefits to other patient populations and exploring new therapeutic areas.

Expanding Otoprotection Indications

• Medulloblastoma: A currently active Phase 3 clinical trial (NCT04324227) is specifically investigating the efficacy of Sodium Thiosulfate in reducing cisplatin-induced ototoxicity in children with average-risk medulloblastoma.[49] This is a critical area of research, as these patients receive intensive therapy that puts them at a very high risk for severe, life-altering hearing loss.
• Adult Head and Neck Cancer: Research is expanding into adult populations. A Phase 2 clinical trial (NCT04541355) is currently underway to evaluate the feasibility and otoprotective effect of Sodium Thiosulfate in adult patients with locally advanced squamous cell cancer of the head and neck who are being treated with high-dose cisplatin as part of their chemoradiation regimen.[51] Success in this trial could open a significant new indication for the drug.

Other Investigational Areas

Clinical trials are also exploring the use of Sodium Thiosulfate in other oncological settings. One active trial is examining its role in the context of Heated Intraperitoneal Chemotherapy (HIPEC), a procedure used to treat cancers that have spread to the lining of the abdominal cavity, such as those from ovarian or colorectal cancer.[50]

Formulation and Delivery Research

A major limitation of Sodium Thiosulfate is its lack of oral bioavailability, which necessitates intravenous administration for all systemic indications. This presents a significant barrier to its use in chronic conditions or for long-term prophylaxis. A key area for future research is therefore the development of novel formulations or prodrugs that could enable effective oral delivery. Early preclinical research into cyanide antidotes has explored orally active prodrugs of a different sulfur donor, 3-mercaptopyruvate, demonstrating that this concept is feasible.[22] Applying similar medicinal chemistry strategies to develop an orally bioavailable form of thiosulfate could dramatically expand its therapeutic potential and improve patient convenience.

IX. Concluding Analysis and Expert Recommendations

Synthesis

Sodium Thiosulfate exemplifies the remarkable therapeutic potential that can be unlocked by applying modern scientific rigor to an established chemical compound. Its journey from an industrial commodity to a targeted, life-saving, and function-preserving medicine is a testament to the power of mechanism-based drug development. The utility of this simple inorganic salt is rooted in the fundamental chemical reactivity of the thiosulfate anion, which allows it to perform distinct pharmacological roles depending on the clinical context: as a sulfur donor in enzymatic detoxification, as a direct chemical inactivator and antioxidant, and as a powerful metal-chelating and solubilizing agent.

While its role as a cyanide antidote is a long-standing pillar of emergency medicine, its recent approval for the prevention of cisplatin-induced ototoxicity represents a landmark achievement in pediatric supportive oncology. This development signals a crucial paradigm shift away from simply managing toxic side effects toward proactively preventing irreversible, life-altering harm. The success of this indication was built on a sophisticated understanding of both the pathophysiology of the toxicity and the pharmacology of the protective agent, culminating in a precisely timed administration protocol that preserves anti-tumor efficacy.

Expert Recommendations

Based on the comprehensive evidence reviewed in this report, the following recommendations are provided for clinical practice and future research:

• Clinical Practice for Ototoxicity Prevention: It is imperative that clinicians strictly adhere to the approved Pedmark®/Pedmarqsi™ formulation for the prevention of cisplatin-induced ototoxicity. As highlighted by the FDA, substitution with generic or compounded Sodium Thiosulfate products is not supported by safety or efficacy data and should be avoided. The specified dosing regimen based on body weight and the administration schedule—infusion over 15 minutes, starting exactly 6 hours after cisplatin completion—must be followed precisely to ensure both otoprotection and unimpeded anti-cancer activity. Mandatory monitoring of serum sodium and potassium is essential to manage potential electrolyte disturbances.
• Clinical Practice for Hemodialysis Patients: When using Sodium Thiosulfate off-label for calciphylaxis in patients on hemodialysis, the timing of administration relative to the dialysis session should be a deliberate clinical decision. This decision should be guided by the intended primary mechanism of action: administration just before or during dialysis may maximize the clearance of mobilized calcium, whereas administration on non-dialysis days may provide more sustained antioxidant effects.
• Future Research Priorities: The expansion of otoprotection studies into adult oncology populations, such as in head and neck cancer, is a logical and high-priority next step. Success in these trials would address a major unmet need. Furthermore, a concerted research effort should be directed toward the development of orally bioavailable formulations or prodrugs of Sodium Thiosulfate. Overcoming the challenge of its poor oral absorption would represent a transformative advance, dramatically improving its accessibility and convenience for chronic or prophylactic applications. The successful repurposing of Sodium Thiosulfate should serve as a powerful encouragement for the systematic re-evaluation of other established chemical compounds for novel, mechanistically-driven therapeutic applications.

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