Sodium Thiosulfate (Protectant) (Monograph)

Brand name: Pedmark
Drug class: Protective Agents
Chemical name: dioxido-oxo-sulfanylidene-lambda6-sulfane
Molecular formula: 2NA•O₃S₂•5H₂O
CAS number: 14383-50-7, 10102-17-7

Introduction

Sodium thiosulfate is an inorganic salt that decreases cytotoxicity of cisplatin to tumor cells.

Uses for Sodium Thiosulfate (Protectant)

Ototoxicity Associated with Cisplatin

Sodium thiosulfate 125 mg/mL injection (Pedmark) is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients ≥1 month of age with localized, non-metastatic solid tumors. The safety and efficacy of sodium thiosulfate have not been established when administered following cisplatin infusions longer than 6 hours.

Sodium thiosulfate may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

Efficacy of sodium thiosulfate injection in reducing the risk of cisplatin-associated ototoxicity was evaluated in 2 multicenter, randomized, controlled, open-label studies (SIOPEL 6 and COG ACCL0431) in pediatric patients 1–18 years of age who were receiving a chemotherapy regimen that included cisplatin. Sodium thiosulfate was administered as an IV infusion over 15 minutes 6 hours after completion of each cisplatin dose. In both studies, the incidence of hearing loss was significantly lower in patients who received sodium thiosulfate and cisplatin compared with those who received cisplatin alone. In the SIOPEL 6 study, hearing loss occurred in 18 of 55 children (33%) who received sodium thiosulfate compared with 29 of 46 (63%) children who did not receive the drug. In the COG ACCL0431 study, hearing loss occurred in 14 of 49 (28.6%) children who received sodium thiosulfate and in 31 of 55 (56.4%) children who did not receive the drug.

Sodium Thiosulfate (Protectant) Dosage and Administration

General

Sodium thiosulfate is available in the following dosage form(s) and strength(s):

Injection: 12.5 g/100 mL (125 mg/mL) in a single-dose vial.

Sodium thiosulfate products are not substitutable/interchangeable.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Cisplatin-associated Ototoxicity (Pedmark)

Ensure serum sodium level is within normal range prior to initiating sodium thiosulfate.

Administer sodium thiosulfate as an IV infusion over 15 minutes starting 6 hours after completion of a cisplatin infusion. For multiday cisplatin regimens, administer sodium thiosulfate 6 hours after each cisplatin infusion and at least 10 hours before the next cisplatin infusion. Do not administer sodium thiosulfate if the next cisplatin infusion is scheduled to begin in less than 10 hours.

The recommended dose of sodium thiosulfate is based on surface area according to actual body weight as summarized in Table 1.

Cautions for Sodium Thiosulfate (Protectant)

Contraindications

• History of severe hypersensitivity to sodium thiosulfate or any components of the formulation.

Warnings/Precautions

Hypersensitivity

Hypersensitivity reactions occurred in 8% to 13% of patients in clinical trials of sodium thiosulfate injection in pediatric patients with cisplatin-associated ototoxicity.

The sodium thiosulfate preparation indicated for cisplatin-associated ototoxicity (Pedmark) is contraindicated in patients with a history of severe hypersensitivity to sodium thiosulfate or its components. Monitor patients for hypersensitivity reactions. Immediately discontinue sodium thiosulfate and institute appropriate care if a hypersensitivity reaction occurs. Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of sodium thiosulfate.

Sodium thiosulfate preparations may contain sodium sulfite. Sulfite exposure can cause hypersensitivity reactions, including anaphylactic symptoms and life-threatening or severe asthma episodes, in patients with sulfite sensitivity. The overall prevalence of sulfite sensitivity in the general population is unknown; sulfite sensitivity is seen more frequently in people with asthma compared to people without asthma.

Hypernatremia and Hypokalemia

At the recommended dosage of sodium thiosulfate for cisplatin-associated ototoxicity, a 20 g/m² dose delivers a sodium load of 162 mmol/m², a 15 g/m² dose delivers a sodium load of 121 mmol/m², and a 10 g/m² dose delivers a sodium load of 81 mmol/m².

Hypernatremia occurred in 12% to 26% of patients in clinical trials evaluating sodium thiosulfate for cisplatin-associated ototoxicity, including a single grade 3 case. Hypokalemia occurred in 15% to 27% of patients in these clinical trials, with grade 3 or 4 occurring in 9% to 27% of the patients.

Pediatric patients <1 month of age have less well-developed sodium homeostasis compared to other pediatric patients. Sodium thiosulfate is not indicated and not recommended for use in pediatric patients <1 month of age for cisplatin-associated ototoxicity.

Monitor serum sodium and potassium levels at baseline and as clinically indicated. Do not initiate sodium thiosulfate infusions in patients with baseline serum sodium greater than 145 mmol/L. Withhold sodium thiosulfate in patients with serum sodium greater than 145 mmol/L. Monitor for signs and symptoms of hypernatremia and hypokalemia. Provide supportive care and supplementation as appropriate.

Nausea and Vomiting

Nausea occurred in 8% to 40% of patients in clinical trials evaluating sodium thiosulfate for cisplatin-associated ototoxicity, with grade 3 or 4 in 3.8% to 8% of the patients. Vomiting occurred in 7% to 85% of patients in these clinical trials, with grade 3 or 4 in 7% to 8% of the patients.

Administer antiemetics prior to each sodium thiosulfate administration. Provide additional antiemetics and supportive care as appropriate.

Specific Populations

Pregnancy

There are no available data on sodium thiosulfate use in pregnant women to evaluate for a drug-associated risk. Oral or IV administration of sodium thiosulfate during the period of organogenesis resulted in no signs of malformations or lethality, but at doses and exposures that were lower than those in humans.

Sodium thiosulfate (Pedmark) is administered following cisplatin infusions, which can cause embryo-fetal harm. Refer to cisplatin prescribing information for additional information.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal studies, sodium thiosulfate was not embryotoxic or teratogenic in pregnant mice, rats, hamsters, or rabbits at daily (5 to 13 daily doses during the period of organogenesis) oral maternal doses of up to 550, 400, 400, and 580 mg/kg/day (0.08 to 0.35 times the highest clinical dose of 20 g/m² based on body surface area [BSA]), respectively, of sodium thiosulfate; exposure in these animals compared to humans may be much lower due to poor oral bioavailability. Sodium thiosulfate was not embryotoxic or teratogenic in hamsters following a total daily dose of 1500 mg/kg (0.38 times the highest clinical dose of 20 g/m² based on BSA). Additionally, an IV pharmacokinetic study in gravid ewes indicated that sodium thiosulfate does not cross the placenta.

Lactation

There are no data on the presence of sodium thiosulfate in human milk or its effects on the breastfed child or on milk production.

The manufacturer states that when sodium thiosulfate is administered in combination with cisplatin to reduce the risk of ototoxicity, refer to the cisplatin prescribing information for additional information.

Pediatric Use

The safety and effectiveness of sodium thiosulfate have been established to reduce the risk of ototoxicity associated with cisplatin in pediatric patients ≥1 month of age with localized, non-metastatic solid tumors. The safety and effectiveness of sodium thiosulfate have not been established in pediatric patients <1 month of age or in pediatric patients with metastatic cancer. Sodium thiosulfate is not recommended in pediatric patients <1 month of age due to the increased risk of hypernatremia.

Renal Impairment

Sodium thiosulfate is substantially excreted by the kidney. No dosage adjustment is recommended for patients with renal impairment or end-stage renal disease. Monitor for signs and symptoms of hypernatremia and hypokalemia more closely if the GFR falls below 60 mL/min/1.73 m².

Common Adverse Effects

Most common adverse reactions are vomiting, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments.

Actions

Mechanism of Action

Cisplatin-induced ototoxicity is caused by irreversible damage to hair cells in the cochlea hypothesized to be due to a combination of reactive oxygen species (ROS) production and direct alkylation of DNA leading to cell death. Sodium thiosulfate interacts directly with cisplatin to produce an inactive platinum species. In addition, sodium thiosulfate can enter cells through the sodium sulfate cotransporter 2 and cause intracellular effects such as the increase in antioxidant glutathione levels and inhibition of intracellular oxidative stress. Both activities may contribute to the ability of sodium thiosulfate to reduce the risk of ototoxicity.

Concurrent incubation of sodium thiosulfate with cisplatin decreased the in vitro cytotoxicity of cisplatin to tumor cells; delaying the addition of sodium thiosulfate to these cultures prevented the protective effect.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (patient information).

• Inform patients and caregivers that sodium thiosulfate can cause hypersensitivity reactions.

• Inform patients and caregivers that sodium thiosulfate can cause hypernatremia and hypokalemia, and to promptly report signs and symptoms consistent with these electrolyte abnormalities

• Inform patients and caregivers that sodium thiosulfate can cause nausea and vomiting.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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