The Food and Drug Administration (FDA) has approved Pedmark® (sodium thiosulfate) to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, nonmetastatic solid tumors.
Cisplatin-induced ototoxicity is caused by irreversible damage to hair cells in the cochlea believed to be due to a combination of reactive oxygen species production and direct alkylation of DNA leading to cell death. Sodium thiosulfate interacts directly with cisplatin to produce an inactive platinum species. Intracellular effects produced by sodium thiosulfate such as an increase in antioxidant glutathione levels and inhibition of intracellular oxidative stress may also contribute to the reduction in ototoxicity.
The approval was based on data from 2 multicenter, randomized, controlled, open-label phase 3 trials, SIOPEL 6 (ClinicalTrials.gov Identifier: NCT00652132) and COG ACCL0431 (ClinicalTrials.gov Identifier: NCT00716976), which evaluated the efficacy of sodium thiosulfate in the prevention of cisplatin-induced hearing loss in pediatric patients receiving cisplatin-based chemotherapy. SIOPEL 6 enrolled 114 patients 1 month to 18 years of age with standard risk hepatoblastoma. COG ACCL0431 included 125 patients 1 to 18 years of age with solid tumors.
Results from SIOPEL 6 showed that the incidence of hearing loss of Brock Grade 1 or greater was significantly lower in the sodium thiosulfate plus cisplatin arm (39%; n=24/61) vs the cisplatin alone arm (68%; n=36/53), indicating a 42% lower incidence of hearing loss in the sodium thiosulfate group (unadjusted relative risk [RR] 0.58; 95% CI, 0.40-0.83). Hearing was assessed using pure tone audiometry after study treatment or at an age of at least 3.5 years, whichever was later.
Among 77 evaluable patients in the COG ACCL0431 trial, the incidence of hearing loss was significantly lower in the sodium thiosulfate plus cisplatin arm (44%; n=17/39) vs the cisplatin alone arm (58%; n=22/38), indicating a 25% lower incidence of hearing loss in the sodium thiosulfate group (unadjusted RR 0.75; 95% CI, 0.48-1.18).
As for safety, the most common adverse reactions reported in SIOPEL 6 were vomiting, nausea, decreased hemoglobin, and hypernatremia; in COG ACCL0431, it was hypokalemia.
The safety and efficacy of Pedmark have not been established when administered following cisplatin infusions longer than 6 hours. Pedmark may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.
“Historically, there have been no approved treatments for preventing cisplatin-induced hearing loss,” said David R. Freyer, DO, MS, Primary Investigator, COG ACCL0431, and Director of the Survivorship & Supportive Care Program, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles. “As a physician focused in pediatric cancer for many years, and a primary investigator in the pivotal Pedmark phase 3 Clinical Oncology Group (COG) trial, the FDA approval of Pedmark addresses an enormous unmet need and for many children and young adults, has the potential to greatly improve everyday activities for these patients.”
Pedmark is supplied as a single-dose vial containing 12.5 grams of sodium thiosulfate pentahydrate in 100mL solution (125mg/mL). It is not substitutable with other sodium thiosulfate products.
- FDA approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, non-metastatic solid tumors. News release. US Food and Drug Administration. Accessed September 21, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients
- Fennec Pharmaceuticals announces FDA approval of Pedmark® (sodium thiosulfate injection). News release. Fennec Pharmaceuticals, Inc. Accessed September 21, 2022. https://www.globenewswire.com/news-release/2022/09/21/2520026/0/en/Fennec-Pharmaceuticals-Announces-FDA-Approval-of-PEDMARK-Sodium-Thiosulfate-Injection.html
- Pedmark. Package insert. Fennec Pharmaceuticals, Inc.; 2022. Accessed September 20, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212937s000lbl.pdf