FDA Approves Sodium Thiosulfate for Cisplatin-Associated Ototoxicity in Pediatric Patients
On September 20, 2022, the U.S. Food and Drug Administration (FDA) approved (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients) the use of sodium thiosulfate (Pedmark®) to reduce the risk of ototoxicity associated with cisplatin in pediatric patients aged 1 month and older with localized, nonmetastatic solid tumors.
Sodium thiosulfate’s efficacy was evaluated in two multicenter, open-label, randomized controlled trials in pediatric patients undergoing treatment with cisplatin-based chemotherapy for cancer: SIOPEL 6 (NCT00652132) and COG ACCL0431 (NCT00716976).
SIOPEL 6 enrolled 114 patients with standard risk hepatoblastoma undergoing six cycles of perioperative cisplatin-based chemotherapy. Patients were randomized 1:1 to receive cisplatin-based chemotherapy with or without sodium thiosulfate administered at various doses of 10 g/m2, 15 g/m2, or 20 g/m2, based on body weight. The primary outcome was the percentage of patients with Brock Grade of at least 1 hearing loss, assessed using pure tone audiometry after treatment or at least 3.5 years old, whichever was later. Incidence of hearing loss was lower in the sodium thiosulfate and cisplatin arm (39%) compared with the cisplatin alone arm (68%; unadjusted relative risk = 0.58 [95% CI = 0.40, 0.83]).
COG ACCL0431 enrolled 125 patients with solid tumors undergoing a chemotherapy regimen with cumulative cisplatin doses of 200 mg/m2 or higher. Patients were randomized 1:1 to receive cisplatin-based chemotherapy with or without sodium thiosulfate. Efficacy was evaluated in a subset of 77 patients with localized, nonmetastatic solid tumors. The primary outcome was hearing loss, according to American Speech-Language-Hearing Association criteria, assessed at baseline and four weeks after the final cisplatin dose. Incidence of hearing loss was lower in the sodium thiosulfate and cisplatin arm (44%) compared with the cisplatin alone arm (58%; unadjusted relative risk = 0.75 [95% CI = 0.48, 1.18]).
The most common adverse reactions reported by at least 25% of patients in the two trials, with the difference between arms of greater than 5% compared to cisplatin alone, were vomiting, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.
The recommended sodium thiosulfate dosage is based on surface area according to actual body weight. Sodium thiosulfate is administered as an IV infusion over 15 minutes following cisplatin infusions of 1–6 hours.
The review used the Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate FDA’s assessment.
The application also was granted Orphan Drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics).
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088.
For assistance with single-patient investigational new drug applications, contact OCE’s Project Facilitate (https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).