Limitations of Use

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.

2.1 Important Dosing Information

PEDMARK is not substitutable with other sodium thiosulfate products.

Ensure serum sodium level is within normal range prior to initiating PEDMARK [see Warnings and Precautions (5.2)].

2.2 Recommended Dosage and Administration

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

Administer PEDMARK as an intravenous infusion over 15 minutes, following cisplatin infusions that are 1 to 6 hours in duration [see Indications and Usage (1)].

Infuse PEDMARK as described below to minimize the potential interference with the antitumor activity of cisplatin [see Clinical Pharmacology (12.1), Clinical Studies (14)].

• Administer PEDMARK 6 hours after completion of a cisplatin infusion.
• For multiday cisplatin regimens, administer PEDMARK 6 hours after completion of each cisplatin infusion and at least 10 hours before the next cisplatin infusion. Do not administer PEDMARK if the next cisplatin infusion is scheduled to begin in less than 10 hours [see Clinical Pharmacology (12.3), Clinical Studies (14)].

2.3 Recommended Premedications

Administer antiemetics before each PEDMARK infusion [see Warnings and Precautions (5.3)].

For patients who experience a hypersensitivity reaction, administer antihistamines and glucocorticoids (if appropriate) before each subsequent PEDMARK infusion [see Warnings and Precautions (5.1)].

2.4 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for adverse reactions are provided in Table 2.

2.5 Preparation

• Calculate the dose (grams) and determine the number of vial(s) needed.
• Visually inspect the contents of the vial for particulate matter and discoloration. Discard the vial(s) if discolored or contains visible particulates.
• Withdraw the calculated dose from the vial(s) into a syringe or transfer the calculated dose into an empty infusion bag.
• Use immediately after withdrawing into a syringe or transferring to an empty infusion bag. If not used immediately, PEDMARK can be stored in an infusion bag for no more than 18 hours at 20°C to 22°C (68°F to 72°F). Discard unused portion.

No incompatibilities have been observed between PEDMARK with infusion bags made of polyvinyl chloride, ethylene vinyl acetate, or polyolephin.

5.1 Hypersensitivity

Hypersensitivity reactions occurred in 8% to 13% of patients in clinical trials [see Adverse Reactions (6.1)].

PEDMARK is contraindicated in patients with a history of severe hypersensitivity to sodium thiosulfate or its components [see Contraindications (4)].

Monitor patients for hypersensitivity reactions. Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs [see Dosage and Administration (2.4)]. Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK [see Dosage and Administration (2.3)].

PEDMARK 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.

5.2 Hypernatremia and Hypokalemia

At the recommended dosage of PEDMARK, 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, including a single Grade 3 case. Hypokalemia occurred in 15% to 27% of patients in clinical trials, with Grade 3 or 4 occurring in 9% to 27% [see Adverse Reactions (6.1)].

Pediatric patients younger than 1 month have less well-developed sodium homeostasis compared to other pediatric patients. PEDMARK is not indicated and not recommended for use in pediatric patients younger than 1 month of age.

Monitor serum sodium and potassium levels at baseline and as clinically indicated. Do not initiate PEDMARK infusions in patients with baseline serum sodium greater than 145 mmol/L [see Clinical Pharmacology (12.2), Dosage and Administration (2.3)].

Withhold PEDMARK in patients with serum sodium greater than 145 mmol/L [see Clinical Pharmacology (12.2), Dosage and Administration (2.4)].

Monitor for signs and symptoms of hypernatremia and hypokalemia. Provide supportive care and supplementation as appropriate.

5.3 Nausea and Vomiting

Nausea occurred in 8% to 40% of patients in clinical trials, with Grade 3 or 4 in 3.8 to 8%. Vomiting occurred in 7% to 85% of patients in clinical trials, with Grade 3 or 4 in 7% to 8% [see Adverse Reactions (6.1)].

Administer antiemetics prior to each PEDMARK administration [see Dosage and Administration (2.3)]. Provide additional antiemetics and supportive care as appropriate.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience/Spontaneous Reports

The following adverse reactions have been identified from spontaneous reports based on medical literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular Disorders: hypertension, hypotension

Metabolic and Nutritional Disorders: metabolic acidosis, hypocalcemia

8.1 Pregnancy

8.2 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.

PEDMARK is administered in combination with cisplatin. Refer to cisplatin prescribing information for additional information.

8.4 Pediatric Use

The safety and effectiveness of PEDMARK have been established to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors.

The safety and effectiveness of PEDMARK have not been established in pediatric patients younger than 1 month old or in pediatric patients with metastatic cancer.

PEDMARK is not recommended in pediatric patients younger than 1 month old due to the increased risk of hypernatremia [see Warnings and Precautions (5.2)].

8.6 Renal Impairment

Sodium thiosulfate is substantially excreted by the kidney [see Clinical Pharmacology (12.3)]. No dose 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 [see Warnings and Precautions (5.2)].

12.1 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics (PK) of thiosulfate was assessed in pediatric patients. At the recommended dosage, the mean (±SD) maximum concentration (Cmax) was 13 ± 1.2 mM. The Cmax of thiosulfate increased proportionally to dose over the range of 4 g/m2 to 20 g/m2. No accumulation of thiosulfate is expected following administration of PEDMARK on two consecutive days.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate. In an in vitro Bacterial Reverse Mutation Assay (Ames Assay), sodium thiosulfate was not mutagenic in the absence of metabolic activation in S. typhimurium strains TA98, TA100, TA1535, TA1537, or TA1538, nor in the presence of metabolic activation in strains TA98, TA1535, TA1537, or TA1538 or E. coli strain WP2. Sodium thiosulfate at up to 1000 µM did not increase the frequency of sister chromatid exchanges in human lymphocytes in vitro.

There are no animal studies examining the effects of sodium thiosulfate on fertility.

SIOPEL 6

SIOPEL 6 (NCT00652132) was a multicenter, randomized, controlled, open-label study. Eligible patients were between 1 month and 18 years of age and were receiving cisplatin-based chemotherapy for standard-risk hepatoblastoma. Patients were randomized 1:1 to receive 6 cycles of perioperative cisplatin-based chemotherapy without (cisplatin alone arm) or with PEDMARK (PEDMARK + cisplatin arm). Patients received PEDMARK at a dose based on body weight administered intravenously over 15 minutes, beginning 6 hours after completion of each cisplatin infusion. Doses of PEDMARK were 10 g/m2 for patients weighing <5 kg; 15 g/m2 for patients weighing 5 kg to 10 kg; and 20 g/m2 for patients weighing >10 kg. Randomization was stratified by country, age (above vs below 15 months), and PRETEXT (I and II vs III). The major efficacy outcome measure was hearing loss defined as a Brock Grade ≥1; hearing was assessed using pure tone audiometry after study treatment or at an age of at least 3.5 years, whichever was later.

A total of 114 patients were randomized, 61 patients to the PEDMARK + cisplatin arm and 53 patients to the cisplatin alone arm. The median age was 1.1 years (range: 1.2 months to 8.2 years); 55% were male; 60% were White, 11% were Asian, and 1.8% were Black or African American.

The incidence of hearing loss was lower in the PEDMARK + cisplatin arm compared with the cisplatin alone arm. Efficacy results are provided in Table 5.

COG ACCL0431

COG ACCL0431 (NCT00716976) was a multicenter, randomized, controlled, open-label study. Eligible patients were between 1 and 18 years of age and were receiving a chemotherapy regimen that included a cumulative cisplatin dose of 200 mg/m2 or higher, with individual cisplatin doses to be infused over 6 hours or less. Patients were randomized 1:1 to receive cisplatin-based chemotherapy without (cisplatin alone arm) or with PEDMARK (PEDMARK + cisplatin arm). Cisplatin was administered according to each site's disease-specific treatment protocols. Patients received PEDMARK intravenously starting 6 hours after the completion of each cisplatin infusion, at a dose bioequivalent to the recommended dose. The PEDMARK infusion must have been completed at least 10 hours before the next cisplatin infusion if the treatment protocol required multiple daily doses of cisplatin. Randomization was stratified by prior cranial radiation (yes vs no); for patients without prior cranial radiation, randomization was further stratified by age (<5 years vs ≥5 years) and duration of cisplatin infusion (<2 hours vs ≥2 hours). The major efficacy outcome measure was hearing loss assessed by American Speech-Language-Hearing Association (ASHA) criteria; hearing was assessed at baseline and 4 weeks after the final course of cisplatin.

A total of 125 pediatric patients were randomized, 61 patients to the PEDMARK + cisplatin arm and 64 patients to the cisplatin alone arm. The efficacy was evaluated in patients with localized disease in the ITT population (n = 77). The median age was 8 years (range: 1 to 18); 61% were male; 62% were White, 14% were Black or African American, and 2.6% were Asian. The median Karnofsky or Lansky performance status was 90 (range: 50 to 100). Underlying diagnosis included medulloblastoma (27%), osteosarcoma (26%), germ cell tumor (23%), neuroblastoma (10%), hepatoblastoma (8%), atypical teratoid/rhabdoid tumor (2.6%), choroid plexus carcinoma (1.3%), and anaplastic astrocytoma (1.3%); 7% had prior cranial radiation.

The incidence of hearing loss was lower in the PEDMARK + cisplatin arm compared with the cisplatin alone arm. Efficacy results are provided in Table 6.

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F to 86°F).

Hypersensitivity

Inform patients and caregivers that PEDMARK can cause hypersensitivity reactions [see Warnings and Precautions (5.1)].

Hypernatremia and Hypokalemia

Inform patients and caregivers that PEDMARK can cause hypernatremia and hypokalemia, and to promptly report signs and symptoms consistent with these electrolyte abnormalities [see Warnings and Precautions (5.2)].

Nausea and Vomiting

Inform patients and caregivers that PEDMARK can cause nausea and vomiting [see Warnings and Precautions (5.3)].