CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cisplatin-induced ototoxicity is caused by irreversible damage to hair cells in the cochlea hypothesized to be due to 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 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. Serum Sodium LevelA 20 g/m2 dose delivers sodium load of 162 mmol/m2, 15 g/m2 dose delivers sodium load of 121 mmol/m2, and 10 g/m2 dose delivers sodium load of 81 mmol/m2. In SIOPEL 6, the recommended dosage resulted in an average transient increase in serum sodium levels of approximately mmol/L at hour after infusion [see Warnings and Precautions (5.2)] and levels had returned to baseline by 18 hours or 24 hours after administration. 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 g/m2 to 20 g/m2. No accumulation of thiosulfate is expected following administration of PEDMARK on two consecutive days.. DistributionSodium thiosulfate does not bind to human plasma proteins. Sodium thiosulfate is an inorganic salt and thiosulfate anions do not readily cross cell membranes. The mean volume of distribution of thiosulfate is 0.23 L/kg.. EliminationThe mean half-life (t1/2) of thiosulfate is approximately 20 minutes to 50 minutes. The mean total clearance of thiosulfate is 2.2 mL/min/kg in patients with fully developed renal function (age approximately year). Renal clearance accounts for approximately 50% of total clearance in patients with fully developed renal function.. MetabolismThiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate is metabolized through thiosulfate sulfur transferase and thiosulfate reductase to sulfite, which is oxidized to sulfate.. ExcretionAfter administration of sodium thiosulfate, approximately 50% of the administered sodium thiosulfate was excreted unchanged in urine and >95% of the dose excreted in urine occurs within the first hours after administration. Specific Populations. Patients with Renal ImpairmentThiosulfate Cmax increased approximately 25% and AUC increased approximately 2-fold in subjects on hemodialysis (GFR to mL/min/1.72 m2, estimated by the modification of diet in renal disease [MDRD] equation) compared to subjects with normal renal function (GFR >70 mL/min/1.72 m2, MDRD).. Drug Interaction Studies. In Vitro Studies. Cytochrome P450 Enzymes: Sodium thiosulfate is an inducer of CYP2B6 but not of CYP1A2 or CYP3A4. Sodium thiosulfate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at clinically relevant concentrations.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of PEDMARK in reducing the risk of cisplatin-associated ototoxicity was evaluated in two multicenter studies: SIOPEL and COG ACCL0431. SIOPEL 6SIOPEL (NCT00652132) was multicenter, randomized, controlled, open-label study. Eligible patients were between month and 18 years of age and were receiving cisplatin-based chemotherapy for standard-risk hepatoblastoma. Patients were randomized 1:1 to receive cycles of perioperative cisplatin-based chemotherapy without (cisplatin alone arm) or with PEDMARK (PEDMARK cisplatin arm). Patients received PEDMARK at dose based on body weight administered intravenously over 15 minutes, beginning 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 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 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. 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.Table 5: Efficacy Results for SIOPEL 6Patients Who Experienced Hearing LossPEDMARK Cisplatin(N 616 patients who received PEDMARK cisplatin and patients who received cisplatin alone did not have hearing assessed and were assumed to have hearing loss.)Cisplatin Alone(N 53)Yes, (%)24 (39)36 (68)No, (%)37 (61)17 (32)Unadjusted relative risk (95% CI)0.58 (0.40, 0.83)Adjusted relative risk (95% CI)From Cochran-Mantel-Haenszel test stratified by country group, age group, and PRETEXT group 0.58 (0.41, 0.81). COG ACCL0431COG ACCL0431 (NCT00716976) was multicenter, randomized, controlled, open-label study. Eligible patients were between and 18 years of age and were receiving chemotherapy regimen that included cumulative cisplatin dose of 200 mg/m2 or higher, with individual cisplatin doses to be infused over 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 sites disease-specific treatment protocols. Patients received PEDMARK intravenously starting hours after the completion of each cisplatin infusion, at 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 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 years (range: 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.Table 6: Efficacy Results for COG ACCL0431 Patients with Localized DiseasePatients Who Experienced Hearing LossPEDMARK Cisplatin(N 398 patients who received PEDMARK cisplatin and patients who received cisplatin alone did not have hearing assessed and were assumed to have hearing loss.)Cisplatin Alone(N 38)Yes, (%)17 (44)22 (58)No, (%)22 (56)16 (42)Unadjusted relative risk (95% CI)0.75 (0.48, 1.18)Adjusted relative risk (95% CI)From Cochran-Mantel-Haenszel test stratified by prior cranial irradiation, age group, and duration of cisplatin infusion 0.84 (0.53, 1.35).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Hypersensitivity [see Warnings and Precautions (5.1)] Hypernatremia and Hypokalemia [see Warnings and Precautions (5.2)] Nausea and Vomiting [see Warnings and Precautions (5.3)] Hypersensitivity [see Warnings and Precautions (5.1)] Hypernatremia and Hypokalemia [see Warnings and Precautions (5.2)] Nausea and Vomiting [see Warnings and Precautions (5.3)] Most common adverse reactions (>= 25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL are vomiting, nausea, decreased hemoglobin, and hypernatremia. (6)Most common adverse reaction (>=25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 is hypokalemia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Fennec Pharmaceuticals, Inc. at 1-833-336-6321, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions (>= 25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL are vomiting, nausea, decreased hemoglobin, and hypernatremia. (6). Most common adverse reaction (>=25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 is hypokalemia. (6). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. SIOPEL 6The safety of PEDMARK was evaluated in SIOPEL [see Clinical Studies (14)]. Patients received cisplatin-based chemotherapy with or without PEDMARK administered at dose of 10 g/m2, 15 g/m2, or 20 g/m2 (depending on body weight) as an intravenous infusion over 15 minutes starting hours after completion of each cisplatin infusion. Patients received PEDMARK for median of cycles (range: to cycles) during median of 94 days (range: 2.1 to 5.2 months) of cisplatin-based chemotherapy.Serious adverse reactions occurred in 40% of patients who received PEDMARK in combination with cisplatin-based chemotherapy. Serious adverse reactions in >5% of patients who received PEDMARK included infection, decreased neutrophil count, and pyrexia.PEDMARK was permanently discontinued due to an adverse reaction in patient; this patient discontinued PEDMARK for Grade hypersensitivity.The most common adverse reactions (>=25% with difference between arms of >5% compared to cisplatin alone) were vomiting, nausea, decreased hemoglobin, and hypernatremia.Table summarizes the adverse reactions reported in SIOPEL 6.Table 3.Adverse Reactions (>=10%) in Patients Who Received PEDMARK and Cisplatin with Difference Between Arms of >5% Compared to Cisplatin Alone in SIOPEL Adverse ReactionPEDMARK Cisplatin(N 53)Cisplatin Alone(N 56)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Gastrointestinal disorders Vomiting858543.6 Nausea403.8305Investigations Decreased Hemoglobin34192916Metabolism and nutrition disorders Hypernatremia261.93.60 Hypokalemia1591.80 Hypophosphatemia1591.80 Hypermagnesemia11953.6General disorders Pyrexia15090. COG ACCL0431The safety of PEDMARK was evaluated in COG ACCL0431 [see Clinical Studies (14)]. Patients received cisplatin-based chemotherapy with or without PEDMARK, administered at dose that is bioequivalent to the recommended dose as an intravenous infusion over 15 minutes starting hours after completion of each cisplatin infusion. Patients who received PEDMARK were treated for median of cycles (range: to 6) during median of 15 weeks of cisplatin-based chemotherapy. Serious adverse reactions occurred in 36% of patients who received PEDMARK in combination with cisplatin-based chemotherapy. Serious adverse reactions in >5% of patients who received PEDMARK included febrile neutropenia, decreased neutrophil count, decreased platelet count, decreased white blood cell count, anemia, stomatitis, infections, decreased lymphocyte count, and increased alanine aminotransferase (ALT).PEDMARK was permanently discontinued due to an adverse reaction in patient; this patient discontinued PEDMARK for Grade hypersensitivity.The most common adverse reaction (>=25% with difference between arms of >5% compared to cisplatin alone) was hypokalemia.Table summarizes the adverse reactions reported in COG ACCL0431.Table 4.Adverse Reactions (>=10%) in Patients Who Received PEDMARK and Cisplatin with Difference Between Arms of >5% Compared to Cisplatin Alone in COG ACCL0431Adverse ReactionPEDMARK Cisplatin(N 59)Cisplatin Alone(N 64)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Metabolism and nutrition disorders Hypokalemia27272020 Hypophosphatemia20201111 Hyponatremia141266 Hypernatremia12060Gastrointestinal disorders Stomatitis141466. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular Disorders: hypertension, hypotension Metabolic and Nutritional Disorders: metabolic acidosis, hypocalcemia.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. SIOPEL 6The safety of PEDMARK was evaluated in SIOPEL [see Clinical Studies (14)]. Patients received cisplatin-based chemotherapy with or without PEDMARK administered at dose of 10 g/m2, 15 g/m2, or 20 g/m2 (depending on body weight) as an intravenous infusion over 15 minutes starting hours after completion of each cisplatin infusion. Patients received PEDMARK for median of cycles (range: to cycles) during median of 94 days (range: 2.1 to 5.2 months) of cisplatin-based chemotherapy.Serious adverse reactions occurred in 40% of patients who received PEDMARK in combination with cisplatin-based chemotherapy. Serious adverse reactions in >5% of patients who received PEDMARK included infection, decreased neutrophil count, and pyrexia.PEDMARK was permanently discontinued due to an adverse reaction in patient; this patient discontinued PEDMARK for Grade hypersensitivity.The most common adverse reactions (>=25% with difference between arms of >5% compared to cisplatin alone) were vomiting, nausea, decreased hemoglobin, and hypernatremia.Table summarizes the adverse reactions reported in SIOPEL 6.Table 3.Adverse Reactions (>=10%) in Patients Who Received PEDMARK and Cisplatin with Difference Between Arms of >5% Compared to Cisplatin Alone in SIOPEL Adverse ReactionPEDMARK Cisplatin(N 53)Cisplatin Alone(N 56)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Gastrointestinal disorders Vomiting858543.6 Nausea403.8305Investigations Decreased Hemoglobin34192916Metabolism and nutrition disorders Hypernatremia261.93.60 Hypokalemia1591.80 Hypophosphatemia1591.80 Hypermagnesemia11953.6General disorders Pyrexia15090. COG ACCL0431The safety of PEDMARK was evaluated in COG ACCL0431 [see Clinical Studies (14)]. Patients received cisplatin-based chemotherapy with or without PEDMARK, administered at dose that is bioequivalent to the recommended dose as an intravenous infusion over 15 minutes starting hours after completion of each cisplatin infusion. Patients who received PEDMARK were treated for median of cycles (range: to 6) during median of 15 weeks of cisplatin-based chemotherapy. Serious adverse reactions occurred in 36% of patients who received PEDMARK in combination with cisplatin-based chemotherapy. Serious adverse reactions in >5% of patients who received PEDMARK included febrile neutropenia, decreased neutrophil count, decreased platelet count, decreased white blood cell count, anemia, stomatitis, infections, decreased lymphocyte count, and increased alanine aminotransferase (ALT).PEDMARK was permanently discontinued due to an adverse reaction in patient; this patient discontinued PEDMARK for Grade hypersensitivity.The most common adverse reaction (>=25% with difference between arms of >5% compared to cisplatin alone) was hypokalemia.Table summarizes the adverse reactions reported in COG ACCL0431.Table 4.Adverse Reactions (>=10%) in Patients Who Received PEDMARK and Cisplatin with Difference Between Arms of >5% Compared to Cisplatin Alone in COG ACCL0431Adverse ReactionPEDMARK Cisplatin(N 59)Cisplatin Alone(N 64)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Metabolism and nutrition disorders Hypokalemia27272020 Hypophosphatemia20201111 Hyponatremia141266 Hypernatremia12060Gastrointestinal disorders Stomatitis141466.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. PEDMARK is not substitutable with other sodium thiosulfate products. (2)The recommended dose of PEDMARK is based on surface area according to actual body weight. Administer PEDMARK as an intravenous infusion over 15 minutes starting hours after completion of cisplatin infusion.For multiday cisplatin regimens, administer PEDMARK hours after each cisplatin infusion but at least 10 hours before the next cisplatin infusion.Do not start PEDMARK if less than 10 hours before starting the next cisplatin infusion (2)Actual Body WeightPEDMARK DoseLess than kg10 g/m2 to 10 kg15 g/m2 Greater than 10 kg20 g/m2 Administer PEDMARK as an intravenous infusion over 15 minutes starting hours after completion of cisplatin infusion.. For multiday cisplatin regimens, administer PEDMARK hours after each cisplatin infusion but at least 10 hours before the next cisplatin infusion.. Do not start PEDMARK if less than 10 hours before starting the next cisplatin infusion (2). 2.1Important 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)].. 2.2Recommended Dosage and Administration. The recommended dose of PEDMARK is based on surface area according to actual body weight as summarized in Table 1.Table 1. Recommended Dose for PEDMARKActual Body WeightPEDMARK DoseLess than kg10 g/m2 to 10 kg15 g/m2 Greater than 10 kg20 g/m2 Administer PEDMARK as an intravenous infusion over 15 minutes, following cisplatin infusions that are to 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 hours after completion of cisplatin infusion.For multiday cisplatin regimens, administer PEDMARK 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)]. Administer PEDMARK hours after completion of cisplatin infusion.. For multiday cisplatin regimens, administer PEDMARK 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)]. 2.3Recommended Premedications. Administer antiemetics before each PEDMARK infusion [see Warnings and Precautions (5.3)].For patients who experience hypersensitivity reaction, administer antihistamines and glucocorticoids (if appropriate) before each subsequent PEDMARK infusion [see Warnings and Precautions (5.1)]. 2.4Dosage Modifications for Adverse Reactions. The recommended dosage modifications for adverse reactions are provided in Table 2.Table 2. Recommended PEDMARK Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityDosage ModificationHypersensitivity [see Warnings and Precautions (5.1)] Grade or 4Permanently discontinue PEDMARK.Hypernatremia [see Warnings and Precautions (5.2)] >145 mmol/LWithhold PEDMARK until sodium is within normal limits. Resume at the same dose.Hypokalemia [see Warnings and Precautions (5.2)] Grade or 4Withhold PEDMARK until potassium is within normal limits. Resume at the same dose.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3Withhold until <= Grade 1.Resume at the same dose.Grade 4Permanently discontinue PEDMARK.. 2.5Preparation. 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 syringe or transfer the calculated dose into an empty infusion bag.Use immediately after withdrawing into 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 20C to 22C (68F to 72F). Discard unused portion.No incompatibilities have been observed between PEDMARK with infusion bags made of polyvinyl chloride, ethylene vinyl acetate, or polyolephin.. 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 syringe or transfer the calculated dose into an empty infusion bag.. Use immediately after withdrawing into 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 20C to 22C (68F to 72F). Discard unused portion.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PEDMARK is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients month of age and older with localized, non-metastatic solid tumors.. PEDMARK is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients month of age and older with localized, non-metastatic solid tumors. (1)Limitations of Use:The safety and efficacy of PEDMARK have not been established when administered following cisplatin infusions longer than hours.PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.. Limitations of UseThe safety and efficacy of PEDMARK have not been established when administered following cisplatin infusions longer than hours. PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

PHARMACOKINETICS SECTION.

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 g/m2 to 20 g/m2. No accumulation of thiosulfate is expected following administration of PEDMARK on two consecutive days.. DistributionSodium thiosulfate does not bind to human plasma proteins. Sodium thiosulfate is an inorganic salt and thiosulfate anions do not readily cross cell membranes. The mean volume of distribution of thiosulfate is 0.23 L/kg.. EliminationThe mean half-life (t1/2) of thiosulfate is approximately 20 minutes to 50 minutes. The mean total clearance of thiosulfate is 2.2 mL/min/kg in patients with fully developed renal function (age approximately year). Renal clearance accounts for approximately 50% of total clearance in patients with fully developed renal function.. MetabolismThiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate is metabolized through thiosulfate sulfur transferase and thiosulfate reductase to sulfite, which is oxidized to sulfate.. ExcretionAfter administration of sodium thiosulfate, approximately 50% of the administered sodium thiosulfate was excreted unchanged in urine and >95% of the dose excreted in urine occurs within the first hours after administration. Specific Populations. Patients with Renal ImpairmentThiosulfate Cmax increased approximately 25% and AUC increased approximately 2-fold in subjects on hemodialysis (GFR to mL/min/1.72 m2, estimated by the modification of diet in renal disease [MDRD] equation) compared to subjects with normal renal function (GFR >70 mL/min/1.72 m2, MDRD).. Drug Interaction Studies. In Vitro Studies. Cytochrome P450 Enzymes: Sodium thiosulfate is an inducer of CYP2B6 but not of CYP1A2 or CYP3A4. Sodium thiosulfate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at clinically relevant concentrations.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on PEDMARK used in pregnant women to evaluate for drug-associated risk. Oral or intravenous 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 (see Data ).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.. Data. Animal DataIn 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 total daily dose of 1500 mg/kg (0.38 times the highest clinical dose of 20 g/m2 based on BSA). Additionally, an intravenous pharmacokinetic study in gravid ewes indicated that sodium thiosulfate does not cross the placenta.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment: Monitor for signs and symptoms of hypernatremia and hypokalemia more closely if the glomerular filtration rate (GFR) falls below 60 mL/min/1.73m2. (5.2, 8.6). 8.1 Pregnancy. Risk SummaryThere are no available data on PEDMARK used in pregnant women to evaluate for drug-associated risk. Oral or intravenous 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 (see Data ).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.. Data. Animal DataIn 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 total daily dose of 1500 mg/kg (0.38 times the highest clinical dose of 20 g/m2 based on BSA). Additionally, an intravenous pharmacokinetic study in gravid ewes indicated that sodium thiosulfate does not cross the placenta.. 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 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 month old or in pediatric patients with metastatic cancer.PEDMARK is not recommended in pediatric patients younger than 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: Immediately discontinue PEDMARK and institute appropriate care. Administer premedications before each subsequent dose. PEDMARK may contain sodium sulfite; patients with sulfite sensitivity may have hypersensitivity reactions. (5.1)Hypernatremia and Hypokalemia: PEDMARK is not indicated for use in pediatric patients less than month of age. Monitor serum sodium and potassium at baseline and as clinically indicated. Withhold PEDMARK in patients with serum sodium greater than 145 mmol/L (5.2)Nausea and Vomiting: Administer antiemetics prior to each PEDMARK administration. (5.3). Hypersensitivity: Immediately discontinue PEDMARK and institute appropriate care. Administer premedications before each subsequent dose. PEDMARK may contain sodium sulfite; patients with sulfite sensitivity may have hypersensitivity reactions. (5.1). Hypernatremia and Hypokalemia: PEDMARK is not indicated for use in pediatric patients less than month of age. Monitor serum sodium and potassium at baseline and as clinically indicated. Withhold PEDMARK in patients with serum sodium greater than 145 mmol/L (5.2). Nausea and Vomiting: Administer antiemetics prior to each PEDMARK administration. (5.3). 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 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 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, 20 g/m2 dose delivers sodium load of 162 mmol/m2, 15 g/m2 dose delivers sodium load of 121 mmol/m2 and 10 g/m2 dose delivers sodium load of 81 mmol/m2.Hypernatremia occurred in 12% to 26% of patients in clinical trials, including single Grade case. Hypokalemia occurred in 15% to 27% of patients in clinical trials, with Grade or occurring in 9% to 27% [see Adverse Reactions (6.1)]. Pediatric patients younger than 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 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 or in 3.8 to 8%. Vomiting occurred in 7% to 85% of patients in clinical trials, with Grade or 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.