ark 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/m 2 dose delivers a sodium load of 162 mmol/m 2 , a 15 g/m 2 dose delivers a sodium load of 121 mmol/m 2 and a 10 g/m 2 dose delivers a sodium load of 81 mmol/m 2 . 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.

weight as summarized in table 1. table 1. recommended dose for pedmark actual body weight pedmark dose less than 5 kg 10 g/m 2 5 to 10 kg 15 g/m 2 greater than 10 kg 20 g/m 2 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. table 2. recommended pedmark dosage modifications for adverse reactions adverse reaction severity dosage modification hypersensitivity [see warnings and precautions (5.1) ] grade 3 or 4 permanently discontinue pedmark. hypernatremia [see warnings and precautions (5.2) ] >145 mmol/l withhold pedmark until sodium is within normal limits. resume at the same dose. hypokalemia [see warnings and precautions (5.2) ] grade 3 or 4 withhold pedmark until potassium is within normal limits. resume at the same dose. other adverse reactions [see adverse reactions (6.1) ] grade 3 withhold until ≤ grade 1. resume at the same dose. grade 4 permanently discontinue pedmark. 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.

of another drug and may not reflect the rates observed in practice. siopel 6 the safety of pedmark was evaluated in siopel 6 [see clinical studies (14) ]. patients received cisplatin-based chemotherapy with or without pedmark administered at a dose of 10 g/m 2 , 15 g/m 2 , or 20 g/m 2 (depending on body weight) as an intravenous infusion over 15 minutes starting 6 hours after completion of each cisplatin infusion. patients received pedmark for a median of 6 cycles (range: 2 to 8 cycles) during a 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 1 patient; this patient discontinued pedmark for grade 2 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 3 summarizes the adverse reactions reported in siopel 6. table 3. adverse reactions (≥10%) in patients who received pedmark and cisplatin with a difference between arms of >5% compared to cisplatin alone in siopel 6 adverse reaction pedmark + cisplatin (n = 53) cisplatin alone (n = 56) all grades (%) grade 3 or 4 (%) all grades (%) grade 3 or 4 (%) gastrointestinal disorders vomiting 85 8 54 3.6 nausea 40 3.8 30 5 investigations decreased hemoglobin 34 19 29 16 metabolism and nutrition disorders hypernatremia 26 1.9 3.6 0 hypokalemia 15 9 1.8 0 hypophosphatemia 15 9 1.8 0 hypermagnesemia 11 9 5 3.6 general disorders pyrexia 15 0 9 0 cog accl0431 the safety of pedmark was evaluated in cog accl0431 [see clinical studies (14) ]. patients received cisplatin-based chemotherapy with or without pedmark, administered at a dose that is bioequivalent to the recommended dose as an intravenous infusion over 15 minutes starting 6 hours after completion of each cisplatin infusion. patients who received pedmark were treated for a median of 3 cycles (range: 1 to 6) during a 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 1 patient; this patient discontinued pedmark for grade 2 hypersensitivity. the most common adverse reaction (≥25% with difference between arms of >5% compared to cisplatin alone) was hypokalemia. table 4 summarizes the adverse reactions reported in cog accl0431. table 4. adverse reactions (≥10%) in patients who received pedmark and cisplatin with a difference between arms of >5% compared to cisplatin alone in cog accl0431 adverse reaction pedmark + cisplatin (n = 59) cisplatin alone (n = 64) all grades (%) grade 3 or 4 (%) all grades (%) grade 3 or 4 (%) metabolism and nutrition disorders hypokalemia 27 27 20 20 hypophosphatemia 20 20 11 11 hyponatremia 14 12 6 6 hypernatremia 12 0 6 0 gastrointestinal disorders stomatitis 14 14 6 6 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

gnant 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/m 2 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/m 2 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 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 m 2 [see warnings and precautions (5.2) ] .

of 20 g/m 2 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/m 2 based on bsa). additionally, an intravenous pharmacokinetic study in gravid ewes indicated that sodium thiosulfate does not cross the placenta.

d of 162 mmol/m 2 , a 15 g/m 2 dose delivers a sodium load of 121 mmol/m 2 , and a 10 g/m 2 dose delivers a sodium load of 81 mmol/m 2 . in siopel 6, the recommended dosage resulted in an average transient increase in serum sodium levels of approximately 6 mmol/l at 1 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 (c max ) was 13 ± 1.2 mm. the c max of thiosulfate increased proportionally to dose over the range of 4 g/m 2 to 20 g/m 2 . no accumulation of thiosulfate is expected following administration of pedmark on two consecutive days. distribution sodium 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. elimination the mean half-life (t 1/2 ) 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 1 year). renal clearance accounts for approximately 50% of total clearance in patients with fully developed renal function. metabolism thiosulfate 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. excretion after 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 4 hours after administration. specific populations patients with renal impairment thiosulfate c max increased approximately 25% and auc increased approximately 2-fold in subjects on hemodialysis (gfr 0 to 6 ml/min/1.72 m 2 , estimated by the modification of diet in renal disease [mdrd] equation) compared to subjects with normal renal function (gfr >70 ml/min/1.72 m 2 , 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.

s 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. excretion after 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 4 hours after administration. specific populations patients with renal impairment thiosulfate c max increased approximately 25% and auc increased approximately 2-fold in subjects on hemodialysis (gfr 0 to 6 ml/min/1.72 m 2 , estimated by the modification of diet in renal disease [mdrd] equation) compared to subjects with normal renal function (gfr >70 ml/min/1.72 m 2 , 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.

fficacy 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. table 5: efficacy results for siopel 6 patients who experienced hearing loss pedmark + cisplatin (n = 61 6 patients who received pedmark + cisplatin and 7 patients who received cisplatin alone did not have hearing assessed and were assumed to have hearing loss. ) cisplatin alone (n = 53 ) yes, n (%) 24 (39) 36 (68) no, n (%) 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 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/m 2 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. table 6: efficacy results for cog accl0431 – patients with localized disease patients who experienced hearing loss pedmark + cisplatin (n = 39 8 patients who received pedmark + cisplatin and 5 patients who received cisplatin alone did not have hearing assessed and were assumed to have hearing loss. ) cisplatin alone (n = 38 ) yes, n (%) 17 (44) 22 (58) no, n (%) 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)