PEDMARK

1 INDICATIONS AND USAGE PEDMARK is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors. 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. PEDMARK is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 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 6 hours. PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

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 6 hours after completion of cisplatin infusion. For multiday cisplatin regimens, administer PEDMARK 6 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 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 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. 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.

4 CONTRAINDICATIONS PEDMARK is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its components [see Warnings and Precautions (5.1) ] . History of severe hypersensitivity to sodium thiosulfate or any components. ( 4 )

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 1 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 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/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.

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) ] Most common adverse reactions (≥ 25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL 6 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. 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. 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

8.1 Pregnancy Risk Summary There are no available data on PEDMARK used in pregnant women to evaluate for a 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 Data In 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/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.