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warnings and cautions
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