SODIUM THIOSULFATE: 192 Adverse Event Reports & Safety Profile

Sodium thiosulfate anhydrous is an inorganic salt with a molecular formula of Na 2 S 2 O 3 and a molecular weight of 158.11 g/mol. The structural formula is: It is a white to off-white crystalline solid that is soluble in water, but insoluble in alcohol. The aqueous solution has a pH ranging from 6.5 to 8.0. PEDMARK (sodium thiosulfate injection) is a sterile, preservative-free, clear, colorless solution in a single-dose vial for intravenous use with a pH between 7 and 9. Each vial contains the equivalent of 12.5 grams of sodium thiosulfate pentahydrate (provided as sodium thiosulfate anhydrous 8 grams) in 100 mL solution (125 mg/mL). Each mL contains the equivalent of 125 mg of sodium thiosulfate pentahydrate (provided as sodium thiosulfate anhydrous 80 mg) and 0.25 mg boric acid. Sodium hydroxide and hydrochloric acid may have been used for pH adjustment.

Chemical

Structure

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

If clinical suspicion of cyanide poisoning is high, administer Sodium Thiosulfate Injection without delay and in conjunction with appropriate airway, ventilatory, and circulatory support. ( 2.1 ) The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222. ( 2.1 ) Dosing : Age Intravenous Dose of Sodium Nitrite and Sodium Thiosulfate Adults 1.)

Sodium

Nitrite -10 mL of sodium nitrite at the rate of 2.5 to 5 mL/minute 2.)

Sodium

Thiosulfate - 50 mL of sodium thiosulfate immediately following administration of sodium nitrite.

Children

1.)

Sodium

Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m 2 BSA) of sodium nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL 2.)

Sodium

Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m 2 of BSA) not to exceed 50 mL total dose immediately following administration of sodium nitrite. Redosing : If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate. ( 2.2 ) Monitoring : Blood pressure must be monitored during treatment. ( 2.2 ) Sodium thiosulfate is chemically incompatible with hydroxocobalamin and should not be administered via the same intravenous line. (2.4)

2.1 Important Dosage and Administration Instructions If clinical suspicion of cyanide poisoning is high, administer Sodium Thiosulfate Injection without delay. Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of sodium nitrite and sodium thiosulfate should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed in order to administer sodium nitrite and sodium thiosulfate <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Identifying

Patients with Cyanide Poisoning Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to sodium nitroprusside. The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication.

Table

1.

Common

Signs and Symptoms of Cyanide Poisoning Symptoms Signs Headache Confusion Dyspnea Chest Tightness Nausea Altered Mental Status (e.g., confusion, disorientation) Seizures or Coma Mydriasis Tachypnea/Hyperpnea (early) Bradypnea/Apnea (late) Hypertension (early)/ Hypotension (late)

Cardiovascular Collapse Vomiting Plasma Lactate

Concentration ≥ 8 mmol/L In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Sodium Thiosulfate Injection, smoke-inhalation victims should be assessed for the following: Exposure to fire or smoke in an enclosed area Presence of soot around the mouth, nose, or oropharynx Altered mental status Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed in order to obtain a plasma lactate concentration. Use with Other Cyanide Antidotes The safety of administering other cyanide antidotes simultaneously with Sodium Thiosulfate Injection has not been established. If a decision is made to administer another cyanide antidote with Sodium Thiosulfate Injection, these drugs should not be administered concurrently in the same intravenous (IV) line. [see Dosage and Administration (2.2) ]

2.2 Recommended Dosing Sodium Nitrite Injection and Sodium Thiosulfate Injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium nitrite should be administered first, followed immediately by sodium thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age Intravenous

Dose of Sodium Nitrite and Sodium Thiosulfate Adults 1.)

Sodium

Nitrite -10 mL of sodium nitrite at the rate of 2.5 to 5 mL/minute 2.)

Sodium

Thiosulfate - 50 mL of sodium thiosulfate immediately following administration of sodium nitrite.

Children

1.)

Sodium

Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m 2 BSA) of sodium nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL 2.)

Sodium

Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m 2 of BSA) not to exceed 50 mL total dose immediately following administration of sodium nitrite. NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate. In adult and pediatric patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration. Visually inspect all parenteral drug products for particulate matter and discoloration prior to administration.

2.3 Recommended Monitoring Patients should be monitored for at least 24-48 hours after Sodium Thiosulfate Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, obtain hemoglobin/hematocrit when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO 2 are unreliable in the presence of methemoglobinemia.

2.4 Incompatibility Information Chemical incompatibility has been reported between Sodium Thiosulfate Injection and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between sodium thiosulfate and sodium nitrite, when administered sequentially through the same IV line as described in Dosage and Administration. Simultaneous administration of Sodium Thiosulfate Injection and blood products (whole blood, packed red cells, platelet concentrate and/or fresh frozen plasma) through the same intravenous line is not recommended. However, blood products and Sodium Thiosulfate Injection can be administered simultaneously using separate intravenous lines (preferably on contralateral extremities, if peripheral lines are being used).

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 )

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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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 &gt;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 &gt;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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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 &gt;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 &gt;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

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. PEDMARK is contraindicated in patients with a history of severe hypersensitivity to sodium thiosulfate or its components <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. Monitor patients for hypersensitivity reactions. Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . 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% <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) , Dosage and Administration (2.3) ]</span> . Withhold PEDMARK in patients with serum sodium greater than 145 mmol/L <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) , Dosage and Administration (2.4) ]</span> . 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% <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Administer antiemetics prior to each PEDMARK administration <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Provide additional antiemetics and supportive care as appropriate.

INTERACTIONS Formal drug interaction studies have not been conducted with Sodium Thiosulfate Injection.