Pedmark Drug Information
Generic name: SODIUM THIOSULFATE
Uses of 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. 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.
Dosage & Administration of Pedmark
| Less than 5 kg | 10 g/m2 |
|---|---|
| 5 to 10 kg | 15 g/m2 |
| Greater than 10 kg | 20 g/m2 |
Side Effects of Pedmark
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. 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
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
General disorders Pyrexia 15 0 9 0
COG ACCL0431 The safety of PEDMARK was evaluated in COG ACCL0431. 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
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
Warnings & Cautions for Pedmark
Hypersensitivity Hypersensitivity reactions occurred in 8% to 13% of patients in clinical
trials. PEDMARK is contraindicated in patients with a history of severe hypersensitivity to sodium thiosulfate or its components. Monitor patients for hypersensitivity reactions.
Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs . Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK . 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.
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%. 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 . Withhold PEDMARK in patients with serum sodium greater than 145 mmol/L . Monitor for signs and symptoms of hypernatremia and hypokalemia. Provide supportive care and supplementation as appropriate.
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%. Administer antiemetics prior to each PEDMARK administration . Provide additional antiemetics and supportive care as appropriate.
Pregnancy Safety for Pedmark
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 ), 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.
Pediatric Use of Pedmark
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 .
Contraindications for Pedmark
is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its components . History of severe hypersensitivity to sodium thiosulfate or any components.
Clinical Studies of Pedmark
The efficacy of PEDMARK in reducing the risk of cisplatin-associated ototoxicity was evaluated in two multicenter studies: SIOPEL 6 and COG ACCL0431. SIOPEL 6 SIOPEL 6 (NCT00652132) was a multicenter, randomized, controlled, open-label study. Eligible patients were between 1 month and 18 years of age and were receiving cisplatin-based chemotherapy for standard-risk hepatoblastoma. Patients were randomized 1:1 to receive 6 cycles of perioperative cisplatin-based chemotherapy without (cisplatin alone arm) or with PEDMARK (PEDMARK + cisplatin arm). Patients received PEDMARK at a dose based on body weight administered intravenously over 15 minutes, beginning 6 hours after completion of each cisplatin infusion.
Doses of PEDMARK were 10 g/m 2 for patients weighing <5 kg; 15 g/m 2 for patients weighing 5 kg to 10 kg; and 20 g/m 2 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 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 36 No, n (%) 37 17 Unadjusted relative risk (95% CI) 0.58 Adjusted relative risk (95% CI) From Cochran-Mantel-Haenszel test stratified by country group, age group, and PRETEXT group 0.58 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 22 No, n (%) 22 16 Unadjusted relative risk (95% CI) 0.75 Adjusted relative risk (95% CI) From Cochran-Mantel-Haenszel test stratified by prior cranial irradiation, age group, and duration of cisplatin infusion 0.84
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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