Pedmark Drug Information
Generic name: SODIUM THIOSULFATE
Uses of Pedmark
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
Important Dosing Information PEDMARK is not substitutable with other sodium thiosulfate products. Ensure serum sodium level is within normal range prior to initiating PEDMARK.
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 Administer PEDMARK as an intravenous infusion over 15 minutes, following cisplatin infusions that are 1 to 6 hours in duration.
Infuse PEDMARK as described below to minimize the potential interference with the antitumor activity of cisplatin. Administer PEDMARK 6 hours after completion of a cisplatin infusion. Do not administer PEDMARK if the next cisplatin infusion is scheduled to begin in less than 10 hours.
Recommended Premedications
Administer antiemetics before each PEDMARK infusion. For patients who experience a hypersensitivity reaction, administer antihistamines and glucocorticoids (if appropriate) before each subsequent PEDMARK infusion.
Dosage Modifications for Adverse Reactions
The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2. Recommended PEDMARK
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.
| 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 |
| 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 |
| 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. |
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, 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.
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 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. 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).
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.
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
| 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 |
| 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 |
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. Hypernatremia occurred in 12% to 26% of patients in clinical trials, including a single Grade 3 case. 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.
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 Vomiting occurred in 7% to 85% of patients in clinical trials, with Grade. 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 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 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.
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
PEDMARK is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its 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. 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 incidence of hearing loss was lower in the PEDMARK + cisplatin arm compared with the cisplatin alone arm.
Efficacy results are provided in Table 5. 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 Karnofsky or Lansky performance status was 90 (range: 50 to 100).
Efficacy results are provided in Table 6. Table 6: Efficacy Results for COG ACCL0431 – Patients with Localized Disease 0.84
| 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) | |
| 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) | |
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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