4.1. Therapeutic indications

Pedmarqsi is indicated for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to < 18 years of age with localised, non-metastatic, solid tumours.

4.2. Posology and method of administration

Pedmarqsi is intended for hospital use only, under the supervision of an appropriately qualified physician.

Posology

The recommended dose of sodium thiosulfate for the prevention of cisplatin-induced ototoxicity is weight based and normalised to body surface area according to the table below:

Table 1. Recommended dose of sodium thiosulfate for intravenous infusion

Body Weight

Dose

Volume

> 10 kg

12.8 g/m2

160 mL/m2

5 to 10 kg

9.6 g/m2

120 mL/m2

< 5 kg

6.4 g/m2

80 mL/m2

Sodium thiosulfate should be administered as a 15-minute intravenous infusion, 6 hours after the completion of each cisplatin administration, when cisplatin is infused for no longer than 6 hours (see Method of administration).

Pre-treatment with antiemetics is recommended to reduce the incidence of nausea and vomiting (see section 4.4).

Special populations

Preterm and term newborn infants from birth to less than 1 month of age

Sodium thiosulfate is contraindicated in preterm and term newborn infants from birth to less than 1 month of age (see sections 4.3 and 4.4).

Renal impairment

No dose adjustment is recommended for patients with renal impairment (see section 5.2). Due to the sodium content of sodium thiosulfate, there is an increased risk of adverse reactions in patients with renal impairment (see section 4.4).

Hepatic impairment

No dose adjustment is recommended for patients with hepatic impairment (see section 5.2).

Method of administration

For intravenous use.

Due to the hypertonic formulation, administration through a central vein is recommended.

Sodium thiosulfate is administered as a 15-minute infusion.

Each vial is for single use only.

Time of administration in relation to cisplatin

The timing of sodium thiosulfate administration relative to cisplatin chemotherapy is critical.

If sodium thiosulfate is administered:

• Less than 6 hours after end of cisplatin infusion: may reduce cisplatin efficacy against the tumour

• More than 6 hours after end of cisplatin infusion: may not be effective in preventing ototoxicity

Only use sodium thiosulfate following cisplatin infusion duration of 6 hours or less.

Do not use sodium thiosulfate if:

• Cisplatin infusion exceeds 6 hours, or

• A subsequent cisplatin infusion is planned within 6 hours

When cisplatin is administered on consecutive days, ensure a minimum 6-hour gap after sodium thiosulfate infusion before a subsequent cisplatin infusion is given.

After end of cisplatin infusion:

• Provide highly effective multi-agent intravenous antiemetic therapy 30 minutes prior to administration of sodium thiosulfate i.e. 5.5 hours after completion of cisplatin infusion (see section 4.4)

• This medicinal product is a ready to use solution for infusion

• Inspect visually the content of the vial(s) for particulate matter and discoloration prior to administration

• Prepare the required dose of sodium thiosulfate, from the vial(s), in a syringe or add to an empty, sterile infusion bag

• Stop cisplatin hydration fluid and flush line with 0.9% sodium chloride

• Infuse sodium thiosulfate over 15 minutes (6 hours after completion of cisplatin infusion)

• Flush line with 0.9% sodium chloride and restart the cisplatin hydration immediately afterwards

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Neonates under the age of 1 month due to the risk of hypernatremia (see section 4.4).

4.4. Special warnings and precautions for use

Hypersensitivity

Hypersensitivity reactions were reported in clinical studies following the administration of sodium thiosulfate (see section 4.8). Symptoms included rash, tachycardia, chills and dyspnoea.

Sodium thiosulfate may contain a trace amount of sodium sulfite. It may rarely cause several hypersensitivity reactions and bronchospasm. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

Antihistamines (e.g. diphenhydramine) and steroids should be immediately available to administer in the event of an allergic reaction, as clinically indicated.

If the hypersensitivity reaction is such that the patient is to continue with sodium thiosulfate after the next cisplatin administration, premedication with antihistamines and steroids should be given and the patient observed carefully.

Electrolyte imbalance

A 12.8 g/m2 dose delivers a sodium load of 162 mmol/m2, a 9.6 g/m2 dose delivers a sodium load of 121 mmol/m2 and a 6.4 g/m2 dose delivers a sodium load of 81 mmol/m2. Electrolyte balance and blood pressure should be monitored carefully, and sodium thiosulfate should not be given if serum sodium is > 145 mmol/litre at baseline before sodium thiosulfate is administered within a treatment cycle.

Patients < 1 month of age have less well-developed sodium homeostasis; therefore, sodium thiosulfate is contraindicated in neonates (see section 4.3).

Serum magnesium, potassium and phosphate levels should also be monitored, and supplementation given if needed as the combination of fluid loading in association with cisplatin-based chemotherapy and the administration of sodium thiosulfate may cause transient electrolyte disturbance.

Nausea and vomiting

Transient increases in incidence and severity of nausea and vomiting may be observed with sodium thiosulfate infusion, due to the high sodium levels administered over a short time period (see section 4.8). In addition to any prophylactic antiemetics administered prior to cisplatin administration, additional multi-agent antiemetics should be given in the 30 minutes prior to sodium thiosulfate administration. Nausea and vomiting tend to stop soon after the sodium thiosulfate infusion has finished.

Renal impairment

Sodium thiosulfate is known to be substantially excreted by the kidney (see section 5.2), and the risk of adverse reactions of sodium thiosulfate may be greater in patients with impaired renal function. Because cisplatin chemotherapy is associated with renal toxicity, renal function should be monitored and caution applied with close monitoring of electrolytes if the glomerular filtration rate (GFR) falls below 60 mL/min/1.73 m2.

Excipients with known effect

This medicinal product contains 0.25 mg/mL boric acid as a buffer. Boric acid can affect fertility when chronically administered at doses greater than 0.2 mg/kg/day. This medicinal product is administered between 6-30 times intermittently over a 6-month period in conjunction with cisplatin chemotherapy. Along with boric acid from drinking water, this amounts to 0.17-0.22 mg/kg/day depending on the age and size of the child.

This medicinal product contains 23 mg sodium per mL, equivalent to 1.15% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This is also equivalent to 1.15-2.1% of the European Food Safety Authority (EFSA) safe daily intake of 1.1-2 g sodium for children aged 1 to 17 years and equivalent to 11.5% of the EFSA safe daily intake of 0.2 g in babies aged 7 to 11 months. This has to be taken into consideration for patients on a controlled sodium diet.

4.5. Interaction with other medicinal products and other forms of interaction

Sodium thiosulfate should only be given at least 6 hours after the end of cisplatin infusion. Sodium thiosulfate should not be given when cisplatin is infused for longer than 6 hours or if a subsequent cisplatin infusion is planned within 6 hours (see section 4.2). The delayed administration prevents potential interference with cisplatin chemotherapy efficacy against the tumour.

No other drug interaction studies have been performed. Relevant pharmacokinetic interactions are unlikely as administration of sodium thiosulfate is infrequent, only in conjunction with cisplatin and sodium thiosulfate is rapidly eliminated within hours after administration. Sodium thiosulfate potentially induces CYP2B6 (see section 5.2).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of sodium thiosulfate in pregnant women. Animal studies are insufficient with respect to reproductive toxicity with intravenous infusion of sodium thiosulfate (see section 5.3). As a precautionary measure, it is preferable to avoid the use of sodium thiosulfate during pregnancy.

Sodium thiosulfate is only intended to be administered in conjunction with cisplatin chemotherapy. Cisplatin is not used during pregnancy unless the clinician considers the risk in an individual patient to be clinically justified. Patients receiving cisplatin are warned of the need to use appropriate contraception during treatment and for 6 months following cisplatin treatment, as cisplatin is embryotoxic and fetotoxic.

Breast-feeding

It is unknown whether sodium thiosulfate/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. As a precautionary measure, it is preferable to avoid the use of sodium thiosulfate during breast-feeding.

Sodium thiosulfate is only intended to be administered in conjunction with cisplatin chemotherapy, during which breastfeeding is contraindicated in female patients.

Fertility

There are no clinical data available on the effects of sodium thiosulfate on fertility. There is insufficient information from animal studies to assess the effects of intravenous infusion of sodium thiosulfate on fertility.

Sodium thiosulfate is only intended to be administered in conjunction with cisplatin chemotherapy. Cisplatin treatment is known to adversely affect fertility.

This medicinal product contains 0.25 mg/mL boric acid which can affect fertility when chronically administered at doses greater than 0.2 mg/kg/day (see section 4.4).

4.7. Effects on ability to drive and use machines

Sodium thiosulfate has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with a frequency of ≥ 1 case per 10 patients are vomiting (44%), nausea (23%), hypokalaemia (21%), hypernatraemia (19%), hypophosphataemia (18%) and hypersensitivity (11%).

One serious case of hypersensitivity, leading to discontinuation, was observed in one of the clinical studies (SIOPEL 6 treatment arm).

Tabulated list of adverse reactions

Table 2 presented below is according to the MedDRA system organ classification (SOC), Preferred Term (PT) level and frequency. Frequencies have been evaluated according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse reactions from clinical studies

System organ class

Undesirable effect

Frequency

Immune system disorders

Hypersensitivity

Very common (11%)

Metabolism and nutrition disorders

Hypokalaemia

Very common (21%)

Hypernatraemia

Very common (19%)

Hypophosphataemia

Very common (18%)

Metabolic acidosis

Common (3%)

Hypocalcaemia

Common (7%)

Vascular disorders

Hypertension

Common (2%)

Hypotension

Common (2%)

Gastrointestinal disorders

Vomiting

Very common (44%)

Nausea

Very common (23%)

Description of selected adverse reactions

Nausea and vomiting

Administration of sodium thiosulfate is associated with a high incidence of nausea and vomiting. This nausea and vomiting tends to stop soon after the sodium thiosulfate infusion has finished (see section 4.4).

Hypernatraemia

A 12.8 g/m2 dose delivers a sodium load of 162 mmol/m2, a 9.6 g/m2 dose delivers a sodium load of 121 mmol/m2 and a 6.4 g/m2 dose delivers a sodium load of 81 mmol/m2. In clinical studies doses of sodium thiosulfate equivalent to these resulted in a small, transient increase in serum sodium levels, independent of age, body surface area, body weight, total daily sodium thiosulfate dose or cisplatin cycle. Sodium levels return to baseline by 18 hours or 24 hours after administration.

Electrolyte imbalance

Hypophosphataemia and hypokalaemia are very common following sodium thiosulfate treatment. Electrolyte balance and blood pressure should be monitored carefully (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Excessive doses of sodium thiosulfate may be expected to produce severe nausea and vomiting as well as electrolyte imbalance, changes to blood pressure and acidosis. Treatment of an overdose should consist of general supportive measures including administration of fluids and observation of the clinical status of the patient. There is no specific antidote for overdose with sodium thiosulfate.