Pedmarqsi 80 mg/mL solution for infusion

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.

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:

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.

For single use only.

Sodium thiosulfate is administered as a 15-minute infusion.

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

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

• Prepare the required mL of sodium thiosulfate, 80 mg/mL, in a syringe or add to an empty, sterile infusion bag

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

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

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

CIS = cisplatin

• 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).

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. If the reaction is such that the patient is to continue with sodium thiosulfate after the next cisplatin administration, premedication with antihistamines 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.

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 interaction studies have been performed. Relevant pharmacokinetic interactions are unlikely as administration of thiosulfate is infrequent, only in conjunction with cisplatin and thiosulfate is rapidly eliminated within hours after administration. Sodium thiosulfate potentially induces CYP2B6 (see section 5.2).

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).

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

Summary of the safety profile

The most serious adverse reaction is hypersensitivity, observed at a frequency of ≥ 1 case per 10 patients (11%) (see section 4.4).

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

Tabulated list of adverse reactions

Table 1 presented below is according to the MedDRA system organ classification (SOC and Preferred Term 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.

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.

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.

Pharmacotherapeutic group: Antidotes, ATC code: V03AB06

Mechanism of action

The mechanism of sodium thiosulfate protection against ototoxicity is not fully understood, but may include increasing levels of endogenous antioxidants, inhibition of intracellular oxidative stress, and direct interaction between cisplatin and the thiol group in sodium thiosulfate to produce inactive platinum species.

Concurrent incubation of sodium thiosulfate with cisplatin decreased the in vitro cytotoxicity of cisplatin to tumour cells; delaying the addition of sodium thiosulfate to these cultures prevented the protective effect.

Pharmacodynamic effects

The is no clinical pharmacodynamic information available beyond that given within the mechanism of action section.

Clinical efficacy and safety

The efficacy of sodium thiosulfate (STS) in preventing cisplatin (CIS)-induced ototoxicity was studied in two multicentre studies in which 112 paediatric patients with various solid tumour types were treated with STS following each administration of CIS. Safety has been established using 1 to 5 doses of sodium thiosulfate per chemotherapy cycle, with regimens varying from 1 dose of CIS+STS per cycle to 5 doses of CIS+STS per cycle.

Study 1 – pivotal study

Study 1 was a multicentre, randomised, controlled, open-label study to assess the efficacy and safety of STS in reducing ototoxicity in children receiving CIS chemotherapy for standard risk hepatoblastoma (SR-HB). Children between 1 month and 18 years of age with histologically confirmed newly diagnosed HB were eligible. Children were randomised 1:1 to receive STS after each CIS dose (CIS+STS arm) or to receive CIS alone.

CIS was administered as a 6-hour intravenous infusion. Four courses of CIS were given pre-surgery and 2 additional courses were given post-surgery.

In the CIS+STS arm, the STS intravenous infusion was administered over 15 minutes, beginning 6 hours after completion of each CIS infusion. Doses of STS were dependent on the child's weight as follows: children > 10 kg received an equivalent of 12.8 g/m² STS, children ≥ 5 to ≤ 10 kg received an equivalent of 9.6 g/m² STS, and children < 5 kg received an equivalent of 6.4 g/m² STS.

A total of 129 children were registered and 114 children were randomised in the study (61 patients in the CIS+STS arm and 53 patients in the CIS Alone arm). Of the 114 patients randomised, 5 patients withdrew prior to treatment: 2 patients due to withdrawal of parental consent, 2 patients due to reclassification as high risk HB, and 1 due to ineligibility.

Hearing loss was defined as a Brock Grade ≥ 1 measured using audiologic evaluations after the end of study treatment or at an age of at least 3.5 years when a reliable result could be obtained, whichever was later. The proportion of children in the CIS+STS arm with hearing loss at age ≥ 3.5 years (20 children [35.1%]) was approximately one half compared with the CIS Alone arm (35 children [67.3%] (Table 2). Event free survival and OS were also evaluated.

The risk of having hearing loss was statistically significantly lower in the CIS+STS arm compared with the CIS Alone arm, corresponding to a clinically meaningful 48% lower risk after STS treatment.

At a median of 4.27 years of follow up, the hazard ratio between the treatment arms in Event-free survival (EFS) was ([CIS+STS vs CIS Alone]: 0.96; 95% CI: 0.42, 2.23) and in overall survival (OS) (hazard ratio: 0.48; 95% CI: 0.09, 2.61).

Study 2 – supportive study

Study 2 was a multicentre, randomised, controlled, open label study to assess the efficacy and safety of STS in preventing hearing loss in children receiving CIS chemotherapy for the treatment of newly diagnosed germ cell tumour (25.6%), hepatoblastoma (5.6%), medulloblastoma (20.8%), neuroblastoma (20.8%), osteosarcoma (23.2%), atypical teratoid/rhabdoid tumour (1.6%), choroid plexus carcinoma (0.8%), and anaplastic astrocytoma (0.8%); or any other malignancy treated with CIS; 7.5% had prior cranial radiation. Children between 1 year and 18 years of age and scheduled to receive a chemotherapy regimen that included a cumulative CIS dose of ≥ 200 mg/m², with individual CIS doses to be infused over ≤ 6 hours, were eligible. Children were randomised 1:1 to receive either STS 6 hours after each CIS dose (CIS+STS) or chemotherapy that included CIS, without subsequent STS (CIS Alone).

CIS was administered according to the sites' disease-specific cancer treatment protocols in use at the time. When multiple daily doses of CIS were scheduled, the protocol stipulated at least a 10-hour delay between any STS infusion and the beginning of the next day's CIS infusion.

In the CIS+STS arm, 10.2 g/m² STS was administered by intravenous infusion over 15 minutes, beginning 6 hours after the completion of each CIS infusion. A dose reduction was included for children whose therapeutic protocol administered CIS on a per kg basis due to young age or low body weight, which was 341 mg/kg STS.

The primary endpoint was the proportional incidence of hearing loss between the CIS+STS arm and the CIS alone arm, as defined by comparison of American Speech-language-Hearing Association (ASHA) criteria assessed at baseline and 4-weeks after the final course of cisplatin. EFS, i.e. presence or absence of tumour progression or recurrence or development of subsequent malignant neoplasm, and OS were also evaluated.

A total of 131 children were registered and 125 children were randomised in the study (61 patients in the CIS+STS arm and 64 patients in the CIS Alone arm). Of the 125 patients randomised, 2 patients withdrew prior to treatment: 1 patient due to withdrawal of parental consent, and 1 due to investigator decision.

In the 104 patients who had both baseline and 4-week follow-up hearing assessments, the proportion of children in the CIS+STS arm with hearing loss (14 patients [28.6%]) was approximately one-half of the proportion in the CIS Alone arm (31 patients [56.4%]) (Table 3).

The risk of having hearing loss was statistically significantly lower in the CIS+STS arm compared with the CIS Alone arm, corresponding to a clinically meaningful 48% lower risk after STS treatment.

At a median of 5.33 years of follow up, the hazard ratio in EFS between arms was ([CIS+STS vs CIS Alone]: 1.27; 95% CI: 0.73, 2.18). A disparity in OS was observed (hazard ratio: 1.79; 95% CI: 0.86, 3.72). In patients categorised post-hoc with localised disease, the hazard ratio between arms in EFS was (hazard ratio: 1.02; 95% CI: 0.49, 2.15) and in OS (hazard ratio: 1.23; 95% CI: 0.41, 3.66).

Absorption

Sodium thiosulfate is poorly absorbed after oral administration and has to be administered intravenously. At the end of a sodium thiosulfate intravenous infusion, plasma levels of sodium thiosulfate are maximal and decline rapidly thereafter with a terminal elimination half-life of approximately 50 minutes. A return to pre-dose levels occurs within 3 to 6 hours after infusion. More than 95% of sodium thiosulfate excretion in urine occurs within the first 4 hours after administration. Hence, there is no plasma accumulation when sodium thiosulfate is administered on 2 consecutive days.

In children and adults, the maximum sodium thiosulfate plasma levels after a 15-minute infusion of a dose equivalent to 12.8 g/m2 was approximately 13 mM. Thiosulfate plasma levels change in a dose proportional manner. Age did not appear to influence the maximum plasma levels of sodium thiosulfate or the decline afterwards. A population PK model incorporating growth and maturation variables for the paediatric population showed that the predicted sodium thiosulfate plasma levels at the end of infusion were consistent across the recommended dose levels for the indicated age and body weight ranges.

Distribution

Sodium thiosulfate does not bind to human plasma proteins. Sodium thiosulfate is an inorganic salt and thiosulfate anions do not readily cross membranes. Hence, the volume of distribution appears largely confined to extracellular spaces and estimated at 0.23 L/kg in adults. In animals, sodium thiosulfate has been found to distribute to the cochlea. Distribution across the blood brain barrier or placenta appears absent or limited. Thiosulfate is an endogenous compound ubiquitously present in all cells and organs. Endogenous serum thiosulfate levels were 5.5 ± 1.8 µ M in adult volunteers.

Biotransformation

Metabolites of sodium thiosulfate have not been determined as part of clinical studies. Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate metabolism does not involve CYP enzymes; it is metabolised through thiosulfate sulfur transferase and thiosulfate reductase activity to sulfite, which is rapidly oxidised to sulfate.

Elimination

Sodium thiosulfate (thiosulfate) is excreted through glomerular filtration. After administration, thiosulfate levels in urine are high, and approximately half of the sodium thiosulfate dose is retrieved unchanged in urine, nearly all excreted within the first 4 hours after administration. Thiosulfate renal clearance compared well with inulin clearance as a measure for the GFR.

Excretion of endogenously produced thiosulfate in bile was very low and did not increase after sodium thiosulfate administration. No mass balance studies have been performed, but it is expected that non renal clearance will mainly result in renal excretion of sulfates. A small part of the sulfane sulfur of sodium thiosulfate may become part of endogenous cellular sulfur metabolism.

Renal impairment

In haemodialysis patients, total clearance of sodium thiosulfate was 2.04 ± 0.72 mL/min/kg (off dialysis) compared to 4.11 ± 0.77 mL/min/kg in healthy volunteers. This clearance was essentially similar to the non-renal clearance observed in the healthy volunteers (1.86 ± 0.45 mL/min/kg). In the absence of any glomerular filtration in haemodialysis patients, this only resulted in approximately a 25% increase in the maximum thiosulfate plasma levels and nearly a 2-fold increase in total exposure. The plasma concentration of thiosulfate is deemed to be the most important parameter associated with the efficacy of the product. Moreover, the most frequent adverse reactions are considered to be related to the sodium load with sodium thiosulfate administration and concurrent electrolyte imbalances (see section 4.4). Non-clinical studies indicated that dose limiting acute effects were related to the sodium intake. Sodium thiosulfate is only intended to be administered in conjunction with cisplatin chemotherapy. Cisplatin is contraindicated in patients with pre-existing renal impairment and, therefore, in the absence of cisplatin administration sodium thiosulfate would not be administered.

Hepatic impairment

No information is available for use of sodium thiosulfate in patients with hepatic impairment. However, thiosulfate sulfur transferase/reductase activity is ubiquitous, including tissue like red blood cells, liver, kidney, intestine, muscle and brain. Therefore, the changes in thiosulfate pharmacokinetics in hepatically impaired patients are likely limited and without clinical significance.

Interactions studies

Sodium thiosulfate does not bind to human plasma proteins. The chemical properties of sodium thiosulfate, along with the observations that sodium thiosulfate does not distribute readily across membrane barriers and is excreted through glomerular filtration, make an interaction with membrane drug transporters unlikely.

In vitro studies

Cytochrome P450 enzymes

Sodium thiosulfate is an inducer of CYP2B6 but not of CYP1A2 or CYP3A4. Sodium thiosulfate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 at clinically relevant concentrations.

Genotoxicity

Sodium thiosulfate was not genotoxic in an in vitro bacterial reverse mutation assay (Ames test) with or without metabolic activation and was not clastogenic in an in vitro mammalian cell assay (sister chromatid exchange) using human peripheral lymphocytes.

Carcinogenicity

Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.

Impairment of fertility

There is insufficient information from animal studies to assess the effects of intravenous infusion of sodium thiosulfate on fertility.

Developmental toxicity

There is insufficient information from animal studies to assess developmental risks with intravenous infusion of sodium thiosulfate.

Boric acid

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years

From a microbiological point of view, the product should be used immediately after opening. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C - 8° C.

Chemical and physical in-use stability has been demonstrated for 24 hours at controlled room temperature for product stored in polyvinyl chloride, ethylene vinyl acetate and polyolephine intravenous bags.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Type I, 100 mL, clear glass vials sealed with a chlorinated butyl rubber stopper and an aluminium flip-off overseal. Each vial contains 100 mL of solution for infusion.

Vials are supplied in cartons of 1 vial pack.

This medicinal product is a sterile and ready to use solution for infusion.

Each vial is intended for single use only, and any unused solution should be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.