Pedmarqsi · 4.4 Special warnings and precautions for use · 1

HOS-287805 · has-adverse-reaction-information · PDF-Seite 6

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 Hypokalaemia Very common (21%) disorders 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 6 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

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HOS-287801 · has-contraindication-information · PDF-Seite 4

 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).

HOS-287800 · has-indication-information · PDF-Seite 2

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.

HOS-287803 · has-interaction-information · PDF-Seite 5

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).

HOS-287804 · has-pregnancy-information · PDF-Seite 5

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. 5 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).

HOS-287802 · has-warning-information · PDF-Seite 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, as clinically indicated. If the hypersensitivity reaction is such that the patient is to continue with sodium thiosulfate after the next cisplatin administration, pre-medication 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 4 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

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