YONDELIS Powder for Injection 1mg/vial

INJECTION, POWDER, FOR SOLUTION

**Dosage and Administration** YONDELIS® must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to personnel specialized in the administration of cytotoxic agents. **Dosage** The recommended starting dose is 1.5 mg/m2 body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles. Administration through a central venous line is strongly recommended ( _see Warnings and Precautions and Instructions for Use and Handling and Disposal_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). All patients must be premedicated with corticosteroids such as dexamethasone 20 mg IV, 30 minutes before each infusion; not only as anti-emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be administered as needed ( _see Interactions_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). The following criteria are required to allow treatment with YONDELIS®: - Absolute neutrophil count (ANC) ≥ 1500/mm3 - Platelet count ≥ 100000/mm3 - Haemoglobin ≥ 9g/dL - Bilirubin ≤ upper limit of normal (ULN) - Alkaline phosphatase of non-osseous origin ≤ 2.5 × ULN (consider hepatic isoenzymes 5-nucleotidase or GGT, to distinguish if the elevation could be osseous in origin) - Albumin ≥ 25 g/L - Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 × ULN - Creatinine clearance ≥ 30 mL/min; - Creatine phosphokinase (CPK) ≤ 2.5 × ULN The same criteria as above must be met prior to initiation of next cycles. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met. If these toxicities persist beyond 3 weeks, treatment discontinuation should be considered. Additional monitoring of hematological and biochemical parameters \[alkaline phosphatase, bilirubin, CPK, and aminotransferases (AST and ALT)\] should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles. The same dose should be given for all cycles provided that no Grade 3–4 toxicities are seen and the patient fulfills the re-treatment criteria. _**Dose adjustments during treatment**_ Prior to re-treatment, patients must fulfill the baseline criteria defined above. If any of the following events occur at any time between cycles, the YONDELIS® dose must be reduced to 1.2 mg/m2 in subsequent cycles: - Neutropenia < 500/mm3 lasting for more than 5 days or neutropenia associated with fever or infection - Thrombocytopenia < 25000/mm3 - Increase of bilirubin > ULN - Alkaline phosphatase of non-osseous origin > 2.5 × ULN - Increase of aminotransferases (AST or ALT) > 2.5 × ULN which has not recovered by day 21 - Any other Grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue) Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the YONDELIS® dose may be further reduced to 1 mg/m2. In the event that further dose reductions are necessary, treatment discontinuation should be considered. Colony stimulating factors can be administered for hematologic toxicity in subsequent cycles according to local standard practice. _**Duration of Treatment**_ In clinical trials, there were no pre-defined limits to the number of cycles administered. Treatment continued whilst clinical benefit was noted. Trabectedin has been administered for 6 or more cycles in 168 out of 569 (29.5%) patients treated with the proposed dose and schedule. This regime has been used for up to 38 cycles. No cumulative toxicities have been observed in patients treated with multiple cycles. _**Special populations**_ _**Pediatrics (18 years of age and younger)**_ In a Phase 2 study investigating the activity of YONDELIS® at 1.5 mg/m2 24-hour infusion once every 3 weeks, in 42 pediatric patients with recurrent sarcomas (non-rhabdomyosarcoma soft tissue sarcoma (STS), Ewing sarcoma, and rhabdomyosarcoma), the safety profile was consistent with that of adults. However, as no efficacy was observed, YONDELIS® should not be used in pediatric patients with pediatric sarcomas. _**Elderly (65 years of age and older)**_ No specific studies in elderly patients have been performed. Based on an integrated safety analysis of single agent clinical trials in several tumor types, no relevant differences in the safety profile or effectiveness were seen in the elderly patient population as compared to patients <65 years of age. Consistent with this analysis, no differences in safety and effectiveness were observed in the elderly patient population in a Phase 3 study (ET743-SAR-3007). Results from population pharmacokinetic analyses indicate that the plasma clearance and distribution volume of trabectedin are not influenced by age. Therefore, dose adjustments based on age are not recommended. _**Renal impairment**_ Studies including patients with renal insufficiency (creatinine clearance < 30 mL/min) have not been conducted and therefore YONDELIS® must not be used in these patient populations (see _Warnings and Precautions_). The pharmacokinetics of trabectedin are not expected to be impacted by mild or moderate renal impairment (see _Pharmacokinetic Properties_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). _**Hepatic impairment**_ Recommendations for a starting dose in these patients cannot be made because the use of trabectedin in patients with impaired hepatic function has not been adequately studied. Trabectedin exposure is increased in patients with hepatic impairment. Patients with elevated serum bilirubin levels at baseline must not be dosed with YONDELIS®. Liver function tests should be monitored during treatment with YONDELIS® as dose adjustments may be indicated (see _Dosage and Administration_ and _Warnings and Precautions_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Administration** Intravenous infusion. Administration through a central venous line is strongly recommended (see _Warnings and Precautions_ and _Instructions for Use and Handling and Disposal_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). For instructions on reconstitution and dilution of the medicinal product before administration, see _Instructions for Use and Handling and Disposal_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_.