Yondelis Dosage/Direction for Use

Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents.
Posology: For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m² body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles.
For the treatment of ovarian cancer, Yondelis is administered every three weeks as a 3-hour infusion at a dose of 1.1 mg/m², immediately after PLD 30 mg/m². To minimize the risk of PLD infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent PLD infusions may be administered over a 1-hour period (see also PLD Summary of Product Characteristics [SmPC] for specific administration advice).
All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or Yondelis (in monotherapy); not only as anti-emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be administered as needed.
The following criteria are required to allow treatment with Yondelis: Absolute neutrophil count (ANC) ≥1,500/mm³; Platelet count ≥100,000/mm³; Bilirubin ≤ upper limit of normal (ULN); Alkaline phosphatase ≤2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or gamma glutamyl transpeptidase (GGT), if the elevation could be osseous in origin); Albumin ≥25 g/l; Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 x ULN; Creatinine clearance ≥30 ml/min (monotherapy), serum creatinine ≤1.5 mg/dl (≤132.6 μmol/l) or creatinine clearance ≥60 ml/min (combination therapy); Creatine phosphokinase (CPK) ≤2.5 x ULN; Haemoglobin ≥9 g/dl.
The same criteria as previously mentioned must be met prior to re-treatment. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met.
Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK 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 that the patient fulfils the re-treatment criteria.
Dose adjustments during treatment: Prior to re-treatment, patients must fulfil the baseline criteria defined previously. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to Table 3 as follows, for subsequent cycles: Neutropenia <500/mm³ lasting for more than 5 days or associated with fever or infection; Thrombocytopenia <25,000/mm³; Increase of bilirubin > ULN and/or alkaline phosphatase >2.5 x ULN; Increase of aminotransferases (AST or ALT) >2.5 x ULN (monotherapy) or >5 x ULN (combination therapy), 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 dose may be further reduced (see Table 3). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.

Click on icon to see table/diagram/image

In the event that further dose reductions are necessary, treatment discontinuation should be considered.
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. Yondelis has been administered for 6 or more cycles in 29.5% and 52% of patients treated with the monotherapy and combination dose and schedule, respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles, respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.
Paediatric population: Yondelis should not be used in children below 18 years with paediatric sarcomas because of efficacy concerns (see Pharmacology: Pharmacodynamics under Actions for results of paediatric sarcoma study).
Elderly: No specific studies in older people have been performed. Overall, 20% of the 1,164 patients in the integrated safety analysis of monotherapy clinical trials were over 65 years. Of the 333 patients with ovarian cancer who received trabectedin in combination with PLD, 24% were 65 years of age or older and 6% were over 75 years. No relevant differences in the safety profile were seen in this patient population. It seems that plasma clearance and distribution volume of trabectedin are not influenced by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.
Hepatic impairment: Special caution is advised and dose adjustments may be necessary in patients with hepatic impairment since systemic exposure to trabectedin is increased and the risk of hepatotoxicity might be increased. Patients with elevated serum bilirubin levels at baseline must not be treated with Yondelis. Liver function tests should be monitored during treatment with Yondelis as dose adjustments may be indicated (see Table 3 and Precautions).
Renal impairment: Studies including patients with renal insufficiency (creatinine clearance <30 ml/min for the monotherapy, and <60 ml/min for the combination regimen) have not been conducted and therefore Yondelis must not be used in this patient population (see Precautions). Considering the pharmacokinetic characteristics of trabectedin (see Pharmacology: Pharmacokinetics under Actions), no dose adjustments are warranted in patients with mild or moderate renal impairment.
Method of administration: Intravenous administration through a central venous line is strongly recommended (see Precautions and Special precautions for disposal and other handling under Cautions for Usage).
For instructions on reconstitution and dilution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.