Posology : מינונים

4.2 Posology and method of administration
Yondelis 1mg 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.

Posology

For the treatment of soft tissue sarcoma, 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.

All patients must be premedicated with corticosteroids such as dexamethasone 20 mg intravenously 30 minutes before each Yondelis 1mg 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).

The following criteria are required to allow treatment with Yondelis 1mg: - Absolute neutrophil count (ANC) ≥ 1,500/mm3
- Platelet count ≥ 100,000/mm3
- Haemoglobin ≥ 9 g/dl
- Bilirubin ≤ upper limit of normal (ULN)
- Alkaline phosphatase of non-osseous origin ≤ 2.5 x 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 x ULN -   Creatinine clearance ≥ 30 ml/min
-   Creatine phosphokinase (CPK) ≤ 2.5 x 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 haematological and biochemical parameters [bilirubin, alkaline phosphatase, aminotransferases (AST and ALT) 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

Dose adjustments during treatment
Prior to re-treatment, patients must fulfil the baseline criteria defined above. If any of the following events occur at any time between cycles, the Yondelis 1mg dose must be reduced to 1.2mg/m2 in 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
-       alkaline phosphatase of non-osseous origin > 2.5 x ULN
-       Increase of aminotransferases (AST or ALT) > 2.5 x 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 1mg 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. Yondelis 1mg has been administered for 6 or more cycles in 29.5% of patients. The monotherapy regimen has been used for up to 38 cycles. No cumulative toxicities have been observed in patients treated with multiple cycles.

Special patient populations

Paediatric patients (18 years of age and younger)
The safety and efficacy of trabectedin in paediatric patients have not been established.
Therefore, this medicinal product must not be used in children and adolescents 
Elderly patients (65 years of age and older)
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. 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
Patients with hepatic impairment may be at increased risk for toxicity. 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. However, special caution is advised and dose adjustments may be necessary in these patients since systemic exposure may be increased and the risk of hepatotoxicity might be increased. Patients with elevated bilirubin at the time of initiation of cycle must not be treated with Yondelis (see Warnings and Precautions).

Renal impairment
Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min ) have not been conducted and therefore Yondelis 1mg must not be used in this patient population (see section 4.4). The pharmacokinetics of trabectedin are not expected to be impacted by mild or moderate renal impairment. (see section 5.2) 
Method of Administration
Intravenous infusion.
Administration through a central venous line is strongly recommended (see section  4.4 and Section 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration (see Section 6.6).

Intravenous infusion over 24 hours with a three-week interval between cycles