YONDELIS Powder for concentrate for solution for infusion Ref.[9078] Active ingredients: Trabectedin

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 above 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 above. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to table 1 below, 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 below). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.

Table 1. Dose modification table for Yondelis (as single agent for soft tissue sarcoma (STS) or in combination for ovarian cancer) and PLD:

See the PLD SmPC for more detailed information on PLD dose adjustments.

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 5.1 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 1 and section 4.4).

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 section 4.4). Considering the pharmacokinetic characteristics of trabectedin (see section 5.2), 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 sections 4.4 and 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

There is limited data on the effects of trabectedin overdose. The major anticipated toxicities are gastrointestinal, bone marrow suppression and hepatic toxicity. There is no specific antidote for trabectedin currently available. In the event of an overdose, patients should be closely monitored and symptomatic supportive care measures instituted as required.

Shelf life

Unopened vials: 60 months.

After reconstitution: Chemical and physical stability has been demonstrated for 30 hours up to 25°C.

From a microbiological point of view, the reconstituted solution should be diluted and used immediately. If not diluted and used immediately, in-use storage times and conditions prior to use of the reconstituted product are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

After dilution: Chemical and physical stability has been demonstrated for 30 hours up to 25°C.

Store in a refrigerator (2°C-8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Yondelis 0.25 mg: Type I colourless glass vial with a butyl rubber stopper covered with an aluminium flip-off seal containing 0.25 mg of trabectedin. Each carton contains one vial.

Yondelis 1 mg: Type I colourless glass vial with a butyl rubber stopper covered with an aluminium flip-off seal containing 1mg of trabectedin. Each carton contains one vial.

Preparation for intravenous infusion

Yondelis must be reconstituted and further diluted prior to intravenous infusion. Appropriate aseptic techniques must be used to prepare the infusion solution (see Instructions for reconstitution and for dilution).

When used in combination with PLD the intravenous line should be flushed well with 50 mg/ml (5%) glucose solution for infusion after administration of PLD and before administration of Yondelis. The use of any diluent other than 50 mg/ml (5%) glucose solution for infusion for this line flushing may cause precipitation of PLD (see also PLD Summary of Product Characteristics for specific handling instructions).

Instructions for reconstitution

Yondelis 0.25 mg

Each vial containing 0.25 mg of trabectedin is reconstituted with 5 ml of water for injections. The solution obtained has a concentration of 0.05 mg/ml and is for single-use only.

A syringe is used to inject 5 ml of sterile water for injections into the vial. The vial must be shaken until complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowish solution, essentially free of visible particles.

This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for single-use only.

Yondelis 1 mg

Each vial containing 1 mg of trabectedin is reconstituted with 20 ml of water for injections. The solution obtained has a concentration of 0.05 mg/ml and is for single-use only.

A syringe is used to inject 20 ml of sterile water for injections into the vial. The vial must be shaken until complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowish solution, essentially free of visible particles.

This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for single-use only

Instructions for dilution

The reconstituted solution should be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion. The required volume should be calculated as follows:

Volume (ml) = BSA (m²) x individual dose (mg/m²) / 0.05 mg/ml

BSA = Body Surface Area

If administration is to be made through a central venous line, the appropriate amount of reconstituted solution should be withdrawn from the vial and added to an infusion bag containing ≥50 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion), the concentration of trabectedin in the infusion solution being ≤0.030 mg/ml.

If central venous access is not feasible and a peripheral venous line has to be used, the reconstituted solution should be added to an infusion bag containing ≥1,000 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion).

Parenteral solutions should be inspected visually for particles prior to administration. Once the infusion is prepared, it should be administered immediately.

Instructions for handling and disposal

Yondelis is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, caution should be exercised during handling. Procedures for proper handling and disposal of cytotoxic medicinal products must be followed. Personnel should be trained in the correct techniques to reconstitute and dilute the medicinal product and should wear protective clothing including mask, goggles and gloves during the reconstitution and dilution. Pregnant staff must be excluded from working with this medicinal product.

Accidental contact with the skin, eyes or mucous membranes must be treated immediately with copious amounts of water.

No incompatibilities have been observed between Yondelis and type I glass bottles, polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs and titanium implantable vascular access systems.

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