TRABECTEDIN

Trabectedin 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.

5 mg/m2 body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles. 1 mg/m2, immediately after PLD 30 mg/m2. To minimise 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). g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or Trabectedin (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. 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.

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.

75 mg/m2 20 mg/m2 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.

4% in combination therapy) and less than one third serious adverse reactions of grade 3 or 4 severity (10% in monotherapy and 25% in combination therapy). The most common adverse reactions of any severity grade were neutropenia, nausea, vomiting, increase in AST/ALT, anaemia, fatigue, thrombocytopenia, anorexia and diarrhoea.

6% of patients treated with the monotherapy and combination regimens respectively. They were often the result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal or multiorgan failure and rhabdomyolysis.

Tabulated summary of adverse reactions The following safety profile of Trabectedin is based on adverse reactions reported in clinical trials, post-authorisation safety studies and spontaneous reporting. The table below displays the adverse reactions reported in patients with soft tissue sarcoma and ovarian cancer that were treated with Trabectedin recommended regimen in each indication.

Both adverse reactions and laboratory values have been used to provide frequencies. Adverse reactions are listed by System Organ Class and frequency. The frequencies are classified as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000).

1 mg/m2) every 3 weeks or PLD alone (50 mg/m2) every 4 weeks. In the ET743-OVA-301 trabectedin + PLD arm, non-white (mainly Asian) patients had a higher incidence than white patients in grade 3 or 4 adverse reactions (96% versus 87%), and serious adverse reactions (44% versus 23% all grades).

The differences were mainly observed in relation with neutropenia (93% versus 66%), anaemia (37% versus 14%) and thrombocytopenia (41% versus 19%). However, the incidences of clinical complications related to haematological toxicity such as severe infections or bleeding, or those leading to death or treatment termination, were similar in both subpopulations.

Hepatic impairment Patients must meet specific criteria on hepatic function parameters to start treatment with Trabectedin. 2) due to hepatic impairment and therefore the risk of toxicities might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose adjusted if needed.

2). Renal impairment Creatinine clearance must be monitored prior to and during treatment. 2). Neutropenia and thrombocytopenia Grades 3 or 4 neutropenia and thrombocytopenia associated with Trabectedin therapy have been very commonly reported.

2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately. Trabectedin should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 and platelet count of less than 100,000 cells/mm3.

2). 2). 2). Rhabdomyolysis has been uncommonly reported, usually in association with myelotoxicity, severe liver function test abnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain.

If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with Trabectedin should be discontinued until the patient fully recovers.

g. statins), are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased. Liver Function Test (LFT) abnormalities Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients.

Trabectedin must not be used in patients with elevated bilirubin. 2). 2). Patients may develop a potentially severe injection site reaction when trabectedin is administered through a peripheral venous line. Trabectedin extravasation may cause tissue necrosis requiring debridement.

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