Pharma Mar, S.A.

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4.2          Posology and method of administration

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

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.

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 Product Characteristics for specific administration advice).

Administration through a central venous line is strongly recommended (see section 6.6).

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) ³ 1,500/mm³

-                 Platelet count ³ 100,000/mm³

-                 Bilirubin £ upper limit of normal (ULN)

-                 Alkaline phosphatase £ 2.5 x ULN (consider hepatic isoenzymes 5‑nucleotidase or GGT, if the elevation could be osseous in origin).

-                 Albumin ³ 25 g/l

-                 Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) £ 2.5 x ULN

-                 Creatinine clearance ³ 30 ml/min (monotherapy), serum creatinine £ 1.5 mg/dl (£ 132.6 μmol/l) or creatinine clearance ³ 60 ml/min (combination therapy)

-                 Creatine phosphokinase (CPK) £ 2.5 x ULN

-                 Haemoglobin ³ 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 hematologic toxicity according to local standard practice.

Table 1 Dose modification table for Yondelis (as single agent for STS or

in combination for ovarian cancer) and PLD

See the PLD SPC 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.

Special patient populations

Paediatric patients

The safety and efficacy of trabectedin in paediatric patients have not yet been established. Therefore, this medicinal product must not be used in children and adolescents until further data become available.

Elderly patients

No specific studies in elderly patients have been performed. Overall 20% of the 1164 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.

Patients with impaired hepatic function

No studies with the proposed regimen have been conducted in patients with liver dysfunction. Thus, data are not available to recommend a lower starting dose in patients with hepatic impairment. However, special caution is advised and dose adjustments may be necessary in these patients since systemic exposure is probably increased and the risk of hepatotoxicity might be increased. Patients with elevated bilirubin must not be treated with Yondelis (see section 4.4).

Patients with impaired renal function

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

Administration through a central venous line is strongly recommended (see section 6.6).

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

4.6          Fertility, pPregnancy and lactation

Pregnancy

No sufficient clinical data on exposed pregnancies are available. However, based on its known mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy. Trabectedin should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus (see section 5.3) and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns.

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4.1 Therapeutic indications

Yondelis in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer.

4.2 Posology and method of administration

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 Product Characteristics 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:

-                 Alkaline phosphatase ≤ 2.5 x ULN (consider hepatic isoenzymes 5‑nucleotidase or GGT, if the elevation could be osseous in origin).

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, to 1.2 mg/m² for subsequent cycles:

-                 Increase of aminotransferases (AST or ALT) > 2.5 x ULN (monotherapy) or > 5 x ULN (combination therapy), which has not recovered by day 21

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)to 1 mg/m². Colony stimulating factors can be administered for hematologic toxicity according to local standard practice.

Table 1 Dose modification table for Yondelis (as single agent for STS or

in combination for ovarian cancer) and PLD

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

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 Yondelis has been administered for 6 or more cycles in 168 out of 569 (29.5%) and 52% of patients treated with the monotherapy and combinationproposed dose and schedule respectively. Theis monotherapy and combination regimens haves been used for up to 38 and 21 cycles respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.

Elderly patients

Patients with impaired hepatic function

No studies with the proposed regimen have been conducted in patients with liver dysfunction. Thus, data are not available to recommend a lower starting dose in patients with hepatic impairment. However, special caution is advised and dose adjustments may be necessary in these patients since systemic exposure is probably increased and the risk of hepatotoxicity might be increased. Patients with elevated bilirubin must not be treated with Yondelis (see section 4.4).

Patients with impaired renal function

Studies including patients with severe 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.

Renal impairment

Creatinine clearance must be monitored prior to and during treatment. Trabectedin Yondelis monotherapy and combination regimens must not be used in patients with creatinine clearance < 30 ml/min and < 60 ml/min respectively (see section 4.2).

Neutropenia and thrombocytopenia

Grades 3 or 4 neutropenia and thrombocytopenia associated with trabectedin Yondelis therapy have been very commonly reported. A full blood cell count including differential and platelet count must be performed at baseline, weekly for the first two cycles and then once between cycles (see section 4.2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately.

Yondelis should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³ and platelets count of less than 100,000 cells/mm³. If severe neutropenia (ANC < 500 cells/mm³) lasting more than 5 days or associated with fever or infection occurs, dose reduction is recommended (see section 4.2).

 

Nausea and vomiting

Anti-emetic prophylaxis with corticosteroids such as dexamethasone must be administered to all patients (see section 4.2).

Rhabdomyolysis and severe CPK elevations (> 10 5 x ULN)

Trabectedin must not be used in patients with CPK > 2.5 x ULN (see section 4.2). 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 Yondelis should be discontinued until the patient fully recovers.

Others

See also PLD Summary of Product Characteristics for more detailed information on warnings and precautions.

4.8       Undesirable effects

Unless otherwise specified, the following safety profile of Yondelis is based on the evaluation in clinical trials of 569 patients treated up to April 2007 with the recommended treatment regimens for both indications. in several cancer types including soft tissue sarcoma, breast cancer, osteosarcoma, ovarian cancer, GIST, melanoma and renal carcinoma.

Most Approximately 91% of patients treated with Yondelis can be expected to have adverse reactions of any grade (91% in monotherapy and 99% in combination therapy). Around  40% of patients are expected to have 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, increases in AST/ALT, anemia, fatigue, thrombocytopenia vomiting, anorexia, neutropenia, and increases in AST/ALT. diarrhoea.

Fatal adverse reactions have occurred in 1.9% and 0.9% 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.

Adverse reactions

The table below displays the adverse reactions reported in ≥ 1% of patients treated with the soft tissue sarcoma recommended regimen (1.5 mg/m², 24 hour infusion every 3 weeks) according to the standard MedDRA system organ class. Both adverse reactionsevents and laboratory values have been used to provide frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Derived from laboratory data

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug and reported in ≥ 5% of patients with ovarian cancer randomised to receive Yondelis 1.1 mg/m²/PLD 30 mg/m² or PLD 50 mg/m² in the pivotal trial ET743‑OVA-301. Both adverse reactions and laboratory values have been used. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Derived from laboratory data

The following reactions have been reported with a frequency below 5% in the combination arm, but are included here for their clinical relevance: neutropenic infection (< 1%), neutropenic sepsis (< 1%), pancytopenia (1.8%), bone marrow failure (1.5%), granulocytopenia (1.5%), dehydration, insomnia, peripheral sensory neuropathy, syncope, left ventricular dysfunction (< 1%), pulmonary embolism (1.2%), pulmonary edema (< 1%), cough, hepatotoxicity (< 1%), gamma-glutamyltransferase increased, bilirubin conjugated increased, musculoskeletal pain, myalgia, blood creatinine increased, oedema/peripheral oedema, catheter site reactions.

In the Yondelis+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.

Most frequent adverse reactions

Blood and Lymphatic system disorders

Neutropenia: Neutropenia occurred in 77% of patients. Grade 3 and 4 neutropenia occurred in 26% and 24% of patients respectively). Neutropenia is the most common haematological toxicity. It followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection. Neutrophil nadirs occurred at a median of 15 days and recovered within a week. The analysis per cycle performed in patients treated with the monotherapy regimen showed that neutropenia of grade 3 and 4 occurred in approximately 19% and 8% of cycles respectively. In this population fFebrile neutropenia occurred in 2% of patients and in < 1% of cycles.

Neutropenia followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection.

Thrombocytopenia: Bleeding events associated to thrombocytopenia occurred in < 1% of patients treated with the monotherapy regimen. Grade 3 and 4 thrombocytopenia occurred in 11% and 2% of patients respectively. The analysis per cycle performed in these patients showed that thrombocytopenia of grade 3 and 4 occurred in approximately 3% and < 1% of cycles respectively. Bleeding events associated to thrombocytopenia occurred in < 1% of patients.

Anaemia: Anaemia occurred in 93% and 94% of patients treated with the monotherapy and combination regimens respectively. The percentages of patients anaemic at baseline werealthough 46% and 35% respectivelyof patients were anaemic at baseline.. Grade 3 and 4 anaemia occurred in 10% and 3% of patients respectively. The analysis per cycle performed in patients treated with the monotherapy regimen showed that anaemia of grade 3 and 4 occurred in approximately 3% and 1% of cycles respectively.

Hepatobiliary disorders

AST/ALT increases: The median time to reach the peak values was 5 days for both AST and ALT. Most of the values had decreased to grade 1 or resolved by day 14‑15 (see section 4.4). The analysis per cycle performed in patients treated with the monotherapy regimen showed Ggrade 3 elevations of AST and ALT occurred in 12% and 20% of cycles respectively. Grade 4 elevations of AST and ALT occurred in 1% and 2% of cycles respectively. Most transaminase elevations improved to grade 1 or to pre-retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25 days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.

Hyperbilirubinemia: Grades 1 to 2 bilirubin increases were observed in 23% of the patients. Grade 3 hyperbilirubinemia occurred in 1% of patients. Bilirubin peaks approximately a week after onset and resolves approximately two weeks after onset.

Liver function tests predicting severe toxicity (meeting Hy´s law) and cClinical manifestations of severe hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in less than 1% of patients in both regimens.

Other adverse reactions

Stomatitis: Grade 3‑4 mucositis was reported in less than 1% of the patients.

Fatigue/Asthenia: Grade 3‑4 fatigue/asthenia occurred in 9 and 1% of patients respectively.

Anorexia: Grade 3‑4 anorexia occurred in less than 1% of the patients.

CPK elevations and rhabdomyolysis: CPK elevations of any grade were observed in 23‑2626% of patients in both regimens. Grade 3 or 4 increases of CPK were observed in 4% of patients. CPK increases in association with rhabdomyolysis were reported in less than 1% of patients.

Dyspnoea: Grade 3‑4 dyspnoea reported as trabectedin related occurred in 2% of the patients.

Alopecia: Alopecia was reported in approximately 3% of all patients treated with the monotherapy regimen, of which the majority was grade 1 alopecia.

5.1     Pharmacodynamic properties

Clinical efficacy

The efficacy and safety of trabectedin in soft tissue sarcoma is based in a randomised trial in patients with locally advanced or metastatic liposarcoma or leiomyosarcoma, whose disease had progressed or relapsed after treatment with at least anthracyclines and ifosfamide. In this trial trabectedin was administered either at 1.5 mg/m² as a 24‑hour intravenous infusion every 3 weeks or at 0.58 mg/m² weekly as a 3‑hour intravenous infusion for 3‑weeks of a 4‑week cycle. The protocol specified final time to progression (TTP) analysis showed a 26.6% reduction in the relative risk of progression for patients treated in the 24‑h q3wk group [(Hazard Ratio (HR)=0.734, CI: 0.554‑0.974]). Median TTP values were 3.7 months (CI: 2.1‑5.4 m) in the 24‑h q3wk group and 2.3 months (CI: 2.0‑3.5 m) in the 3‑h qwk group (p=0.0302). No significant differences were detected in overall survival (OS). Median OS with the 24‑h q3wk regimen was 13.9 months (CI: 12.5‑18.6) and 60.2% of patients were alive at 1 year (CI: 52.0‑68.5%).

Additional efficacy data are available from 3 single‑arm Phase II trials with similar populations treated with the same regimen. These trials evaluated a total of 100 patients with lipo and leiomyosarcoma and 83 patients with other types of sarcoma.

The efficacy of Yondelis/PLD combination in relapsed ovarian cancer is based on ET743‑OVA‑301, a randomized phase 3 study of 672 patients who received either trabectedin (1.1 mg/m²) and PLD (30 mg/m²) every 3 weeks or PLD (50 mg/m²) every 4 weeks. The primary analysis of progression free survival (PFS) was performed in 645 patients with measurable disease and assessed by independent radiology review. Treatment with the combination arm resulted in a 21% risk reduction for disease progression compared to PLD alone (HR=0.79, CI: 0.65-0.96, p=0.0190). Secondary analyses of PFS and response rate also favoured the combination arm. The results of the main efficacy analyses are summarised in the table below:

Efficacy analyses from ET743-OVA-301

* Primary efficacy analysis

^{a Log rank test}

^{b Fisher´s test}

Based on independent oncology review, patients with platinum-free interval (PFI) < 6 months (35% in Yondelis+PLD and 37% in PLD arm) had similar PFS in the two arms with both showing median PFS of 3.7 months (HR=0.89, CI: 0.67-1.20). In patients with PFI  ³ 6 months (65% in Yondelis+PLD and 63% in PLD arm), median PFS was 9.7 months in the Yondelis+PLD arm compared with 7.2 months in the PLD monotherapy arm (HR=0.66, CI: 0.52-0.85).

In the interim analysis, the effect of the Yondelis+PLD combination on overall survival was more pronounced in patients with PFI ³  6 months (27.0 vs. 24.3 months, HR=0.82, CI: 0.63-1.06) than in those with PFI < 6 months (14.2 vs. 12.4 months, HR=0.90, CI: 0.68-1.20).

No data are available comparing Yondelis+PLD to a platinum-based regimen in platinum-sensitive patients.

No statistically significant differences were found between treatment arms in global measures of Quality of Life.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of soft tissue sarcomathe disease, it has not been possible to obtain complete information on Yondelis inthis medicinal product. this indication.

5.2       Pharmacokinetic properties

Systemic exposure after intravenous administration as a 24 hour constant rate intravenous infusion is dose proportional at doses up to and including 1.8 mg/m². Trabectedin pharmacokinetic profile is consistent with a multiple‑compartment disposition model.

Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half‑life is long (population value of the terminal elimination phase: 180‑hr). After a dose of radiolabelled trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is 58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for plasma clearance of trabectedin (31.530.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedin in whole blood is approximately 35 l/h. This value is approximately one‑half the rate of human hepatic blood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter‑patient variability of the population estimate for plasma clearance of trabectedin was 5149% and intra‑patient variability was 28%.

A population pharmacokinetic analysis showed that when administered in combination with PLD, the plasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were not influenced by the concomitant administration of trabectedin.

Special populations

A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is not influenced by age (range 19‑83 years), or gender, total body weight (range: 36 to 148 kg) or body surface area (range: 0.9 to 2.8 m²),. An analysis made on a limited number of patients shows that The effects of race and ethnicity are not expected to have clinically significant effects on trabectedin pharmacokinetics. have not been studied.

Impaired renal function

There is no relevant influence of renal function measured by creatinine clearance on trabectedin pharmacokinetics within the range of values (≥ 30.34.4 ml/min) present in the patients included in the clinical studies. No data are available in patients with a creatinine clearance of less than 30.34.4 ml/min. The low recovery (< 9% in all studied patients) of total radioactivity in the urine after a single dose of ¹⁴C‑labelled trabectedin indicates that renal impairment has little influence on the elimination of trabectedin or its metabolites.

6.6       Special precautions for disposal and other handling

Preparation for intravenous infusion

0.25 mg vial

Appropriate aseptic techniques must be used. Yondelis must be reconstituted and further diluted prior to infusion. When used in combination 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 may cause precipitation of PLD. (See also PLD Summary Product Characteristics for specific handling instructions).

1 mg vial

Appropriate aseptic techniques must be used. Yondelis must be reconstituted and further diluted prior to infusion. When used in combination 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 may cause precipitation of PLD. (See also PLD Summary Product Characteristics for specific handling instructions).

10. DATE OF REVISION OF THE TEXT

22 June28 October 2009

Section 4.4 Special warning and precautions for use

Injection site reactions

New paragraph added: “Trabectedin extravasation may cause.....local standard practice.”

Others

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4.5 Interaction with other medicinal products and other forms of interaction

Effects of other substances on trabectedin

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3^rd paragraph: “....of Pgp, e.g....” has been replaced by “P-gp, e.g...”

4.8 Undesirable effects

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During....(see section 4.4).”

6.6 Special precautions for disposal and other handling

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“....infusion), being the...” has been replaced by “infusion), the concentration of trabectedin in the infusion solution being....”

10. DATE OF REVISION OF THE TEXT

22 June 2009

Section 6.6 - Special precautions for disposal and other handing - Instructions for dilution - (2nd paragraph)

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If administration is to be made through a central venous line, tThe appropriate amount of reconstituted solution should be withdrawn from the vial and added to an infusion bag containing ³ 500 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion), being the concentration of trabectedin in the infusion solution ≤ 0.030 mg/ml.if administration is to be made through a central venous line.

Section 6.6 - Special precautions for disposal and other handing - Instructions for handling and disposal - (4th paragraph)

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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.

Section 10 - DATE OF REVISION OF THE TEXT

03/2009