This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder contains 0.25 mg of trabectedin. One ml of reconstituted solution contains 0.05 mg of trabectedin. Excipientswithknowneffect: Each vial of powder contains 2 mg of potassium and 0.1 g of sucrose. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

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.

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 mmol/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.

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.

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.

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).

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.

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).

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.

Intravenous 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.

Contraindications

Special warnings and precautions for use

Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since systemic exposure to trabectedin is probably increased due to hepatic impairment and therefore the risk of hepatotoxicity might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose adjusted if needed. Patients with elevated bilirubin must not be treated with trabectedin (see section 4.2).

Creatinine clearance must be monitored prior to and during treatment. 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). Neutropeniaandthrombocytopenia Grades 3 or 4 neutropenia and thrombocytopenia associated with 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).

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

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. Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins), are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased

Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients. Yondelis must not be used in patients with elevated bilirubin. Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate dose reduction (see section 4.2).

The use of central venous access is strongly recommended (see section 4.2). 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. There is no specific antidote for extravasation of trabectedin. Extravasation should be managed by local standard practice.

During postmarketing experience, hypersensitivity reactions with very rare occurrence of fatal outcome, have been reported in association with trabectedin administration either alone or in combination with PLD (see sections 4.3 and 4.8).

Co-administration of Yondelis with potent inhibitors of the enzyme CYP3A4 should be avoided (see section 4.5). If this is not possible, close monitoring of toxicities are required and dose reductions of trabectedin should be considered. Caution should be taken if medicinal products associated with hepatotoxicity are administered concomitantly with trabectedin, since the risk of hepatotoxicity may be increased. Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to an exacerbation of convulsions. Combination of trabectedin with phenytoin or live attenuated vaccines is not recommended and with yellow fever vaccine is specifically contraindicated (see section 4.3). The concomitant use of trabectedin with alcohol must be avoided (see section 4.5). Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs (see section 5.3). Men in fertile age must use effective contraception during treatment and 5 months after treatment (see section 4.6). This medicine contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially "potassium-free". See also PLD Summary of Product Characteristics for more detailed information on warnings and precautions.

Interaction with other medicinal products and other forms of interaction

interaction studies have not been performed. Since trabectedin is metabolised mainly by CYP3A4, co-administration of substances that inhibit this isoenzyme e.g. ketoconazole, fluconazole ritonavir, clarithromycin or aprepitant could decrease metabolism and increase trabectedin concentrations. If such combinations are needed, close monitoring of toxicities is required (see section 4.4). Likewise co-administration with potent inducers of this enzyme (e.g. rifampicin, phenobarbital, Saint John's Wort) may decrease the systemic exposure to trabectedin.

Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of the medicinal product (see section 4.4). Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or elimination. The relevance of this interaction e.g. central nervous system (CNS) toxicity has not been established. Caution should be taken in such situations.

Fertility, pregnancy and lactation

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.

Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs (see section 5.3). If pregnancy occurs during treatment the possibility of genetic counselling should be considered. Breast-feeding It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been studied in animals. Breast-feeding is contraindicated during treatment and 3 months thereafter (see section 4.3).

Men in fertile age must use effective contraception during treatment and 5 months after treatment (see section 4.4). Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Yondelis. Genetic counselling is also recommended for patients wishing to have children after therapy.

Effects on ability to drive and use machines

No studies on the effects of the ability to drive and to use machines have been performed. However, fatigue and/or asthenia have been reported in patients receiving trabectedin. Patients who experience any of these adverse reactions during therapy must not drive or operate machines.

Undesirable effects

Summaryofthesafetyprofile

Unless otherwise specified, the following safety profile of Yondelis is based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for both indications. Most patients treated with Yondelis can be expected to have adverse reactions of any grade (91% in monotherapy and 99% 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, increases in AST/ALT, anemia, fatigue, thrombocytopenia, anorexia and 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.

Tabulatedsummaryofadversereactions

The frequencies of the adverse reactions reported below are classified as very common (>= 1/10), common (>= 1/100 to < 1/10) and uncommon (>= 1/1,000 to < 1/100). 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 (Medical Dictionary for Regulatory Activities) system organ class. Both adverse reactions and laboratory values have been used to provide frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Adverse reactions reported in >= 1% of patients with soft tissue sarcoma in clinical trials.
Infections and Infestations	Common Infection
Blood and Lymphatic System Disorders	Very Common Neutropenia * (Grade 3 = 26%, Grade 4 = 24%), Thrombocytopenia * (Grade 3 = 11%, Grade 4 = 2%), Anaemia * (Grade 3 = 10%, Grade 4 = 3%), Leukopenia * Common Febrile neutropenia
Metabolism and Nutrition Disorders	Very Common Anorexia (Grade 3-4 < 1%) Common Dehydration, Decreased appetite, Hypokalaemia
Psychiatric Disorders	Common Insomnia
Nervous System Disorders	Very Common Headache Common Peripheral sensory neuropathy, Dysgeusia, Dizziness, Paraesthesia
Vascular Disorders	Common Hypotension, Flushing
Respiratory, Thoracic and Mediastinal Disorders	Common Dyspnoea (Grade 3-4 = 2%), Cough
Gastrointestinal disorders	Very Common Vomiting (Grade 3-4 = 6.5%), Nausea (Grade 3-4 = 6%), Constipation (Grade 3-4 < 1%) Common Diarrhoea (Grade 3-4 < 1%), Stomatitis (Grade 3-4 < 1%), Abdominal pain, Dyspepsia, Upper abdominal pain
Hepatobiliary Disorders	Very Common Hyperbilirubinemia * (Grade 3 = 1%), Alanine aminotransferase increased * (Grade 3 = 38%, Grade 4 = 3%), Aspartate aminotransferase increased * (Grade 3 = 44%, Grade 4 = 7%), Blood alkaline phosphatase increased , Gamma-glutamyltransferase increased
Skin and Subcutaneous Tissue Disorders	Common Alopecia
Musculoskeletal and Connective Tissue Disorders	Common Myalgia, Arthralgia, Back pain
General Disorders and Administration Site Conditions	Very Common Fatigue (Grade 3-4 = 9%), Asthenia (Grade 3-4 = 1%) Common Pyrexia, Oedema, Oedema peripheral, Injection site reaction
Investigations	Very Common Blood creatine phosphokinase increased * (Grade 3-4 = 4%), Blood creatinine increased , Blood albumin decreased Common Weight decreased

* Derived from laboratory data The table below provides the frequency and severity of undesirable effects considered possibly related to study medicinal product and reported in >= 5% of patients with ovarian cancer randomised to receive Yondelis 1.1 mg/m2/PLD 30 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.

Adverse reactions reported in >= 5% of patients in clinical trial ET743-OVA-301
System Organ Class	Frequency		Event		Yondelis+PLD n=333
			All Grades (%)			Grade 3 (%)	Grade 4 (%)
Blood and lymphatic system disorders	Very common	Neutropenia *		91.6		29.7	42.3
		Leukopenia *		94.9		44.7	17.7
		Anaemia *		94.9		12.9	5.7
		Thrombocytopenia *		63.7		12.3	10.8
	Common	Febrile neutropenia *		6.9		4.5	2.4
Metabolism and nutrition disorders	Very common	Anorexia		28.8		2.1
	Common	Hypokalaemia		6.3		2.1
Nervous system disorders	Common	Headache		6.6		0.3
		Dysgeusia		5.4		0.3
Respiratory, thoracic and mediastinal disorders	Common	Dyspnoea		6.6		0.3
Gastrointestinal disorders	Very common	Nausea		70.9		8.7
		Vomiting		51.7		9.9	0.3
		Constipation		20.4		0.9
		Stomatitis		19.2		0.9
		Diarrhoea		17.1		2.1
	Common	Abdominal pain		9.3		0.6
		Dyspepsia		7.5		0.3
Hepatobiliary disorders	Very common	Hyperbilirubinaemia *		(25.2)		(0.3)
		Alanine aminotransferase increased *		96.1		45.6	4.5
		Aspartate aminotransferase increased *		89.5		12.0	1.8
		Blood alkaline phosphatase increased *		61.3		1.5
Skin and subcutaneous tissue disorders	Very common	Palmar-plantar erythrodysaesthesia syndrome		24		3.9
		Alopecia		12
	Common	Rash		8.1
		Skin hyperpigmentation		5.4

Adverse reactions reported in >= 5% of patients in clinical trial ET743-OVA-301
System Organ Class	Frequency	Event	Yondelis+PLD n=333
System Organ Class	Frequency	Event	All Grades (%)	Grade 3 (%)	Grade 4 (%)
General disorders and administration site conditions	Very common	Fatigue	42.3	5.7	0.3
		Asthenia	15.3	1.2
		Mucosal inflammation	11.4	2.1
		Pyrexia	10.2	0.9
Investigations	Common	Blood creatine phosphokinase increased *	22.0	0.9	0.9

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.

Descriptionofselectedadversereactions

Most frequent adverse reactions Blood and lymphatic system disorders

Neutropenia: 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 neutropenia of grade 3 and 4 in approximately 19% and 8% of cycles respectively. In this population febrile neutropenia occurred in 2% of patients and in < 1% of cycles. Thrombocytopenia: Bleeding events associated to thrombocytopenia occurred in < 1% of patients treated with the monotherapy regimen. The analysis per cycle performed in these patients showed thrombocytopenia of grade 3 and 4 in approximately 3% and < 1% of cycles respectively. Anaemia: Anaemia occurred in 93% and 94% of patients treated with the monotherapy and combination regimens respectively. The percentages of patients anaemic at baseline were 46% and 35% respectively. The analysis per cycle performed in patients treated with the monotherapy regimen showed anaemia of grade 3 and 4 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 grade 3 elevations of AST and ALT 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: 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 clinical 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

CPK elevations and rhabdomyolysis:

CPK elevations of any grade were observed in 23-26% of patients in both regimens. CPK increases in association with rhabdomyolysis were reported in less than 1% of patients.

Alopecia:

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

Hepatic failure:

Rare cases of hepatic failure (including cases with fatal outcomes) have been reported in patients with serious underlying medical conditions treated with trabectedin, both in clinical trials and in post marketing setting. Some potential risk factors that may have contributed to increased trabectedin toxicity observed in these cases were dose management inconsistent with recommended guidelines, potential CYP3A4 interaction due to multiple competing CYP3A4 substrates or CYP3A4 inhibitors, or lack of dexamethasone prophylaxis.

Allergic Reactions:

During clinical trials, hypersensitivity was reported in 2% of patients receiving trabectedin either alone or in combination with PLD, and most of these cases were Grade 1 or 2 in severity.

During post marketing experience, hypersensitivity reactions with very rare occurrence of fatal outcome, have been reported in association with trabectedin administration either alone or in combination with PLD (see sections 4.3 and 4.4).

Extravasation and Tissue necrosis:

During post-marketing surveillance, a few cases of trabectedin extravasation with subsequent tissue necrosis requiring debridement have been reported (see section 4.4).

Septic shock:

Cases of septic shock, some of which were fatal, have been uncommonly reported in clinical studies and postmarketing experience, in patients treated either with monotherapy or combination therapy.

Reportingofsuspectedadversereactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in AppendixV.

Overdose

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.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01. Mechanismofaction Trabectedin binds to the minor groove of deoxyribonucleic acid (DNA), bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle.

Trabectedin has been shown to exert antiproliferative in vitro and in vivo activity against a range of human tumour cell lines and experimental tumours, including malignancies such as sarcoma, breast, non-small cell lung, ovarian and melanoma.

In a placebo-controlled QT/QTc study, trabectedin did not prolong the QTc interval in patients with advanced solid malignancies.

The efficacy and safety of trabectedin in soft tissue sarcoma is based in a randomised trial in patients with locally advanced or metastatic lipo- 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, Confidence Interval (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. Results from an expanded access program for patients with STS (study ET743-SAR- 3002) show that among the 903 subjects assessed for OS, the median survival time was 11.9 months (95% CI: 11.2, 13.8). The median survival by histology tumor type was 16.2 months [95% CI: 14.1, 19.5] for subjects with leiomyosarcomas and liposarcomas and 8.4 months [95% CI: 7.1, 10.7] for subjects with other types of sarcomas. The median survival for subjects with liposarcoma was 18.1 months [95% CI: 15.0, 26.4] and for subjects with leiomyosarcoma 16.2 months [95% CI: 11.7, 24.3]. 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

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 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 final analysis, the effect of the Yondelis+PLD combination vs. PLD alone on overall survival was more pronounced in patients with PFI 6 months (platinum-sensitive population: 27.0 vs. 24.1 months, HR=0.83, CI: 0.67-1.04) than in those with PFI < 6 months (platinum-resistant population: 14.2 vs. 12.4 months, HR=0.92, CI: 0. 70-1.21). The benefit in OS with Yondelis plus PLD was not due to the effect of subsequent therapies, which were well balanced between the two treatment arms. In the multivariate analyses including PFI, treatment effect on overall survival was statistically significant favouring the Yondelis+PLD combination over PLD alone (all randomised: p=0.0285; platinum-sensitive population: p=0.0319). 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.

In SAR-2005 phase I-II study, a total of 50 paediatric patients with rhabdomyosarcoma, Ewing sarcoma or non rhabdomyosarcoma soft tissue sarcoma were enrolled. Eight patients were treated with a dose of 1.3 mg/m2 and 42 with 1.5 mg/m2. Trabectedin was administered as a 24-hour intravenous infusion every 21 days. Forty patients were fully evaluable for response. One partial response (PR) centrally confirmed was observed: overall RR: 2.5% CI95% (0.1%-13.2%). The PR corresponded to a patient with an alveolar rhabdomyosarcoma. Duration of the response was 6.5 months No responses were observed for Ewing sarcoma and NRSTS, [RR: 0% CI95% (0%-30.9%)]. Three patients achieved stable disease (one with rhabdomyosarcoma after 15 cycles, one with spindle cell sarcoma after 2 cycles, and one with Ewing sarcoma after 4 cycles. Adverse reactions, included reversible elevation of liver enzymes and haematological events; in addition, fever, infection, dehydration and thrombosis/embolism were also reported. This medicinal product has been authorised under "exceptional circumstances". This means that due to the rarity of soft tissue sarcoma, it has not been possible to obtain complete information on this medicinal product in this indication. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Pharmacokinetic properties

Systemic exposure after intravenous administration as a constant rate 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. Following intravenous administration, trabectedin demonstrates a high apparent volume of distribution, consistent with extensive tissue and plasma protein binding (94 to 98% of trabectedin in plasma is protein bound). The distribution volume at steady state of trabectedin in human subjects exceeds 5,000 l.

Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative metabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute to metabolism. Trabectedin does not induce or inhibit major cytochrome P450 enzymes.

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 (30.9 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 49% 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.

A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is not influenced by age (range 19-83 years), 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 race and ethnicity are not expected to have clinically significant effects on trabectedin pharmacokinetics.

There is no relevant influence of renal function measured by creatinine clearance on trabectedin pharmacokinetics within the range of values (>= 30.3 ml/min) present in the patients included in the clinical studies. No data are available in patients with a creatinine clearance of less than 30.3 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.

Although the population analysis showed no relationship between the serum liver enzymes concentrations and the plasma clearance of trabectedin, systemic exposure to trabectedin may be increased in patients with hepatic impairment; therefore close monitoring of toxicity is warranted.

Preclinical safety data

Preclinical data indicate that trabectedin has limited effect on the cardiovascular, respiratory and central nervous system at exposures below the therapeutic clinical range, in terms of AUC. The effects of trabectedin on cardiovascular and respiratory function have been investigated in vivo (anesthetised Cynomolgus monkeys). A 1 hour infusion schedule was selected to attain maximum plasma levels (Cmax values) in the range of those observed in the clinic. The plasma trabectedin levels attained were 10.6 5.4 (Cmax), higher than those reached in patients after infusion of 1,500 g/m2 for 24 (Cmax of 1.8 +- 1.1 ng/ml) and similar to those reached after administration of the same dose by 3 hour infusion (Cmax of 10.8 +- 3.7 ng/ml). Myelosupression and hepatoxicity were identified as the primary toxicity for trabectedin. Findings observed included haematopoietic toxicity (severe leukopenia, anaemia, and lymphoid and bone marrow depletion) as well as increases in liver function tests, hepatocellular degeneration, intestinal epithelial necrosis, and severe local reactions at the injection site. Renal toxicological findings were detected in multi-cycle toxicity studies conducted in monkeys. These findings were secondary to severe local reaction at the administration site, and therefore uncertainly attributable to trabectedin; however, caution must be guaranteed in the interpretation of these renal findings, and treatment-related toxicity cannot be excluded. Trabectedin is genotoxic both in vitro and in vivo. Long-term carcinogenicity studies have not been performed. Fertility studies with trabectedin were not performed but limited histopathological changes were observed in the gonads in the repeat dose toxicity studies. Considering the nature of the compound (cytotoxic and mutagenic), it is likely to affect the reproductive capacity.

PHARMACEUTICAL PARTICULARS

List of excipients

Sucrose Potassium dihydrogen phosphate Phosphoric acid (for pH-adjustment) Potassium hydroxide (for pH-adjustment)

Incompatibilities

Yondelis must not be mixed or diluted with other medicinal products except those mentioned in section 6.6.

Shelf life

60 months. Afterreconstitution Chemical and physical stability has been demonstrated for 30 hours up to 25oC. 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 2oC to 8oC, unless reconstitution has taken place in controlled and validated aseptic conditions.

Special precautions for storage

Store in a refrigerator (2oC - 8oC). For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Nature and contents of container

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.

Special precautions for disposal and other handling

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).

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.

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.

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.

MARKETING AUTHORISATION HOLDER

Pharma Mar, S.A. Avda. de los Reyes 1, Poligono Industrial La Mina 28770 Colmenar Viejo (Madrid) Spain

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 September 2007 Date of latest renewal: 17 September 2012

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions

	Soft tissue sarcoma	Ovarian cancer
	Yondelis	Yondelis	PLD
Starting dose	1.5 mg/m 2	1.1 mg/m 2	30 mg/m 2
First reduction	1.2 mg/m 2	0.9 mg/m 2	25 mg/m 2
Second reduction	1 mg/m 2	0.75 mg/m 2	20 mg/m 2

	Yondelis+PLD	PLD	Hazard/Odds ratio	p-value
Progression Free Survival
Independent radiology review, measurable disease *	n=328	n=317
Median PFS (95% CI) (months)	7.3 (5.9-7.9)	5.8 (5.5-7.1)	0.79 (0.65-0.96)	0.0190 a
12 months PFS rate (95% CI) (%)	25.8 (19.7-32.3)	18.5 (12.9-24.9)
Independent oncology review, all randomised	n=336	n=335
Median PFS (95% CI) (months)	7.4 (6.4-9.2)	5.6 (4.2-6.8)	0.72 (0.60-0.88)	0.0008 a
Overall Survival (Final analysis - n=522 events)
All randomised	n=337	n=335
Median OS (95% CI) (months)	22.2 (19.3-25.0)	18.9 (17.1-21.5)	0.86 (0.72-1.02)	0.0835 a
Overall survival in platinum-sensitive population (Final analysis n=316 events)
	n=218	n=212
Median OS (95% CI) (months)	27.0 (24.1-31.4)	24.1 (20.9-25.9)	0.83 (0.67-1.04)	0.1056 a
Overall Response Rate (ORR)
Independent radiology review, all randomised	n=337	n=335
ORR (95% CI) (%)	27.6 (22.9-32.7)	18.8 (14.8-23.4)	1.65 (1.14-2.37)	0.0080 b

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS