YONDELIS 0.25mg powder for concentrate infusion solution medication leaflet

Yondelis 0.25 mg powder for concentrate for solution for infusion.

Yondelis 1 mg powder for concentrate for solution for infusion.

Yondelis 0.25 mg

Each vial of powder contains 0.25 mg of trabectedin.

One ml of reconstituted solution contains 0.05 mg of trabectedin.

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.

Yondelis 1 mg

Each vial of powder contains 1 mg of trabectedin.

One ml of reconstituted solution contains 0.05 mg of trabectedin.

Each vial of powder contains 8 mg of potassium and 0.4 g of sucrose.

For the full list of excipients, see section 6.1

Powder for concentrate for solution for infusion.

White to off-white powder.

Yondelis is indicated for the treatment of adult patients with advanced soft tissue sarcoma, after failureof anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are basedmainly on liposarcoma and leiomyosarcoma patients.

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

Yondelis must be administered under the supervision of a physician experienced in the use ofchemotherapy. Its use should be confined to qualified oncologists or other health professionalsspecialised 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 ata dose of 1.1 mg/m2, immediately after PLD 30 mg/m2. To minimize the risk of PLD infusionreactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reactionis 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 priorto 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 beadministered 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 gammaglutamyl 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 forup 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 leastonce 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 thepatient fulfils the re-treatment criteria.

Prior to re-treatment, patients must fulfil the baseline criteria defined above. If any of the followingevents occur at any time between cycles, the dose must be reduced one level, according to table 1below, 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 notrecommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinicalbenefit, the dose may be further reduced (see below). Colony stimulating factors can be administeredfor haematologic toxicity according to local standard practice.

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

Soft tissue sarcoma Ovarian cancer

Yondelis Yondelis PLD

Starting dose 1.5 mg/m2 1.1 mg/m2 30 mg/m2

First reduction 1.2 mg/m2 0.9 mg/m2 25 mg/m2

Second reduction 1 mg/m2 0.75 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.

In clinical trials, there were no pre-defined limits to the number of cycles administered. Treatmentcontinued whilst clinical benefit was noted. Yondelis has been administered for 6 or more cycles in29.5% and 52% of patients treated with the monotherapy and combination dose and schedulerespectively. The monotherapy and combination regimens have been used for up to 38 and 21 cyclesrespectively. 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 efficacyconcerns (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 theintegrated safety analysis of monotherapy clinical trials were over 65 years. Of the 333 patients withovarian cancer who received trabectedin in combination with PLD, 24% were 65 years of age or olderand 6% were over 75 years. No relevant differences in the safety profile were seen in this patientpopulation. It seems that plasma clearance and distribution volume of trabectedin are not influencedby age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.

Special caution is advised and dose adjustments may be necessary in patients with hepatic impairmentsince 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. Liverfunction tests should be monitored during treatment with Yondelis as dose adjustments may beindicated (see Table 1 and section 4.4).

Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for themonotherapy, 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 thepharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted inpatients with mild or moderate renal impairment.

Intravenous administration through a central venous line is strongly recommended (see sections 4.4and 6.6).

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

- Hypersensitivity to trabectedin or to any of the excipients listed in section 6.1

- Concurrent serious or uncontrolled infection

- Breast-feeding (see section 4.6)

- Combination with yellow fever vaccine (see section 4.4)

Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis.

Since the systemic exposure to trabectedin is on average approximately doubled (see section 5.2) dueto hepatic impairment and therefore the risk of toxicities might be increased, patients with clinicallyrelevant liver diseases, such as active chronic hepatitis, must be closely monitored and the doseadjusted if needed. Patients with elevated serum bilirubin levels must not be treated with trabectedin(see section 4.2).

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

Neutropenia and thrombocytopenia

Grades 3 or 4 neutropenia and thrombocytopenia associated with Yondelis therapy have been verycommonly reported. A full blood cell count including differential and platelet count must beperformed 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 supportivetherapy should be started immediately.

Yondelis should not be administered to patients with baseline neutrophil counts of lessthan 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, dosereduction is recommended (see section 4.2).

Nausea and vomiting

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

Rhabdomyolysis and severe CPK elevations (> 5 x ULN)

Trabectedin must not be used in patients with CPK > 2.5 x ULN (see section 4.2). Rhabdomyolysishas been uncommonly reported, usually in association with myelotoxicity, severe liver function testabnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitoredwhenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. Ifrhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation anddialysis should be promptly established, as indicated. Treatment with Yondelis should be discontinueduntil the patient fully recovers.

Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins), areadministered 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. Yondelis must not be used in patients with elevated bilirubin.

Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate doseadjustments (see section 4.2).

The use of central venous access is strongly recommended (see section 4.2). Patients may develop apotentially severe injection site reaction when trabectedin is administered through a peripheral venousline.

Trabectedin extravasation may cause tissue necrosis requiring debridement. There is no specificantidote for extravasation of trabectedin. Extravasation should be managed by local standard practice.

Allergic Reactions

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

Cardiac Dysfunction

Patients should be monitored for cardiac-related adverse events or myocardial dysfunction.

A thorough cardiac assessment including determination of left ventricular ejection fraction (LVEF) byechocardiogram or multigated acquisition scan (MUGA) should be conducted before initiation oftrabectedin and at 2 to 3-month intervals thereafter until trabectedin is discontinued.

Patients with LVEF less than the lower limit of normal (LVEF < LLN), prior cumulative anthracyclinedose of >300mg/m2, aged > 65 years, or a history of cardiovascular disease (especially in those withcardiac medication) may be at increased risk of cardiac dysfunction at treatment with trabectedin asmonotherapy or in combination with doxorubicin.

For patients with Grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for patients witha LVEF that decreases below the LLN (assessed as either an absolute decrease of LVEF of ≥15% or<LLN with an absolute decrease of ≥5%), trabectedin should be discontinued.

Capillary Leak Syndrome (CLS)

Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases withfatal outcomes). If symptoms of possible CLS develop, such as unexplained oedema with or withouthypotension, the treating physician should reassess serum albumin level. A rapid decline in serumalbumin level may be indicative of CLS. If a diagnosis of CLS is confirmed after exclusion of othercauses, the treating physician should discontinue trabectedin and initiate CLS treatment according toinstitutional guidelines (see sections 4.2 and 4.8).

Co-administration of Yondelis with potent inhibitors of the enzyme CYP3A4 should be avoided (seesection 4.5). If this is not possible, close monitoring of toxicities are required and dose reductions oftrabectedin should be considered.

Caution should be taken if medicinal products associated with hepatotoxicity are administeredconcomitantly with trabectedin, since the risk of hepatotoxicity may be increased.

Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to anexacerbation of convulsions. Combination of trabectedin with phenytoin or live attenuated vaccines isnot 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 highly effective contraception during treatment and 8months thereafter, and immediately inform the treating physician if a pregnancy occurs (see section5.3).

Men in fertile age must use highly effective contraception during treatment and 5 months aftertreatment (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 andprecautions.

Effects of other substances on trabectedin

Interaction studies have only been performed in adults.

Since trabectedin is metabolised mainly by CYP3A4, the concentrations of trabectedin in plasma arelikely to be increased in patients who are co-administered drugs that potently inhibit the activity of thisisoenzyme. Similarly, the co-administration of trabectedin with potent inducers of CPY3A4 mayincrease the metabolic clearance of trabectedin. Two in vivo drug-drug interaction phase 1 studieshave confirmed trends toward increased and decreased trabectedin exposures when administered withketoconazole and rifampicin, respectively.

When ketoconazole was co-administered with trabectedin, the plasma exposure of trabectedin wasincreased by approximately 21% for Cmax and 66% for AUC, but no new safety concerns wereidentified. Close monitoring of toxicities is required in patients receiving trabectedin in combinationwith potent CYP3A4 inhibitors (e.g. oral ketoconazole, fluconazole, ritonavir, clarithromycin oraprepitant) and such combinations should be avoided if possible. If such combinations are needed,appropriate dose adjustments should be applied in the event of toxicities (see sections 4.2 and 4.4).

When rifampicin was co-administered with trabectedin, it resulted in reduced plasma exposure oftrabectedin by approximately 22% for Cmax and 31% for AUC. Therefore, the concomitant use oftrabectedin with strong CYP3A4 inducers (e.g., rifampicin, phenobarbital, Saint John’s Wort) shouldbe avoided if possible (see section 4.4).

Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity ofthe medicinal product (see section 4.4).

Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administrationof inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/orelimination. The relevance of this interaction e.g. central nervous system (CNS) toxicity has not beenestablished. Caution should be taken in such situations.

No sufficient clinical data on exposed pregnancies are available. However, based on its knownmechanism of action, trabectedin may cause serious birth defects when administered duringpregnancy. Trabectedin crossed the placenta when administered to pregnant rats. Trabectedin shouldnot be used during pregnancy. If pregnancy occurs during treatment, the patient must be informed ofthe potential risk to the foetus (see section 5.3) and be monitored carefully. If trabectedin is used at theend of pregnancy, potential adverse reactions should be monitored carefully in the newborns.

Women of childbearing potential must use highly effective contraception during treatment and 8months thereafter, and immediately inform the treating physician if a pregnancy occurs (see section5.3).

If pregnancy occurs during treatment the possibility of genetic counselling should be considered.

It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milkhas not been studied in animals. Breast-feeding is contraindicated during treatment and 3 monthsthereafter (see section 4.3).

Men in fertile age must use highly effective contraception during treatment and 5 months aftertreatment (see section 4.4).

Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be soughtprior 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.

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 experienceany of these adverse reactions during therapy must not drive or operate machines.

Most patients treated with Yondelis can be expected to have adverse reactions of any grade (91% inmonotherapy and 99.4% in combination therapy) and less than one third serious adverse reactions ofgrade 3 or 4 severity (10% in monotherapy and 25% in combination therapy). The most commonadverse reactions of any severity grade were neutropenia, nausea, vomiting, increase in AST/ALT,anaemia, fatigue, thrombocytopenia, anorexia and diarrhoea.

Fatal adverse reactions have occurred in 1.9% and 0.6% of patients treated with the monotherapy andcombination regimens respectively. They were often the result of a combination of events includingpancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal or multiorganfailure and rhabdomyolysis.

The following safety profile of Yondelis 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 andovarian cancer that were treated with Yondelis recommended regimen in each indication. Both adversereactions and laboratory values have been used to provide frequencies.

Adverse reactions are listed by System Organ Class and frequency. The frequencies are classified asvery 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).

System Organ Very Common Common Uncommon Rare

Class

Infections and Neutropenic infection Sepsis Septic shock

Infestations

Blood and Neutropenia Febrile neutropenia

Lymphatic System Thrombocytopenia

Disorders Anaemia

Leukopenia

Immune system Hypersensitivitydisorders

Metabolism and Decreased appetite Dehydration

Nutrition Disorders Hypokalaemia

Psychiatric Insomnia

Disorders

Nervous System Headache Dizziness

Disorders Dysgeusia

Peripheral sensoryneuropathy

Syncope*

Cardiac disorders Palpitations*

Left ventricular dysfunction*

Vascular Disorders Hypotension Capillary leak

Flushing syndrome

Respiratory, Dyspnoea Pulmonary embolism* Pulmonary

Thoracic and Cough oedema

Mediastinal

Disorders

Gastrointestinal Abdominal pain Dyspepsiadisorders Nausea

Stomatitis

Hepatobiliary Alanine aminotransferase Gamma-glutamyltransferase Hepatic

Disorders increased increased failure

Aspartate aminotransferaseincreased

Blood alkaline phosphataseincreased

Blood bilirubin increased

System Organ Very Common Common Uncommon Rare

Class

Skin and Palmar-plantar Rash

Subcutaneous erythrodysaesthesia Alopecia

Tissue Disorders syndrome* Skin hyperpigmentation*

Musculoskeletal Back pain Arthralgia Rhabdomyolysisand Connective Blood creatine Myalgia

Tissue Disorders phosphokinase increased

General Disorders Fatigue Injection site reactions Extravasationand Administration Pyrexia Soft tissue

Site Conditions Oedema necrosis

Mucosal inflammation*

Investigations Blood creatinine increased Weight decreased

Blood albumin decreased

* Adverse drug reaction only for Ovarian cancer patients, including data from ET743-OVA-301, a randomizedphase 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; and from study ET743-OVC-3006 which enrolled 576 patients who receivedeither PLD (30 mg/m2) followed by trabectedin (1.1 mg/m2) every 3 weeks or PLD alone (50 mg/m2) every4 weeks.

In the ET743-OVA-301 Yondelis+PLD arm, non-white (mainly Asian) patients had a higher incidencethan 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 orbleeding, or those leading to death or treatment termination, were similar in both subpopulations.

Most frequent adverse reactions

Neutropenia is the most common haematological toxicity. It followed a predictable pattern of rapidonset and reversibility, and was rarely associated with fever or infection. Neutrophil nadirs occurred ata median of 15 days and recovered within a week. The analysis per cycle performed in patients treatedwith the monotherapy regimen showed neutropenia of grade 3 and 4 in approximately 19% and 8% ofcycles respectively. In this population febrile neutropenia occurred in 2% of patients and in < 1% ofcycles.

Bleeding events associated to thrombocytopenia occurred in < 1% of patients treated with themonotherapy regimen. The analysis per cycle performed in these patients showed thrombocytopeniaof grade 3 and 4 in approximately 3% and < 1% of cycles respectively.

Anaemia occurred in 93% and 94% of patients treated with the monotherapy and combinationregimens respectively. The percentages of patients anaemic at baseline were 46% and 35%respectively. The analysis per cycle performed in patients treated with the monotherapy regimenshowed anaemia of grade 3 and 4 in approximately 3% and 1% of cycles respectively.

AST/ALT increases:

The median time to reach the peak values was 5 days for both AST and ALT. Most of the values haddecreased to grade 1 or resolved by day 14-15 (see section 4.4). The analysis per cycle performed inpatients 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 cyclesrespectively. Most transaminase elevations improved to grade 1 or to pre-retreatment levels within 15days, and less than 2% of cycles had recovering times longer than 25 days. ALT and AST increasesdid 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 severehepatic injury were uncommon with a lower than 1% incidence of individual signs and symptomsincluding jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred inless than 1% of patients in both regimens.

Other adverse reactions

Hepatic failure: Rare cases of hepatic failure (including cases with fatal outcomes) have been reportedin patients with serious underlying medical conditions treated with trabectedin, both in clinical trialsand in post marketing setting. Some potential risk factors that may have contributed to increasedtrabectedin toxicity observed in these cases were dose management inconsistent with recommendedguidelines, potential CYP3A4 interaction due to multiple competing CYP3A4 substrates or CYP3A4inhibitors, or lack of dexamethasone prophylaxis.

Capillary Leak Syndrome (CLS): Cases of Capillary Leak Syndrome (CLS) have been reported withtrabectedin (including cases with fatal outcomes) (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01.

Trabectedin binds to the minor groove of deoxyribonucleic acid (DNA), bending the helix to the majorgroove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNAbinding 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 ofhuman tumour cell lines and experimental tumours, including malignancies such as sarcoma, breast,non-small cell lung, ovarian and melanoma.

Electrocardiogram (ECG) investigations

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

The efficacy and safety of trabectedin in soft tissue sarcoma is based in a randomised trial in patientswith locally advanced or metastatic lipo- or leiomyosarcoma, whose disease had progressed orrelapsed after treatment with at least anthracyclines and ifosfamide. In this trial trabectedin wasadministered either at 1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks or at 0.58 mg/m2weekly as a 3-hour intravenous infusion for 3-weeks of a 4-week cycle. The protocol specified finaltime to progression (TTP) analysis showed a 26.6% reduction in the relative risk of progression forpatients 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 and2.3 months (CI: 2.0-3.5 m) in the 3-h qwk group (p=0.0302). No significant differences were detectedin overall survival (OS). Median OS with the 24-h q3wk regimen was 13.9 months (CI: 12.5-18.6) and60.2% 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 treatedwith the same regimen. These trials evaluated a total of 100 patients with lipo- and leiomyosarcomaand 83 patients with other types of sarcoma.

Results from an expanded access program for patients with STS (study ET743-SAR- 3002) show thatamong 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 tumour type was 16.2 months [95% CI: 14.1, 19.5] forsubjects with leiomyosarcomas and liposarcomas and 8.4 months [95% CI: 7.1, 10.7] for subjects withother 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].

Additional efficacy data are available from a randomized active-controlled phase III study oftrabectedin vs. dacarbazine (Study ET743-SAR-3007), in patients treated for unresectable ormetastatic lipo- or leiomyosarcoma who have been previously treated with at least an anthracyclineand ifosfamide containing regimen, or an anthracycline containing regimen and one additionalcytotoxic chemotherapy regimen. Patients in the trabectedin arm were required to receivedexamethasone 20 mg intravenous injection prior to each trabectedin infusion. Overall, 384 patientswere randomized to the trabectedin group [1.5 mg/m2 once every 3 weeks (q3wk 24-h)] and193 patients to the dacarbazine group (1 g/m2 once every 3 weeks). The median patient age was56 years (range 17 to 81), 30% were male, 77% Caucasian, 12% African American and 4% Asian.

Patients in the trabectedin and dacarbazine arms received a median of 4 and 2 cycles respectively. Theprimary efficacy endpoint of the study was OS, which included 381 death events (66% of allrandomized patients): 258 (67.2%) deaths in the trabectedin group and 123 (63.7%) deaths in thedacarbazine group (HR 0.927 [95% CI: 0.748, 1.150; p=0.4920]). The final analysis showed nosignificant difference with a median survival follow-up of 21.2 months resulted in a median of 13.7months (95% CI: 12.2, 16.0) for the trabectedin arm and 13.1 months [95% CI: 9.1, 16.2] for thedacarbazine arm. The main secondary endpoints are summarized in the table below:

Efficacy results from Study ET743-SAR-3007

Endpoints/Study population Trabectedin Dacarbazine Hazard Ratio/Odds Ratio p value

Primary endpoint n=384 n=193

Overall survival,n (%) 258 (67.2%) 123 (63.7%) 0.927 (0.748-1.150) 0.4920

Secondary endpoints n=345 n=173

PFS(months; 95% CI) 4.2 1.5 0.55 (0.44, 0.70) <0.0001

ORR,n (%); 34 (9.9%) 12 (6.9%) 1.47 (0.72, 3.2) 0.33

Odds ratio (95% CI)

DOR(months; 95% CI) 6.5 4.2 0.47 (0.17, 1.32) 0.14

CBR,n (%); 34.2% 18.5% 2.3 (1.45, 3.7) <0.0002

Odds ratio (95% CI)

Additional efficacy data are available from a randomized, open-label, multicenter phase II study[JapicCTI-121850] conducted in Japanese patients with translocation-related sarcoma (TRS), mostcommon being myxoid round-cell liposarcoma (n=24), synovial sarcoma (n=18), mesenchymalchondrosarcoma (n=6), and extraskeletal Ewing sarcoma/PNET, alveolar soft part sarcoma, alveolarrhabdomyosarcoma and clear cell sarcoma (n=5 each). The study assessed the efficacy and safety oftrabectedin vs. best supportive care (BSC) as second-line or later therapy for patients with advanced

TRS unresponsive or intolerant to standard chemotherapy regimen. The patients received thetrabectedin dose of 1.2 mg/m2 recommended for Japanese patients [1.2 mg/m2 once every 3 weeks(q3wk 24-h)]. A total of 76 Japanese patients were enrolled in the study, among which 73 patientswere included in the final analysis set. The study primary endpoint was PFS, that showed a statisticallysignificant improvement in favour of trabectedin over BSC [HR=0.07; 95% CI: 0.03-0.16; p<0.0001],with a median PFS in the trabectedin group of 5.6 months [95% CI: 4.1-7.5] and in the BSC group of0.9 months [95% CI: 0.7-1.0]. The secondary endpoints included objective response analysed usingthe RECIST and Choi criteria. Using the RECIST criteria the ORR among patients treated withtrabectedin was 3 (8.1%; 95% CI: 1.7.21.9%) and 0 (0%, 95% CI: 0.0-9.7%) among patients treatedwith best supportive care, while the CBR was 24 (64.9%, 95% CI: 47.5-79.9%) versus 0 (0%, 95% CI:0.0-9.7%), respectively. Using the Choi criteria the ORR among patients treated with trabectedin was4 (10.8%; 95% CI: 3.0-25.4%) and 0 (0%, 95% CI: 0.0-9.7%) among patients treated with bestsupportive care, while the CBR was 7 (18.9%, 95% CI: 8.0-35.2%) versus 0 (0%, 95% CI: 0.0-9.7%),respectively.

The efficacy of Yondelis/PLD combination in relapsed ovarian cancer is based on ET743-OVA-301, arandomized 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 progressionfree survival (PFS) was performed in 645 patients with measurable disease and assessed byindependent radiology review. Treatment with the combination arm resulted in a 21% risk reductionfor disease progression compared to PLD alone (HR=0.79, CI: 0.65-0.96, p=0.0190). Secondaryanalyses of PFS and response rate also favoured the combination arm. The results of the main efficacyanalyses are summarised in the table below:

Efficacy analyses from ET743-OVA-301

Yondelis+PLD PLD Hazard/Odds ratio p-value

Progression Free Survival

Independent radiology review, n=328 n=317measurable disease *

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 a12 months PFS rate (95% CI) (%) 25.8 (19.7-32.3) 18.5 (12.9-24.9)

Independent oncology review, n=336 n=335all randomised

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, n=337 n=335all randomised

ORR (95% CI) (%) 27.6 (22.9-32.7) 18.8 (14.8-23.4) 1.65 (1.14-2.37) 0.0080 b

* Primary efficacy analysisa Log rank testb 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 PFSof 3.7 months (HR=0.89, CI: 0.67-1.20). In patients with PFI ≥ 6 months (65% in Yondelis+PLD and63% in PLD arm), median PFS was 9.7 months in the Yondelis+PLD arm compared with 7.2 monthsin 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 survivalwas 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-resistantpopulation: 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, whichwere well balanced between the two treatment arms.

In the multivariate analyses including PFI, treatment effect on overall survival was statisticallysignificant favouring the Yondelis+PLD combination over PLD alone (all randomised: p=0.0285;platinum-sensitive population: p=0.0319).

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

Quality of Life.

The Yondelis+PLD combination in relapsed ovarian cancer also was evaluated in study ET743-OVC-3006, a phase 3 study in which women with ovarian cancer after failure of a second platinum-containing regimen were randomized to Yondelis (1.1 mg/m2) and PLD (30 mg/m2) every 3 weeks or

PLD (50 mg/m2) every 4 weeks. Study participants were required to be platinum sensitive (PFI ≥ 6months) following their first platinum-containing regimen and have a complete or partial response to asecond line platinum-based chemotherapy (without PFI restrictions) meaning that these patients couldbe either platinum-sensitive (PFI ≥ 6 months) or platinum-resistant (PFI < 6 months) following theirsecond platinum-containing regimen. A post hoc analysis determined that 42% of enrolled subjectswere platinum-resistant (PFI < 6 months) following their last platinum-containing regimen.

The primary endpoint of study ET743-OVC-3006 was OS and secondary endpoints included PFS and

ORR. The study was sized to enrol approximately 670 patients in order to observe 514 deaths to detecta HR of 0.78 for OS with 80% power given a two-sided significance level of 0.05 spread across twoplanned analyses on OS, at interim (60% or 308/514 deaths) and final analysis (514 deaths). Two earlyunscheduled futility analyses were performed at the request of the Independent Data Monitoring

Committee (IDMC). Following the second futility analysis performed at 45% of planned events(232/514 deaths), the IDMC recommended discontinuing the study due to (1) futility of the primaryanalysis on OS and (2) excessive risk based on imbalance of adverse events not in favour of

Yondelis+PLD. At early termination of the study, 9% (52/572 treated) of subjects stopped treatment,45% (260/576 randomized) stopped follow-up, and 54% (310/576 randomized) were censored from

OS assessment, precluding reliable estimates of PFS and OS endpoints.

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

In SAR-2005 phase I-II study, a total of 50 paediatric patients with rhabdomyosarcoma, Ewingsarcoma or non rhabdomyosarcoma soft tissue sarcoma were enrolled. Eight patients were treated witha dose of 1.3 mg/m2 and 42 with 1.5 mg/m2. Trabectedin was administered as a 24-hour intravenousinfusion 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 apatient with an alveolar rhabdomyosarcoma. Duration of the response was 6.5 months No responseswere observed for Ewing sarcoma and NRSTS, [RR: 0% CI95% (0%-30.9%)]. Three patientsachieved stable disease (one with rhabdomyosarcoma after 15 cycles, one with spindle cell sarcomaafter 2 cycles, and one with Ewing sarcoma after 4 cycles.

Adverse reactions, included reversible elevation of liver enzymes and haematological events; inaddition, fever, infection, dehydration and thrombosis/embolism were also reported.

Systemic exposure after intravenous administration as a constant rate infusion is dose proportional atdoses up to and including 1.8 mg/m2. Trabectedin pharmacokinetic profile is consistent with amultiple-compartment disposition model.

Following intravenous administration, trabectedin demonstrates a high apparent volume ofdistribution, consistent with extensive tissue and plasma protein binding (94 to 98% of trabectedin inplasma is protein bound). The distribution volume at steady state of trabectedin in human subjectsexceeds 5,000 l.

Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidativemetabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute tometabolism. 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 islong (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelledtrabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate forplasma clearance of trabectedin (30.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedinin whole blood is approximately 35 l/h. This value is approximately one-half the rate of human hepaticblood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter-patientvariability of the population estimate for plasma clearance of trabectedin was 49% and intra-patientvariability was 28%.

A population pharmacokinetic analysis showed that when administered in combination with PLD, theplasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were notinfluenced by the concomitant administration of trabectedin.

A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is notinfluenced by age (range 19-83 years), gender, total body weight (range: 36 to 148 kg) or body surfacearea (range: 0.9 to 2.8 m2). A population pharmacokinetic analysis showed that plasma trabectedinconcentrations observed in the Japanese population at dose level 1.2 mg/m2 were equivalent to thoseobtained in the non-Japanese western population at 1.5 mg/m².

There is no relevant influence of renal function measured by creatinine clearance on trabectedinpharmacokinetics within the range of values (≥ 30.3 ml/min) present in the patients included in theclinical 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 of14C-labelled trabectedin indicates that renal impairment has little influence on the elimination oftrabectedin or its metabolites.

The effect of hepatic impairment on the pharmacokinetics of trabectedin was assessed in 15 cancerpatients at doses ranging from 0.58 to 1.3 mg/m2 administered as 3-hour infusion. The geometric meandose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in 6 patientswith moderate hepatic impairment (increased serum bilirubin levels from 1.5 to 3 x ULN and increaseof aminotransferases (AST or ALT) < 8 x ULN) following administration of a single trabectedin doseof 0.58 mg/m2 (n=3) or 0.9 mg/m2 (n=3) compared to 9 patients with normal liver function followingadministration of a single trabectedin dose of 1.3 mg/m2 (see sections 4.2 and 4.4).

Preclinical data indicate that trabectedin has limited effect on the cardiovascular, respiratory andcentral 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 maximumplasma levels (Cmax values) in the range of those observed in the clinic. The plasma trabectedin levelsattained were 10.6 ± 5.4 (Cmax), higher than those reached in patients after infusion of 1,500 µg/m2 for24 (Cmax of 1.8 ± 1.1 ng/ml) and similar to those reached after administration of the same dose by3 hour infusion (Cmax of 10.8 ± 3.7 ng/ml).

Myelosupression and hepatoxicity were identified as the primary toxicity for trabectedin. Findingsobserved included haematopoietic toxicity (severe leukopenia, anaemia, and lymphoid and bonemarrow depletion) as well as increases in liver function tests, hepatocellular degeneration, intestinalepithelial necrosis, and severe local reactions at the injection site. Renal toxicological findings weredetected in multi-cycle toxicity studies conducted in monkeys. These findings were secondary tosevere local reaction at the administration site, and therefore uncertainly attributable to trabectedin;however, caution must be guaranteed in the interpretation of these renal findings, andtreatment-related toxicity cannot be excluded.

Trabectedin is genotoxic both in vitro and in vivo. Long-term carcinogenicity studies have not beenperformed.

Fertility studies with trabectedin were not performed but limited histopathological changes wereobserved 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.

Placental transfer of trabectedin and fetal exposure to trabectedin were observed in a study in pregnantrats that received a single i.v. 14C-trabectedin dose at 0.061 mg/kg. Maximum fetal tissue radioactivityconcentration was similar to that in maternal plasma or blood.

Sucrose

Potassium dihydrogen phosphate

Phosphoric acid (for pH-adjustment)

Potassium hydroxide (for pH-adjustment)

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

Unopened vials60 months.

Chemical and physical stability has been demonstrated for 30 hours up to 25 ºC.

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

Chemical and physical stability has been demonstrated for 30 hours up to 25 ºC.

Store in a refrigerator (2 ºC - 8 ºC).

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 sealcontaining 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 sealcontaining 1mg of trabectedin.

Each carton contains one vial.

Preparation for intravenous infusion

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

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. Theuse of any diluent other than 50 mg/ml (5%) glucose solution for infusion for this line flushing maycause precipitation of PLD (see also PLD Summary of Product Characteristics for specific handlinginstructions).

Yondelis 0.25 mg

Each vial containing 0.25 mg of trabectedin is reconstituted with 5 ml of water for injections. Thesolution 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 shakenuntil complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowishsolution, essentially free of visible particles.

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

Yondelis 1 mg

Each vial containing 1 mg of trabectedin is reconstituted with 20 ml of water for injections. Thesolution 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 shakenuntil complete dissolution. The reconstituted solution results in a clear, colourless or slightly yellowishsolution, essentially free of visible particles.

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

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

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 reconstitutedsolution 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 forinfusion), 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 reconstitutedsolution should be added to an infusion bag containing ≥ 1,000 ml of diluent (sodium chloride9 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 theinfusion 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 cytotoxicmedicinal products must be followed. Personnel should be trained in the correct techniques toreconstitute 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 fromworking with this medicinal product.

Accidental contact with the skin, eyes or mucous membranes must be treated immediately withcopious 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 implantablevascular access systems.

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

Pharma Mar, S.A.

Avda. de los Reyes 1, Polígono Industrial La Mina28770 Colmenar Viejo (Madrid)

Spain

Yondelis 0.25 mg

EU/1/07/417/001

Yondelis 1 mg

EU/1/07/417/002

Date of first authorisation: 17 September 2007

Date of latest renewal: 03 August 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.