Yondelis 0.25 mg powder for concentrate for solution for infusion/Yondelis 1 mg powder for concentrate for solution for infusion

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4.8         Undesirable effects

Summary of the safety profile

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

Fatal adverse reactions have occurred in 1.9% and 0.90.6% of patients treated with the monotherapy and combination regimens respectively. They were often the result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal or multiorgan failure and rhabdomyolysis.

Tabulated summary of adverse reactions

*   Adverse drug reaction only for Ovarian cancer patients, including data from 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; and from study ET743-OVC-3006 which enrolled 576 patients who received either PLD (30 mg/m²) followed by trabectedin (1.1 mg/m²) every 3 weeks or PLD alone (50 mg/m²) every 4 weeks.

In the ET743‑OVA‑301 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.

10.       DATE OF REVISION OF THE TEXT

24/07/202022/07/2021

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5.1       Pharmacodynamic properties

Section is unchanged up to this point

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.

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 ≥ 6 months) following their first platinum-containing regimen and have a complete or partial response to a second line platinum-based chemotherapy (without PFI restrictions) meaning that these patients could be either platinum-sensitive (PFI ≥ 6 months) or platinum-resistant (PFI < 6 months) following their second platinum-containing regimen. A post hoc analysis determined that 42% of enrolled subjects were 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 detect a HR of 0.78 for OS with 80% power given a two-sided significance level of 0.05 spread across two planned analyses on OS, at interim (60% or 308/514 deaths) and final analysis (514 deaths). Two early unscheduled 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 primary analysis 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-sensitive patients.

10.       DATE OF REVISION OF THE TEXT

12/201924/07/2020

Date leaflet was last revised in changed to state: 07/2020

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4.4       Special warnings and precautions for use

Cardiac Dysfunction

It is recommended to monitor patients for clinical cardiac signs or symptoms. It is also recommended to monitor LVEF at baseline and periodically during the treatment; particularly in patients at risk of cardiomyopathy from previous anthracycline exposure or in patients with symptoms of decreasing cardiac function.

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

A thorough cardiac assessment including determination of left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan (MUGA) should be conducted before initiation of trabectedin 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 anthracycline dose of >300mg/m², aged > 65 years, or a history of cardiovascular disease (especially in those with cardiac medication) may be at increased risk of cardiac dysfunction at treatment with trabectedin as monotherapy or in combination with doxorubicin.

For patients with Grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for patients with a 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.

10.       DATE OF REVISION OF THE TEXT

06/201812/2019

Warnings and precautions

Talk to your doctor before using Yondelis

Yondelis or its combination with PLD must not be used if you have severe liver, kidney or cardiac damage. Tell your doctor if you know or suspect that you have any liver, kidney or cardiac problems before starting the treatment with Yondelis.

Tell your doctor if you know or suspect that you have any of the following before starting the treatment with Yondelis:

• Liver or kidney problems.
•  Cardiac problems or a history of cardiac problems.
• Left ventricular ejection fraction (LVEF) under the lower limit of normal.
• Received high anthracycline dose treatment in the past.

Note: sections only provided where amendments have been made

4.4       Special warnings and precautions for use

Capillary Leak Syndrome (CLS)

Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases with fatal outcomes).  If symptoms of possible CLS develop, such as unexplained oedema with or without hypotension, the treating physician should reassess serum albumin level. A rapid decline in serum albumin level may be indicative of CLS. If a diagnosis of CLS is confirmed after exclusion of other causes, the treating physician should discontinue trabectedin and initiate CLS treatment according to institutional guidelines (see sections 4.2 and 4.8).

4.8       Undesirable effects

 Updates made to this section.

10.       DATE OF REVISION OF THE TEXT

06/2018

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1.            NAME OF THE MEDICINAL PRODUCT

Yondelis 0.25 mg

Yondelis 0.25 mg powder for concentrate for solution for infusion.

Yondelis 1 mg

Yondelis 1 mg powder for concentrate for solution for infusion.

4.2         Posology and method of administration

Hepatic impairment

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, sSpecial caution is advised and dose adjustments may be necessary in these patients with hepatic impairment since systemic exposure to trabectedin is probably increased and the risk of hepatotoxicity might be increased. Patients with elevated serum bilirubin levels at baseline must not be treated with Yondelis. Liver function tests should be monitored during treatment with Yondelis as dose adjustments may be indicated (see Table 1 and section 4.4).

4.4         Special warnings and precautions for use

Hepatic impairment

Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since the systemic exposure to trabectedin is probably on average approximately doubled (see section 5.2) increased due to hepatic impairment and therefore the risk of hepatotoxicityies 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 serum bilirubin levels must not be treated with trabectedin (see section 4.2).

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 dose reduction adjustments (see section 4.2).

5.2         Pharmacokinetic properties

Hepatic impairment

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.

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

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4.4         Special warnings and precautions for use

Capillary Leak Syndrome (CLS)

Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin. If symptoms of possible CLS develop, such as unexplained edema with or without hypotension, the treating physician should reassess serum albumin level. A rapid decline in serum albumin level may be indicative of CLS. If a diagnosis of CLS is confirmed after exclusion of other causes, the treating physician should discontinue trabectedin and initiate CLS treatment according to institutional guidelines (see sections 4.2 and 4.8).

4.8         Undesirable effects

Tabulated summary of adverse reactions

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.

* 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.

* Derived from laboratory data

Capillary Leak Syndrome: Cases of suspected capillary leak syndrome have been reported with trabectedin. Frequency uncommon.

10.       DATE OF REVISION OF THE TEXT

06/2017

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4.4         Special warnings and precautions for use

Cardiac Dysfunction

It is recommended to monitor patients for clinical cardiac signs or symptoms. It is also recommended to monitor LVEF at baseline and periodically during the treatment; particularly in patients at risk of cardiomyopathy from previous anthracycline exposure or in patients with symptoms of decreasing cardiac function.

4.8         Undesirable effects

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, anaemia, fatigue, thrombocytopenia, anorexia and diarrhoea.

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 oedema (< 1%), cough, hepatotoxicity (< 1%), gamma‑glutamyltransferase increased, bilirubin conjugated increased, musculoskeletal pain, myalgia, blood creatinine increased, oedema/peripheral oedema, catheter site reactions.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

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 tumour 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].

Additional efficacy data are available from a randomized active-controlled phase III study of trabectedin vs. dacarbazine (Study ET743-SAR-3007), in patients treated for unresectable or metastatic lipo- or leiomyosarcoma who have been previously treated with at least an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and one additional cytotoxic chemotherapy regimen. Patients in the trabectedin arm were required to receive dexamethasone 20 mg intravenous injection prior to each trabectedin infusion. Overall, 384 patients were randomized to the trabectedin group [1.5 mg/m² once every 3 weeks (q3wk 24-h)] and 193 patients to the dacarbazine group (1 g/m² once every 3 weeks). The median patient age was 56 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. The primary efficacy endpoint of the study was OS, which included 381 death events (66% of all randomized patients): 258 (67.2%) deaths in the trabectedin group and 123 (63.7%) deaths in the dacarbazine group (HR 0.927 [95% CI: 0.748, 1.150; p=0.4920]). The final analysis showed no significant difference with a median survival follow-up of 21.2 months resulted in a median of 13.7 months (95% CI: 12.2, 16.0) for the trabectedin arm and 13.1 months [95% CI: 9.1, 16.2] for the dacarbazine arm. The main secondary endpoints are summarized in the table below:

Efficacy results from Study ET743‑SAR‑3007

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), most common being myxoid round-cell liposarcoma (n=24), synovial sarcoma (n=18), mesenchymal chondrosarcoma (n=6), and extraskeletal Ewing sarcoma/PNET, alveolar soft part sarcoma, alveolar rhabdomyosarcoma and clear cell sarcoma (n=5 each). The study assessed the efficacy and safety of trabectedin 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 the trabectedin 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 patients were included in the final analysis set. The study primary endpoint was PFS, that showed a statistically significant 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 of 0.9 months [95% CI: 0.7-1.0]. The secondary endpoints included objective response analysed using the RECIST and Choi criteria. Using the RECIST criteria the ORR among patients treated with trabectedin was 3 (8.1%; 95% CI: 1.7.21.9%) and 0 (0%, 95% CI: 0.0-9.7%) among patients treated with 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 was 4 (10.8%; 95% CI: 3.0-25.4%) and 0 (0%, 95% CI: 0.0-9.7%) among patients treated with best supportive care, while the CBR was 7 (18.9%, 95% CI: 8.0-35.2%) versus 0 (0%, 95% CI: 0.0-9.7%), respectively.

10.       DATE OF REVISION OF THE TEXT

07/2016

Typographical errors  - rectified

6.5 Nature and contents of container

Yondelis 0.25 mg

Type I colourless glass vial with a butyl rubber stopper covered with an aluminium flip‑off seal containing 0.25 mg of trabectedin.

Yondelis 1 mg

Type I colourless glass vial with a butyl rubber stopper covered with an aluminium flip-off seal containing 1mg of trabectedin.

Highlighted changes following approval of:

1. NAME OF THE MEDICINAL PRODUCT

Yondelis 0.25 mg vial

Yondelis 0.25 mg powder for concentrate for solution for infusion.

Yondelis 1 mg vial

Yondelis 1 mg powder for concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Yondelis 0.25 mg vial

Each vial of powder contains 0.25 mg of trabectedin.

One ml of reconstituted solution contains 0.05 mg of trabectedin.

Excipients with known effect:

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 vial

Each vial of powder contains 1 mg of trabectedin.

0.25 mg and 1 mg vials

One ml of reconstituted solution contains 0.05 mg of trabectedin.

Excipients with known effect:

0.25 mg vial

Each vial of powder contains 2 mg of potassium and 0.1 g of sucrose.

1 mg vial

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

0.25 mg and 1 mg vials

For the full list of excipients, see section 6.1.

4.2 Posology and method of administration

Older peopleElderly

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.

Patients with hHepatic impairment

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

Patients with rRenal impairment

Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the monotherapy, and < 60 ml/min for the combination regimen) have not been conducted and therefore Yondelis must not be used in this patient population (see section 4.4). Considering the pharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted in patients with mild or moderate renal impairment.

4.6 Fertility, pregnancy and lactation

Pregnancy

No sufficient clinical data on exposed pregnancies are available. However, based on its known mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy. Trabectedin crossed the placenta when administered to pregnant rats. Trabectedin should not be used during pregnancy unless clearly necessary. If it is used If pregnancy occurs during pregnancytreatment, 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.

Highlighted changes following approval of the 7^th Annual Reassessment (EMEA/H/C/000773/S/0042) and PSUR II (EMEA/H/C/000773/PSUSA/00003001/201409)

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

4.2       Posology and method of administration

Method of administration

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

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

4.8       Undesirable effects

Reporting of suspected adverse reactions

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 Appendix V.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Ísland

til Lyfjastofnunar,  www.lyfjastofnun.is

5.1       Pharmacodynamic properties

Paediatric population

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.

10.       DATE OF REVISION OF THE TEXT

04/201406/2015

Highlighted changes to include new IE Agency - HPRA reporting information following the Agency name change (formerly IMB) in July 2014

4.8        Undesirable effects

Reporting of suspected adverse reactions

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRAIMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imbhpra.ie

e-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie

Malta

ADR Reporting

The Medicines Authority

Post-Licensing Directorate

203 Level 3, Rue D'Argens

GŻR-1368 Gżira

Website: www.medicinesauthority.gov.mt

e-mail: postlicensing.medicinesauthority@gov.mt

Ísland

til Lyfjastofnunar,  www.lyfjastofnun.is

Highlighted changes following approval of the PSUR (EMEA/H/C/000773/PSUV/0038), to include new information related to CT OVC-1002-1003 (interactions).

4.5       Interaction with other medicinal products and other forms of interaction

Effects of other substances on trabectedin

Interaction studies have only been performed in adults.

In vivo 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. the concentrations of trabectedin in plasma are likely to be increased in patients who are co-administered drugs that potently inhibit the activity of this isoenzyme. Similarly, the co-administration of trabectedin with potent inducers of CPY3A4 may increase the metabolic clearance of trabectedin. Two in vivo drug-drug interaction phase 1 studies have confirmed trends toward increased and decreased trabectedin exposures when administered with ketoconazole and rifampicin, respectively.

When ketoconazole was co-administered with trabectedin, the plasma exposure of trabectedin was increased by approximately 21% for C_max and 66% for AUC, but no new safety concerns were identified. Close monitoring of toxicities is required in patients receiving trabectedin in combination with potent CYP3A4 inhibitors (e.g. oral ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant) 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 of trabectedin by approximately 22% for C_max and 31% for AUC. Therefore, the concomitant use of trabectedin with strong CYP3A4 inducers (e.g., rifampicin, phenobarbital, Saint John’s Wort) should be avoided if possible (see section 4.4).

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.

10.       DATE OF REVISION OF THE TEXT

03/201404/2014

Highlighted changes following approval of the variation procedure IB-0039

4.8  Undesirable effects

Summary of the safety profile

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.

Tabulated summary of adverse reactions

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.

* 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.

* 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.

Description of selected adverse reactions

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.

[Black Triangle symbol] 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

4.2       Posology and method of administration

Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents.

Posology

For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m² body surface area, administered as an intravenous infusion over 24 hours with a three‑week interval between cycles.

For the treatment of ovarian cancer Yondelis is administered every three weeks as a 3‑hour infusion at a dose of 1.1 mg/m², immediately after PLD 30 mg/m². To minimize the risk of PLD infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent PLD infusions may be administered over a 1‑hour period. (see also PLD Summary of Product Characteristics [SmPC] for specific administration advice).

All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or Yondelis (in monotherapy); not only as anti‑emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti‑emetics may be administered as needed.

The following criteria are required to allow treatment with Yondelis:

-             Absolute neutrophil count (ANC) ≥ 1,500/mm³

-             Platelet count ≥ 100,000/mm³

-             Bilirubin ≤ upper limit of normal (ULN)

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

-             Albumin ≥ 25 g/l.

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

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

-             Creatine phosphokinase (CPK) ≤ 2.5 x ULN

-             Haemoglobin ≥ 9 g/dl

The same criteria as above must be met prior to re‑treatment. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met.

Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.

The same dose should be given for all cycles provided that no grade 3‑4 toxicities are seen and that the patient fulfils the re‑treatment criteria.

Dose adjustments during treatment

Prior to re‑treatment, patients must fulfil the baseline criteria defined above. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to table 1 below, for subsequent cycles:

-             Neutropenia < 500/mm³ lasting for more than 5 days or associated with fever or infection

-             Thrombocytopenia < 25,000/mm³

-             Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN

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

-             Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)

Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.

Table 1 Dose modification table for Yondelis (as single agent for soft tissue sarcoma (STS) or

in combination for ovarian cancer) and PLD

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

In the event that further dose reductions are necessary, treatment discontinuation should be considered.

Duration of treatment

In clinical trials, there were no pre‑defined limits to the number of cycles administered. Treatment continued whilst clinical benefit was noted. Yondelis has been administered for 6 or more cycles in 29.5% and 52% of patients treated with the monotherapy and combination dose and schedule respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.

Paediatric population

Yondelis should not be used in children below 18 years with paediatric sarcomas because of efficacy concerns (see 5.1 for results of paediatric sarcoma study).

Elderly patientsOlder people

No specific studies in elderly patientsolder 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.

Patients with hepatic impairment

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

Patients with renal impairment

Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the monotherapy, and < 60 ml/min for the combination regimen) have not been conducted and therefore Yondelis must not be used in this patient population (see section 4.4). Considering the pharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted in patients with mild or moderate renal impairment.

Method of administration

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

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

4.4 Special warnings and precautions for use

Hepatic impairment

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).

Renal impairment

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).

Neutropenia and thrombocytopenia

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).

Nausea and vomiting

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

Rhabdomyolysis and severe CPK elevations ( > 5 x ULN)

Trabectedin must not be used in patients with CPK > 2.5 x  ULN (see section 4.2). Rhabdomyolysis has been uncommonly reported, usually in association with myelotoxicity, severe liver function test abnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with Yondelis should be discontinued until the patient fully recovers.

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

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 dose reduction (see section 4.2).

Injection site reactions

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.

Allergic Reactions

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).

Others

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.

4.8  Undesirable effects

Summary of the safety profile

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.

Tabulated summary of adverse reactions

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.

* 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 or PLD 50 mg/m² in the pivotal trial ET743‑OVA-301. Both adverse reactions and laboratory values have been used. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Derived from laboratory data

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

In the Yondelis+PLD arm, non-white (mainly Asian) patients had a higher incidence than white patients in grade 3 or 4 adverse reactions (96% versus 87%), and serious adverse reactions (44% versus 23% all grades). The differences were mainly observed in relation with neutropenia (93% versus 66%), anaemia (37% versus 14%) and thrombocytopenia (41% versus 19%). However, the incidences of clinical complications related to haematological toxicity such as severe infections or bleeding, or those leading to death or treatment termination, were similar in both subpopulations.

Description of selected adverse reactions

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.

New added text highlighted in yellow.  Deleted text marked by strickthrough

4.2       Posology and method of administration

Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents.

Posology

For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m² body surface area, administered as an intravenous infusion over 24 hours with a three‑week interval between cycles.

For the treatment of ovarian cancer Yondelis is administered every three weeks as a 3‑hour infusion at a dose of 1.1 mg/m², immediately after PLD 30 mg/m². To minimize the risk of PLD infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent PLD infusions may be administered over a 1‑hour period. (see also PLD Summary of Product Characteristics [SmPC] for specific administration advice).

All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or Yondelis (in monotherapy); not only as anti‑emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti‑emetics may be administered as needed.

The following criteria are required to allow treatment with Yondelis:

-             Absolute neutrophil count (ANC) ≥ 1,500/mm³

-             Platelet count ≥ 100,000/mm³

-             Bilirubin ≤ upper limit of normal (ULN)

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

-             Albumin ≥ 25 g/l.

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

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

-             Creatine phosphokinase (CPK) ≤ 2.5 x ULN

-             Haemoglobin ≥ 9 g/dl

The same criteria as above must be met prior to re‑treatment. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met.

Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.

The same dose should be given for all cycles provided that no grade 3‑4 toxicities are seen and that the patient fulfils the re‑treatment criteria.

Dose adjustments during treatment

Prior to re‑treatment, patients must fulfil the baseline criteria defined above. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to table 1 below, for subsequent cycles:

-             Neutropenia < 500/mm³ lasting for more than 5 days or associated with fever or infection

-             Thrombocytopenia < 25,000/mm³

-             Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN

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

-             Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)

Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.

Table 1 Dose modification table for Yondelis (as single agent for soft tissue sarcoma (STS) or

in combination for ovarian cancer) and PLD

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

In the event that further dose reductions are necessary, treatment discontinuation should be considered.

Duration of treatment

In clinical trials, there were no pre‑defined limits to the number of cycles administered. Treatment continued whilst clinical benefit was noted. Yondelis has been administered for 6 or more cycles in 29.5% and 52% of patients treated with the monotherapy and combination dose and schedule respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.

Paediatric population

The safety and efficacy of trabectedin in the paediatric population have not yet been established.   No data are available.Yondelis should not be used in children below 18 years with paediatric sarcomas because of efficacy concerns (see 5.1 for results of paediatric sarcoma study).

Elderly patients

No specific studies in elderly patients 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.

Patients with hepatic impairment

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

Patients with renal impairment

Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the monotherapy, and < 60 ml/min for the combination regimen) have not been conducted and therefore Yondelis must not be used in this patient population (see section 4.4). Considering the pharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted in patients with mild or moderate renal impairment.

Method of administration

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

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

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01.

Mechanism of action

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.

Pharmacodynamic effects

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.

Electrocardiogram (ECG) investigations

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

Clinical efficacy

The efficacy and safety of trabectedin in soft tissue sarcoma is based in a randomised trial in patients with locally advanced or metastatic 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

* Primary efficacy analysis

^a Log rank test

^b Fisher’s test

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

In the final analysis, the effect of the Yondelis+PLD combination vs. PLD alone on overall survival was more pronounced in patients with PFI ³ 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.

Paediatric population

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.

10.       DATE OF REVISION OF THE TEXT

13/12/2012