Yondelis

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Yondelis 0.25 mg powder for concentrate for solution for infusion. 
 
Yondelis 1 mg powder for concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
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 
 
Each vial of powder contains 1 mg of trabectedin. 
 
One ml of reconstituted solution contains 0.05 mg of trabectedin. 
 
Excipients with known effect: 
 
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 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to off-white powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Yondelis is indicated for the treatment of adult patients with advanced soft tissue sarcoma, after 
failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are 
based mainly on liposarcoma and leiomyosarcoma patients. 
 
Yondelis in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of 
patients with relapsed platinum-sensitive ovarian cancer. 
 



 

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



 

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- 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 
 

 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.  
 
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 
 
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. 
 
Hepatic impairment 
 
Special caution is advised and dose adjustments may be necessary in patients with hepatic impairment 
since 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. Liver 
function tests should be monitored during treatment with Yondelis as dose adjustments may be 
indicated (see Table 1 and section 4.4). 
 



 

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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 sections 4.4 
and 6.6). 
 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6. 
 
4.3 Contraindications 
 
- 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) 
 
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 on average approximately doubled (see section 5.2) due 
to hepatic impairment and therefore the risk of toxicities might be increased, patients with clinically 
relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose 
adjusted if needed. Patients with elevated serum bilirubin levels 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). 
 



 

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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 
adjustments (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). 
 
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) 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. 



 

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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). 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of other substances on trabectedin 
 
Interaction studies have only been performed in adults. 
 
Since trabectedin is metabolised mainly by CYP3A4, 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 Cmax 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). 
 



 

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When rifampicin was co-administered with trabectedin, it resulted in reduced plasma exposure of 
trabectedin by approximately 22% for Cmax 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.  
 
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. If pregnancy occurs during treatment, the patient must be informed of 
the potential risk to the foetus (see section 5.3) and be monitored carefully. If trabectedin is used at 
the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns. 
 
Women of childbearing potential 
 
Women of childbearing potential must use effective contraception during treatment and 3 months 
thereafter, and immediately inform the treating physician if a pregnancy occurs (see section 5.3).  
 
If pregnancy occurs during treatment the possibility of genetic counselling should be considered. 
 
Breast-feeding 
 
It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk 
has not been studied in animals. Breast-feeding is contraindicated during treatment and 3 months 
thereafter (see section 4.3). 
 
Fertility 
 
Men in fertile age must use effective contraception during treatment and 5 months after treatment (see 
section 4.4). 
 
Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought 
prior to treatment because of the possibility of irreversible infertility due to therapy with Yondelis. 
Genetic counselling is also recommended for patients wishing to have children after therapy. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects of the ability to drive and to use machines have been performed. However, 
fatigue and/or asthenia have been reported in patients receiving trabectedin. Patients who experience 
any of these adverse reactions during therapy must not drive or operate machines. 
 



 

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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% 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 0.9% 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 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 and 
ovarian cancer that were treated with Yondelis recommended regimen in each indication. Both 
adverse reactions and laboratory values have been used to provide frequencies.  
 
Adverse reactions are listed by System Organ Class and frequency. The frequencies are classified as 
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare 
(≥ 1/10,000 to < 1/1,000).  
 

System Organ 
Class 

Very Common Common Uncommon Rare 

Infections and 
Infestations 

Neutropenic infection Sepsis Septic shock  

Blood and 
Lymphatic System 
Disorders 

Neutropenia 
Thrombocytopenia 
Anaemia 
Leukopenia 

Febrile neutropenia   

Immune system 
disorders 

 Hypersensitivity   

Metabolism and 
Nutrition Disorders 

Decreased appetite Dehydration 
Hypokalaemia 

  

Psychiatric 
Disorders 

Insomnia    

Nervous System 
Disorders 

Headache Dizziness 
Dysgeusia 
Peripheral sensory 
neuropathy 
Syncope* 

  

Cardiac disorders  Palpitations* 
Left ventricular dysfunction* 

  

Vascular Disorders  Hypotension 
Flushing 

Capillary leak 
syndrome 

 

Respiratory, 
Thoracic and 
Mediastinal 
Disorders 

Dyspnoea 
Cough 

Pulmonary embolism* Pulmonary 
oedema 

 



 

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System Organ 
Class 

Very Common Common Uncommon Rare 

Gastrointestinal 
disorders 

Abdominal pain 
Nausea 
Vomiting 
Constipation 
Diarrhoea 
Stomatitis 

Dyspepsia 
 
 
 
 

  

Hepatobiliary 
Disorders 

Alanine aminotransferase 
increased 
Aspartate aminotransferase 
increased 
Blood alkaline phosphatase 
increased 
Blood bilirubin increased 

Gamma-glutamyltransferase 
increased 
 
 
 
 

 Hepatic 
failure 

Skin and 
Subcutaneous 
Tissue Disorders 

Palmar-plantar 
erythrodysaesthesia 
syndrome* 

Rash 
Alopecia 
Skin hyperpigmentation* 

  

Musculoskeletal 
and Connective 
Tissue Disorders 

Arthralgia 
Back pain 
Blood creatine 
phosphokinase increased 

Myalgia 
 

Rhabdomyolysis  

General Disorders 
and Administration 
Site Conditions 

Fatigue 
Pyrexia 
Oedema 
Mucosal inflammation* 

Injection site reactions 
 

 

 

Extravasation 
Soft tissue 
necrosis 

 

Investigations Blood creatinine increased 
Blood albumin decreased 

Weight decreased   

 
*   Adverse drug reaction only for Ovarian cancer 
 
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. 



 

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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 
 
Hepatic failure: Rare cases of hepatic failure (including cases with fatal outcomes) have been 
reported in patients with serious underlying medical conditions treated with trabectedin, both in 
clinical trials and in post marketing setting. Some potential risk factors that may have contributed to 
increased trabectedin toxicity observed in these cases were dose management inconsistent with 
recommended guidelines, potential CYP3A4 interaction due to multiple competing CYP3A4 
substrates or CYP3A4 inhibitors, or lack of dexamethasone prophylaxis. 
 
Capillary Leak Syndrome (CLS): Cases of Capillary Leak Syndrome (CLS) have been reported with 
trabectedin (including cases with fatal outcomes) (see section 4.4). 
 
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. 
 
4.9 Overdose 
 
There is limited data on the effects of trabectedin overdose. The major anticipated toxicities are 
gastrointestinal, bone marrow suppression and hepatic toxicity. There is no specific antidote for 
trabectedin currently available. In the event of an overdose, patients should be closely monitored and 
symptomatic supportive care measures instituted as required.  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

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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 and safety 
 
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 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 



 

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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 
 

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 (%); 

Odds ratio (95% CI) 
34 (9.9%) 12 (6.9%) 1.47 (0.72, 3.2) 0.33 

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

CBR, 
n (%); 

Odds ratio (95% CI) 
34.2% 18.5% 2.3 (1.45, 3.7) <0.0002 

 
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. 
 
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 



 

14 

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 
 

 Yondelis+PLD PLD Hazard/Odds ratio p-value 
Progression Free Survival 

Independent radiology review, 
measurable disease * 

n=328 n=317   

Median PFS (95% CI) (months) 7.3 (5.9-7.9) 5.8 (5.5-7.1) 0.79 (0.65-0.96) 0.0190 a 
12 months PFS rate (95% CI) (%) 25.8 (19.7-32.3) 18.5 (12.9-24.9)   
Independent oncology review, 
all randomised 

n=336 n=335   

Median PFS (95% CI) (months) 7.4 (6.4-9.2) 5.6 (4.2-6.8) 0.72 (0.60-0.88) 0.0008 a 
Overall Survival (Final analysis - n=522 events) 

All randomised n=337 n=335   
Median OS (95% CI) (months) 22.2 (19.3-25.0) 18.9 (17.1-21.5) 0.86 (0.72-1.02) 0.0835 a 

Overall survival in platinum-sensitive population (Final analysis n=316 events) 
 n=218 n=212   
Median OS (95% CI) (months) 27.0 (24.1-31.4) 24.1 (20.9-25.9) 0.83 (0.67-1.04) 0.1056 a 

Overall Response Rate (ORR) 
Independent radiology review,  
all randomised 

n=337 n=335   

ORR (95% CI) (%) 27.6 (22.9-32.7) 18.8 (14.8-23.4) 1.65 (1.14-2.37) 0.0080 b 
* 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 ≥ 6 months (65% in Yondelis+PLD and 
63% in PLD arm), median PFS was 9.7 months in the Yondelis+PLD arm compared with 7.2 months 
in the PLD monotherapy arm (HR=0.66, CI: 0.52-0.85). 
  
In the final analysis, the effect of the Yondelis+PLD combination vs. PLD alone on overall survival 
was more pronounced in patients with PFI ≥ 6 months (platinum-sensitive population: 27.0 vs. 
24.1 months, HR=0.83, CI: 0.67-1.04) than in those with PFI < 6 months (platinum-resistant 
population: 14.2 vs. 12.4 months, HR=0.92, CI: 0. 70-1.21). 
 
The benefit in OS with Yondelis plus PLD was not due to the effect of subsequent therapies, which 
were well balanced between the two treatment arms. 
 
In the multivariate analyses including PFI, treatment effect on overall survival was statistically 
significant favouring the Yondelis+PLD combination over PLD alone (all randomised: p=0.0285; 
platinum-sensitive population: p=0.0319). 
 
No data are available comparing Yondelis+PLD to a platinum-based regimen in platinum-sensitive 
patients. 
 
No statistically significant differences were found between treatment arms in global measures of 
Quality of Life. 
 



 

15 

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.  
 
5.2 Pharmacokinetic properties 
 
Distribution 
 
Systemic exposure after intravenous administration as a constant rate infusion is dose proportional at 
doses up to and including 1.8 mg/m2. Trabectedin pharmacokinetic profile is consistent with a 
multiple-compartment disposition model. 
 
Following intravenous administration, trabectedin demonstrates a high apparent volume of 
distribution, consistent with extensive tissue and plasma protein binding (94 to 98% of trabectedin in 
plasma is protein bound). The distribution volume at steady state of trabectedin in human subjects 
exceeds 5,000 l. 
 
Biotransformation 
 
Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative 
metabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute 
to metabolism. Trabectedin does not induce or inhibit major cytochrome P450 enzymes. 
 
Elimination 
 
Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half-life is 
long (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelled 
trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is 
58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for 
plasma clearance of trabectedin (30.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedin 
in whole blood is approximately 35 l/h. This value is approximately one-half the rate of human 
hepatic blood flow. Thus the trabectedin extraction ratio can be considered moderate. The 
inter-patient variability of the population estimate for plasma clearance of trabectedin was 49% and 
intra-patient variability was 28%. 
 
A population pharmacokinetic analysis showed that when administered in combination with PLD, the 
plasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were 
not influenced by the concomitant administration of trabectedin. 
 
Special populations 
 
A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is not 
influenced by age (range 19-83 years), gender, total body weight (range: 36 to 148 kg) or body surface 
area (range: 0.9 to 2.8 m2). A population pharmacokinetic analysis showed that plasma trabectedin 



 

16 

concentrations observed in the Japanese population at dose level 1.2 mg/m2 were equivalent to those 
obtained in the non-Japanese western population at 1.5 mg/m². 
 
Renal impairment 
 
There is no relevant influence of renal function measured by creatinine clearance on trabectedin 
pharmacokinetics within the range of values (≥ 30.3 ml/min) present in the patients included in the 
clinical studies. No data are available in patients with a creatinine clearance of less than 30.3 ml/min. 
The low recovery (< 9% in all studied patients) of total radioactivity in the urine after a single dose of 
14C-labelled trabectedin indicates that renal impairment has little influence on the elimination of 
trabectedin or its metabolites. 
 
Hepatic impairment 
 
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). 
 
5.3 Preclinical safety data 
 
Preclinical data indicate that trabectedin has limited effect on the cardiovascular, respiratory and 
central nervous system at exposures below the therapeutic clinical range, in terms of AUC. 
 
The effects of trabectedin on cardiovascular and respiratory function have been investigated in vivo 
(anesthetised Cynomolgus monkeys). A 1 hour infusion schedule was selected to attain maximum 
plasma levels (Cmax values) in the range of those observed in the clinic. The plasma trabectedin levels 
attained were 10.6 ± 5.4 (Cmax), higher than those reached in patients after infusion of 1,500 µg/m2 for 
24 (Cmax of 1.8 ± 1.1 ng/ml) and similar to those reached after administration of the same dose by 
3 hour infusion (Cmax of 10.8 ± 3.7 ng/ml). 
 
Myelosupression and hepatoxicity were identified as the primary toxicity for trabectedin. Findings 
observed included haematopoietic toxicity (severe leukopenia, anaemia, and lymphoid and bone 
marrow depletion) as well as increases in liver function tests, hepatocellular degeneration, intestinal 
epithelial necrosis, and severe local reactions at the injection site. Renal toxicological findings were 
detected in multi-cycle toxicity studies conducted in monkeys. These findings were secondary to 
severe local reaction at the administration site, and therefore uncertainly attributable to trabectedin; 
however, caution must be guaranteed in the interpretation of these renal findings, and 
treatment-related toxicity cannot be excluded.  
 
Trabectedin is genotoxic both in vitro and in vivo. Long-term carcinogenicity studies have not been 
performed. 
 
Fertility studies with trabectedin were not performed but limited histopathological changes were 
observed in the gonads in the repeat dose toxicity studies. Considering the nature of the compound 
(cytotoxic and mutagenic), it is likely to affect the reproductive capacity. 
 
Placental transfer of trabectedin and fetal exposure to trabectedin were observed in a study in 
pregnant rats that received a single i.v. 14C-trabectedin dose at 0.061 mg/kg. Maximum fetal tissue 
radioactivity concentration was similar to that in maternal plasma or blood. 
 
 



 

17 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose 
 
Potassium dihydrogen phosphate 
 
Phosphoric acid (for pH-adjustment) 
 
Potassium hydroxide (for pH-adjustment) 
 
6.2 Incompatibilities 
 
Yondelis must not be mixed or diluted with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vials  
 
60 months. 
 
After reconstitution 
 
Chemical and physical stability has been demonstrated for 30 hours up to 25ºC.  
 
From a microbiological point of view, the reconstituted solution should be diluted and used 
immediately. If not diluted and used immediately, in-use storage times and conditions prior to use of 
the reconstituted product are the responsibility of the user and would normally not be longer than 24 
hours at 2ºC to 8ºC, unless reconstitution has taken place in controlled and validated aseptic 
conditions. 
 
After dilution 
 
Chemical and physical stability has been demonstrated for 30 hours up to 25ºC. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2ºC - 8ºC). 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
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. 
 
Each carton contains one vial. 
 



 

18 

Yondelis 1 mg 
 
Type I colourless glass vial with a butyl rubber stopper covered with an aluminium flip-off seal 
containing 1mg of trabectedin. 
 
Each carton contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
Preparation for intravenous infusion 
 
Yondelis must be reconstituted and further diluted prior to intravenous infusion. Appropriate aseptic 
techniques must be used to prepare the infusion solution (see Instructions for reconstitution and for 
dilution). 
 
When used in combination with PLD the intravenous line should be flushed well with 50 mg/ml (5%) 
glucose solution for infusion after administration of PLD and before administration of Yondelis. The 
use of any diluent other than 50 mg/ml (5%) glucose solution for infusion for this line flushing may 
cause precipitation of PLD (see also PLD Summary of Product Characteristics for specific handling 
instructions). 
 
Instructions for reconstitution 
 
Yondelis 0.25 mg 
 
Each vial containing 0.25 mg of trabectedin is reconstituted with 5 ml of water for injections. The 
solution obtained has a concentration of 0.05 mg/ml and is for single-use only. 
 
A syringe is used to inject 5 ml of sterile water for injections into the vial. The vial must be shaken 
until complete dissolution. The reconstituted solution results in a clear, colourless or slightly 
yellowish solution, essentially free of visible particles. 
 
This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for 
single-use only. 
 
Yondelis 1 mg 
 
Each vial containing 1 mg of trabectedin is reconstituted with 20 ml of water for injections. The 
solution obtained has a concentration of 0.05 mg/ml and is for single-use only. 
 
A syringe is used to inject 20 ml of sterile water for injections into the vial. The vial must be shaken 
until complete dissolution. The reconstituted solution results in a clear, colourless or slightly 
yellowish solution, essentially free of visible particles. 
 
This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for 
single-use only 
 
Instructions for dilution 
 
The reconstituted solution should be diluted with sodium chloride 9 mg/ml (0.9%) solution for 
infusion or glucose 50 mg/ml (5%) solution for infusion. The required volume should be calculated as 
follows: 
 



 

19 

Volume (ml) = BSA (m2) x individual dose (mg/m2) 
    0.05 mg/ml 
 
BSA = Body Surface Area 
 
If administration is to be made through a central venous line, the appropriate amount of reconstituted 
solution should be withdrawn from the vial and added to an infusion bag containing ≥ 50 ml of diluent 
(sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for 
infusion), the concentration of trabectedin in the infusion solution being ≤ 0.030 mg/ml. 
 
If central venous access is not feasible and a peripheral venous line has to be used, the reconstituted 
solution should be added to an infusion bag containing ≥ 1,000 ml of diluent (sodium chloride 
9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion).  
 
Parenteral solutions should be inspected visually for particles prior to administration. Once the 
infusion is prepared, it should be administered immediately. 
 
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 cytotoxic 
medicinal products must be followed. Personnel should be trained in the correct techniques to 
reconstitute and dilute the medicinal product and should wear protective clothing including mask, 
goggles and gloves during the reconstitution and dilution. Pregnant staff must be excluded from 
working with this medicinal product. 
 
Accidental contact with the skin, eyes or mucous membranes must be treated immediately with 
copious amounts of water. 
 
No incompatibilities have been observed between Yondelis and type I glass bottles, polyvinylchloride 
(PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs and titanium implantable 
vascular access systems. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements for cytotoxic medicinal products. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pharma Mar, S.A. 
Avda. de los Reyes 1, Polígono Industrial La Mina 
28770 Colmenar Viejo (Madrid) 
Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Yondelis 0.25 mg 
 
EU/1/07/417/001 
 
Yondelis 1 mg 
 
EU/1/07/417/002 
 
 



 

20 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 September 2007 
Date of latest renewal: 03 August 2012 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 
 

http://www.ema.europa.eu/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE  

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION  
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT  



 

22 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Pharma Mar, S.A. 
Polígono Industrial La Mina 
Avda. de los Reyes, 1 
E-28770 Colmenar Viejo  
Madrid 
Spain 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2. of the marketing 
authorisation and any agreed subsequent updates of the RMP.  
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



 

23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 

24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

25 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton – 0.25 mg vial 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Yondelis 0.25 mg powder for concentrate for solution for infusion 
trabectedin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 0.25 mg of trabectedin. 
1 ml of reconstituted solution contains 0.05 mg of trabectedin. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: sucrose, potassium dihydrogen phosphate, phosphoric acid and potassium hydroxide. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial of 0.25 mg trabectedin 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and further dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: handle with caution. 
 
 
8. EXPIRY DATE 
 
EXP: 



 

26 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. For storage conditions after reconstitution and dilution of the medicinal 
product, see the package leaflet. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard any unused product or waste material in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pharma Mar, S.A. 
Avda. de los Reyes 1 
Pol. Ind. La Mina 
28770 Colmenar Viejo (Madrid) 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/417/001  
 
 
13. BATCH NUMBER 
 
Lot:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



 

27 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN 
 
 



 

28 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial label – 0.25 mg vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Yondelis 0.25 mg powder for concentrate for solution for infusion 
trabectedin 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP:  
 
 
4. BATCH NUMBER 
 
Lot:  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.25 mg trabectedin 
 
 
6. OTHER 
 
 



29 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton – 1 mg vial  
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Yondelis 1 mg powder for concentrate for solution for infusion 
trabectedin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 mg of trabectedin. 
1 ml of reconstituted solution contains 0.05 mg of trabectedin.  
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: sucrose, potassium dihydrogen phosphate, phosphoric acid and potassium hydroxide. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial of 1 mg trabectedin 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution and further dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic: handle with caution. 
 
 
8. EXPIRY DATE 
 
EXP: 
 



 

30 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. For storage conditions after reconstitution and dilution of the medicinal 
product, see the package leaflet. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard any unused product or waste material in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pharma Mar, S.A. 
Avda. de los Reyes 1 
Pol. Ind. La Mina 
28770 Colmenar Viejo (Madrid) 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/417/002 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



 

31 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN 
 
 
 



 

32 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial label – 1 mg vial  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Yondelis 1 mg powder for concentrate for solution for infusion 
trabectedin 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot:  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 mg trabectedin 
 
 
6. OTHER 
 
 



 

33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



 

34 

Package leaflet: Information for the patient 
 
 

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

trabectedin 
 

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet  
 
1. What Yondelis is and what it is used for 
2. What you need to know before you are given Yondelis 
3. How to use Yondelis 
4. Possible side effects 
5. How to store Yondelis 
6. Contents of the pack and other information 
 
 
1. What Yondelis is and what it is used for 
 
Yondelis contains the active substance trabectedin. Yondelis is an anti-cancer medicine that works by 
preventing the tumour cells from multiplying. 
 
Yondelis is used for the treatment of patients with advanced soft tissue sarcoma, when previous 
medicines have been unsuccessful or the patients are unsuited to receive them. Soft tissue sarcoma is 
a malignant disease that starts somewhere in the soft tissues, such as the muscles, fat or other tissues 
(for example cartilages or vessels). 
 
Yondelis in combination with pegylated liposomal doxorubicin (PLD: another anti-cancer medicine) 
is used for the treatment of patients with ovarian cancer that has come back after at least 1 previous 
therapy and are not resistant to anti-cancer medicines containing platinum compounds. 
 
 
2. What you need to know before you are given Yondelis 
 
Do not use Yondelis 
 
- if you are allergic to trabectedin or any of the other ingredients of this medicine (listed in 

section 6). 
- if you have any serious infections. 
- if you are breast-feeding. 
- if you will receive yellow fever vaccine. 
 
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.  



 

35 

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. 
 
You should seek medical attention immediately if any of the following conditions appear: 
 
• If you develop a fever as Yondelis may cause side-effects affecting your blood and liver. 
 
• If you still feel sick, vomit or are unable to drink fluids and therefore pass less urine despite 

being given anti-sickness medicines. 
 
• If you experience severe muscle pain or weakness as it could be a sign of damage to your 

muscles (rhabdomyolysis; see section 4). 
 
• If you notice that Yondelis infusion leaks out of your vein while you are being given it. It could 

lead to damage and death of your tissue cells around the injection site (tissue necrosis, see also 
section 4) which may require surgery. 

 
• If you have an allergic reaction (hypersensitivity). In this case you may experience one or more 

of the following signs: fever, difficulty in breathing, redness or flushing of the skin or a rash, 
feeling sick (nausea) or being sick (vomiting; see section 4). 
 

• If you notice unexplained partial or general swelling (oedema), with possible lightheadedness, 
dizziness or thirst (low blood pressure). It could be a sign of a condition (capillary leak 
syndrome) that can cause excessive accumulation of fluid in your tissues, and requires urgent 
medical evaluation by your doctor. 

 
Children and adolescents  
 
Yondelis should not be used in children below 18 years of age with paediatric sarcomas. 
 
Other medicines and Yondelis 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
You must not use Yondelis if you will receive yellow fever vaccine and it is not recommended that 
you use Yondelis if you will receive a vaccine containing live virus particles. The effect of medicines 
containing phenytoin (for epilepsy) may be decreased if given together with Yondelis and this is 
therefore not recommended.  
 
If you use any of the following medicines during your treatment with Yondelis, you need to be closely 
monitored as the effects of Yondelis are: 
 
• decreased (examples are medicines containing rifampicin (for bacterial infections), phenobarbital 

(for epilepsy) or St. John’s Wort (Hypericum perforatum, an herbal medicine for depression)) or  
 
• increased (examples are medicines containing ketoconazole or fluconazole (for fungal 

infections), ritonavir (for human immunodeficiency virus [HIV] infection), clarithromycin (for 



 

36 

bacterial infections), aprepitant (to prevent nausea and vomiting), ciclosporin (inhibit the 
defensive system of the body) or verapamil (for high blood pressure and heart conditions)).  

 
Thus the use of any of these medicines together with Yondelis should be avoided, if possible.  
 
If you are given Yondelis or the combination Yondelis+PLD together with a medicine that might 
cause damage to the liver or to the muscles (rhabdomyolysis), you may need to be closely monitored, 
as there could be an increased risk of liver or muscle damage. Medicines containing statins (for 
lowering cholesterol levels and preventing cardiovascular disease) is an example of medicines that 
may cause muscle damage. 
 
Yondelis with alcohol 
 
Alcohol consumption must be avoided during treatment with Yondelis as this may harm the liver. 
 
Pregnancy, breast-feeding and fertility 
 
Pregnancy 
 
Yondelis should not be used during pregnancy. If you are pregnant, think you may be pregnant or are 
planning to have a baby, ask your doctor for advice before you are given this medicine.  
 
Adequate contraceptive precautions must be used by women of childbearing potential when receiving 
Yondelis and for 3 months following the end of treatment.  
 
If a pregnancy should occur you must tell your doctor immediately and genetic counselling is 
recommended since Yondelis can cause genetic damage. 
 
Breast-feeding 
 
Yondelis must not be given to patients who are breast-feeding. Therefore you must stop 
breast-feeding before you start your treatment and you must not begin breast-feeding again until your 
doctor has confirmed that it is safe to do so. 
 
Fertility 
 
Adequate contraceptive precautions must be used by men in fertile age when receiving Yondelis and 
for 5 months following the end of treatment. 
 
Patients should seek advice on ovules or sperm conservation prior to treatment because of the risk of 
irreversible infertility due to therapy with Yondelis. 
 
Genetic counselling is also recommended for patients wishing to have children after therapy.  
 
Driving and using machines 
 
During your treatment with Yondelis you may feel tired and experience a loss of strength. Do not 
drive or use any tools or machines if you are experiencing any of these side effects. 
 
Yondelis contains potassium 
 
This medicine contains potassium, less than 1 mmol (39 mg) per vial, and can therefore be considered 
as essentially “potassium-free”. 
 
 



 

37 

3. How to use Yondelis 
 
Yondelis is given to you 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 medicines. 
 
For the treatment of soft tissue sarcoma, the usual dose is 1.5 mg/m2 of body surface area. During the 
treatment period, your doctor will carefully monitor you and decide the most appropriate dosage of 
Yondelis to give to you. The recommended dose in Japanese patients is lower than the usual dose for 
all other races, and is 1.2 mg/m2 of body surface area. 
 
For the treatment of ovarian cancer, the usual dose is 1.1 mg/m2 body surface area after the 
administration of 30 mg/m2 body surface area of PLD. 
 
Before Yondelis is given to you, it is reconstituted and diluted for intravenous use. Every time you are 
given Yondelis for the treatment of soft tissue sarcoma, it will take about 24 hours for all of the 
solution to enter your blood. It will take 3 hours for the treatment of ovarian cancer. 
 
In order to avoid irritation at the site of injection it is recommended that Yondelis is given to you 
through a central venous line.  
 
You will be given a medicine before and as needed during the treatment with Yondelis in order to 
protect your liver and to reduce the risk of side effects such as feeling sick (nausea) and vomiting.  
 
The infusion is given to you every 3 weeks, although occasionally your doctor may recommend dose 
delays to ensure that you receive the most appropriate dose of Yondelis. 
 
The length of your whole treatment period will depend on your progress and how well you feel. Your 
doctor will tell you how long your treatment lasts. If you have any further questions on the use of this 
medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine or its combination with PLD can cause side effects, although not 
everybody gets them. 
 
If you are not sure what the side effects below are, you should ask your doctor to explain them to you 
in more detail. 
 
Serious side effects caused by the treatment with Yondelis: 
 
Very common: may affect more than 1 in 10 people 
 
• You could have increased levels of the yellow pigment bilirubin in the blood which might cause 

jaundice (a yellowing of the skin, mucous membranes and eyes). 
 
• Your doctor will order regular blood tests to detect any abnormalities in the blood. 
 
Common: may affect up to 1 in 10 people 
 
• You may also have blood infections (sepsis) if your immune system is greatly compromised. If 

you have fever you should seek medical attention immediately. 
 



 

38 

• You could also feel pain in your muscles (myalgia). There could also be damage to your nerves 
which may result in muscle pain, weakness and numbness. You could experience general 
swelling or swelling of the limbs and a sensation of creeping on the skin. 

 
• You may have a reaction at the site of injection. Yondelis infusion may leak out of your vein 

while you are being given it, leading to damage and death of your tissue cells around the 
injection site (tissue necrosis, see also section 2 “Warnings and precautions”) which may 
require surgery. 

 
• You could have an allergic reaction. In this case you may experience fever, difficulty in 

breathing, redness or flushing of the skin or a rash, feeling sick (nausea) or being sick 
(vomiting). 

 
• When Yondelis is used in combination with PLD, you may have syncope also called fainting. 

Furthermore, you could feel like your heart is beating too hard or too fast in your chest 
(palpitations), have a weakness in the ventricles, the heart's major pumping chambers (left 
ventricular dysfunction), or a sudden blockage in a lung artery (pulmonary embolism).  

 
Uncommon: may affect up to 1 in 100 people 

 
• You may feel severe muscle aches and pain, stiffness and muscle weakness. You also may 

experience a darkening of the urine colour. All the previously described, could be a sign of 
damage to your muscles (rhabdomyolysis). 
  

• Your doctor may require blood tests in certain situations in order to avoid that you develop 
muscle damage (rhabdomyolysis). In very severe cases this could lead to kidney failure. If you 
experience severe muscle pain or weakness, you should seek medical attention immediately. 

 
• You may experience difficulty in breathing, irregular heartbeat, decreased urine output, abrupt 

change in mental status, areas of mottled skin, extremely low blood pressure associated with 
abnormal laboratory test results (decrease in platelet count). If you get any of the above 
symptoms or signs, seek medical care immediately. 
 

• You may experience an abnormal build-up of fluid in the lungs, which leads to swelling 
(pulmonary oedema). 
 

• You may notice unexplained partial or general swelling (oedema), with possible 
lightheadedness, dizziness or thirst (low blood pressure). It could be a sign of a condition 
(capillary leak syndrome) that can cause excessive accumulation of fluid in your tissues. If you 
get the above symptoms or signs, seek medical care immediately. 

 
• You may notice that Yondelis infusion leaks out of your vein (extravasation) while you are 

being given it. Then you will notice some redness, swelling, itchiness and discomfort at the 
injection site. If you get any of these symptoms or signs, tell your nurse or doctor 
immediately.  

 
It could lead to damage and death of your tissue cells around the injection site (tissue necrosis) 
which may require surgery. 
 
Some of the symptoms or signs of extravasation may not be visible until several hours after it 
occurred. There may be blistering, peeling and darkening of the skin over the site. It is possible 
for it to take a few days before the full extent of tissue damage is visible. If you get any of the 
previous described symptoms or signs, seek medical care immediately. 

 



 

39 

Rare: may affect up to 1 in 1,000 people 
 
• You may experience yellowing of your skin and eyeballs (jaundice), pain in the upper right area 

of your abdomen, nausea, vomiting, a general sense of not feeling well, difficulty in 
concentrating, disorientation or confusion, sleepiness. These signs could be indicative of the 
inability of the liver to perform its normal function. If you get any of the previous described 
symptoms or signs, seek medical care immediately. 

 
Other less serious side effects: 
 
Very common: may affect more than 1 in 10 people 
 
• You may: 

• feel tired 
• feel difficulty breathing and coughing 
• feel pain in your back and joints 
• feel an excess of fluid in the body (oedema) 
• bruise more easily 
• have nose bleeds 
• be more prone to infections. An infection could also give you a raised temperature 

(fever).  
 If you develop any of these symptoms you should seek medical attention immediately.  
 
• You may present some digestive symptoms such as loss of appetite, sick (nausea) or vomit, pain 

in the abdomen, diarrhoea or constipation. If you still feel sick, vomit or are unable to drink 
fluids and therefore pass less urine, despite being given anti-sickness medicine, you should 
immediately seek medical help. 

 
• You may experience headache and sleeping problems. 
 
• You could have mucosal inflammation as a swelling redness of the inside of the mouth leading 

to painful ulcers and mouth sores inflammation of the mouth (stomatitis), or as an inflammation 
of the gastrointestinal tract when Yondelis is used with PLD. 

 
• Patients receiving Yondelis plus PLD for ovarian cancer may also have the hand and foot 

syndrome. It may present as red skin of the palms, fingers, and soles of the feet that later may 
become swollen and violaceous. The lesions may either dry out and desquamate, or blister with 
ulceration. 

 
Common: may affect up to 1 in 10 people 
 
• You may experience, loss of water from the body, weight loss, digestive discomfort and a 

change in your sense of taste. 
 
• You may lose hair (alopecia). 
 
• You could also experience dizziness, low blood pressure and flushing or skin rash. 

 
• Higher skin pigmentation could occur in patients receiving Yondelis with PLD for ovarian 

cancer. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in 



 

40 

Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Yondelis 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the vial label after 
EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2ºC - 8ºC). 
 
Information on in-use stability of the reconstituted and diluted solutions is included in the section for 
medical and healthcare professionals.  
 
Do not use this medicine if you notice visible particles after the reconstitution or dilution of the 
medicine. 
 
Any unused medicine or waste material should be disposed of in accordance with local requirements 
for cytotoxic medicines. 
 
 
6. Contents of the pack and other information 
 
What Yondelis contains: 
 
- The active substance is trabectedin. 

Yondelis 0.25 mg: Each vial of powder contains 0.25 mg of trabectedin. 
Yondelis 1 mg: Each vial of powder contains 1 mg of trabectedin. 
 

- The other ingredients are sucrose, potassium dihydrogen phosphate, phosphoric acid (for 
pH-adjustment) and potassium hydroxide (for pH-adjustment). 

 
What Yondelis looks like and contents of the pack 
 
Yondelis is a powder for concentrate for solution for infusion. The powder has a white to off-white 
colour and comes in a glass vial. 
 
Each carton contains 1 vial of either 0.25 mg or 1 mg of trabectedin. 
 
Marketing Authorisation Holder and Manufacturer: 
 
Pharma Mar, S.A.  
Avda. de los Reyes 1 
Polígono Industrial La Mina 
28770 Colmenar Viejo (Madrid) 
Spain 
Tel: +34 91 846 60 00 
Fax: +34 91 846 60 01 
 
For any information about this medicine, please contact the Marketing Authorisation Holder. 
 

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41 

This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 
The following information is intended for healthcare professionals only: 
 
Instructions for use – preparation, handling and disposal 
 
Appropriate procedures for proper handling and disposal of cytotoxic medicines must be followed. 
Any unused medicine or waste material should be disposed of in accordance with local requirements 
for cytotoxic medicines. 
 
You should have received training on the correct techniques to reconstitute and dilute Yondelis or its 
combination with PLD and you should wear protective clothing including mask, goggles and gloves 
during the reconstitution and dilution. Accidental contact with the skin, eyes or mucous membranes 
must be treated immediately with copious amounts of water. You should not work with this medicine 
if you are pregnant. 
 
Preparation for intravenous infusion 
 
Yondelis must be reconstituted and further diluted prior to infusion (see also section 3). Appropriate 
aseptic techniques must be used. 
 
Yondelis must not be administered as a mixture with other medicines in the same infusion apart from 
the diluent. No incompatibilities have been observed between Yondelis and type I glass bottles, 
polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, polyisoprene reservoirs and titanium 
implantable vascular access systems. 
 
When Yondelis is used in combination with PLD, the intravenous line should be flushed well with 
50 mg/ml (5%) glucose solution for infusion after administration of PLD and before administration of 
Yondelis. The use of any diluent other than 50 mg/ml (5%) glucose solution for infusion may cause 
precipitation of PLD. (See also PLD Summary of Product Characteristics for specific handling 
instructions). 
 
Instructions for reconstitution 
 
Yondelis 0.25 mg: Inject 5 ml of sterile water for injections into the vial. 
 
Yondelis 1 mg: Inject 20 ml of sterile water for injections into the vial.  
 
A syringe is used to inject the correct amount of sterile water for injections into the vial. Shake the 
vial until complete dissolution. The reconstituted solution results in a clear, colourless or slightly 
yellowish solution, essentially free of visible particles. 
 
This reconstituted solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is for 
single-use only. 
 
Instructions for dilution 
 
Dilute the reconstituted solution with sodium chloride 9 mg/ml (0.9%) solution for infusion or 
glucose 50 mg/ml (5%) solution for infusion. Calculate the required volume as follows: 
 

http://www.ema.europa.eu/


 

42 

Volume (ml) = BSA (m2) x individual dose (mg/m2) 
    0.05 mg/ml 
 
BSA = Body Surface Area 
 
Withdraw the appropriate amount of reconstituted solution from the vial. If intravenous 
administration is to be made via a central venous line, add the reconstituted solution to an infusion 
bag containing ≥ 50 ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 
50 mg/ml (5%) solution for infusion), the concentration of trabectedin in the infusion solution 
being ≤ 0.030 mg/ml. 
 
If central venous access is not feasible and a peripheral venous line has to be used, add the 
reconstituted solution to an infusion bag containing ≥ 1,000 ml of diluent (sodium chloride 
9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion). 
 
Inspect the parenteral solution visually for particles prior to intravenous administration. Once the 
infusion is prepared, it should be administered immediately. 
 
In-use stability of the solutions 
 
Reconstituted solution 
After reconstitution, chemical and physical stability has been demonstrated for 30 hours up to 25ºC.  
 
From a microbiological point of view, the reconstituted solution should be diluted and used 
immediately. If not diluted and used immediately, in-use storage times and conditions prior to use of 
the reconstituted solution are the responsibility of the user and would normally not be longer than 
24 hours at 2ºC to 8ºC, unless reconstitution has taken place in controlled and validated aseptic 
conditions. 
 
Diluted solution 
After dilution, chemical and physical stability has been demonstrated for 30 hours up to 25ºC.  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
	A. LABELLING
	B. PACKAGE LEAFLET