ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Yondelis 0.25 mg powder for concentrate for solution for infusion.
2.
Each vial contains 0.25 mg of trabectedin.
1 ml of reconstituted solution contains 0.05 mg of trabectedin.
Excipients:
Each vial contains 2 mg of potassium and 0.1 g of sucrose.
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
White to off-white powder.
4.
Yondelis is indicated for the treatment of 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.
Yondelis must be administered under the supervision of a physician experienced in the use of
chemotherapy. Its use should be confined to qualified oncologists or other health professionals
specialised in the administration of cytotoxic agents.
For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m
2
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/m
2
, immediately after PLD 30 mg/m
2
. To minimize the risk of PLD infusion
reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction
is observed, subsequent PLD infusions may be administered over a 1-hour period. (See also PLD
Summary Product Characteristics for specific administration advice).
Administration through a central venous line is strongly recommended (see section 6.6).
All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior
to PLD (in combination therapy) or Yondelis (in monotherapy); not only as anti-emetic prophylaxis,
but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be
administered as needed.
2
The following criteria are required to allow treatment with Yondelis:
-
Absolute neutrophil count (ANC) ≥ 1,500/mm
3
-
Platelet count ≥ 100,000/mm
3
-
Bilirubin ≤ upper limit of normal (ULN)
-
Alkaline phosphatase ≤ 2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or GGT, if the
elevation could be osseous in origin).
-
Albumin ≥ 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/mm
3
lasting for more than 5 days or associated with fever or infection
-
Thrombocytopenia < 25,000/mm
3
-
Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN
-
Increase of aminotransferases (AST or ALT) > 2.5 x ULN (monotherapy) or > 5 x ULN
(combination therapy), which has not recovered by day 21
-
Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)
Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not
recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical
benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered
for hematologic toxicity according to local standard practice.
Table 1 Dose modification table for Yondelis (as single agent for STS or
in combination for ovarian cancer) and PLD
Soft Tissue Sarcoma
Ovarian Cancer
Yondelis
Yondelis
PLD
Starting dose
1.5 mg/m
2
1.1 mg/m
2
30 mg/m
2
First reduction
1.2 mg/m
2
0.9 mg/m
2
25 mg/m
2
Second reduction
1 mg/m
2
0.75 mg/m
2
20 mg/m
2
See the PLD SPC for more detailed information on PLD dose adjustments.
In the event that further dose reductions are necessary, treatment discontinuation should be considered.
Duration of treatment
3
In clinical trials, there were no pre-defined limits to the number of cycles administered. Treatment
continued whilst clinical benefit was noted. Yondelis has been administered for 6 or more cycles in
29.5% and 52% of patients treated with the monotherapy and combination dose and schedule
respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles
respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.
Special patient populations
Paediatric patients
The safety and efficacy of trabectedin in paediatric patients have not yet been established. Therefore,
this medicinal product must not be used in children and adolescents until further data become
available.
Elderly patients
No specific studies in elderly patients have been performed. Overall 20% of the 1164 patients in the
integrated safety analysis of monotherapy clinical trials were over 65 years. Of the 333 patients with
ovarian cancer who received trabectedin in combination with PLD, 24% were 65 years of age or older
and 6% were over 75 years. No relevant differences in the safety profile were seen in this patient
population. It seems that plasma clearance and distribution volume of trabectedin are not influenced
by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.
Patients with impaired hepatic function
No studies with the proposed regimen have been conducted in patients with liver dysfunction. Thus,
data are not available to recommend a lower starting dose in patients with hepatic impairment.
However, special caution is advised and dose adjustments may be necessary in these patients since
systemic exposure is probably increased and the risk of hepatotoxicity might be increased. Patients
with elevated bilirubin must not be treated with Yondelis (see section 4.4).
Patients with impaired renal function
Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the
monotherapy, and < 60 ml/min for the combination regimen) have not been conducted and therefore
Yondelis must not be used in this patient population (see section 4.4). Considering the
pharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted in
patients with mild or moderate renal impairment.
For instructions on reconstitution and dilution of the medicinal product before administration, see
section 6.6.
-
Hypersensitivity to trabectedin or to any of the excipients
-
Concurrent serious or uncontrolled infection
-
Combination with yellow fever vaccine (see section 4.4)
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
4
-
Breast-feeding (see section 4.6)
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/mm
3
and platelets count of less than 100,000 cells/mm
3
. If severe neutropenia
(ANC < 500 cells/mm
3
) 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.
5
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).
Men in fertile age and women of childbearing potential must use effective contraception during
treatment and 3 months thereafter for women and immediately inform the treating physician if a
pregnancy occurs, and 5 months after treatment for men (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.
Effects of other substances on trabectedin
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, phenorbarbital,
Saint John’s Wort) may decrease the systemic exposure to trabectedin.
Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of
the medicinal product (see section 4.4).
Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration
of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or
elimination. The relevance of this interaction e.g. CNS toxicity has not been established. Caution
should be taken in such situations.
Pregnancy
No sufficient clinical data on exposed pregnancies are available. However, based on its known
mechanism of action, trabectedin may cause serious birth defects when administered during
pregnancy. Trabectedin should not be used during pregnancy unless clearly necessary. If it is used
during pregnancy, the patient must be informed of the potential risk to the foetus (see section 5.3) and
be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions
should be monitored carefully in the newborns.
Fertility
6
Men in fertile age and women of childbearing potential must use effective contraception during
treatment and 3 months thereafter for women and immediately inform the treating physician if a
pregnancy occurs (see section 5.3) and 5 months after treatment for men (see section 4.4).
Trabectedin can have genotoxic effects. Advice on conservation of sperm should be sought prior to
treatment because of the possibility of irreversible infertility due to therapy with Yondelis.
If pregnancy occurs during treatment the possibility of genetic counselling should be considered.
Genetic counselling is also recommended for patients wishing to have children after therapy.
Lactation
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).
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 events during therapy must not drive or operate machines.
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.
The frequencies of the adverse reactions reported below are classified as very common (≥ 1/10),
common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 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/m
2
, 24 hour infusion every 3 weeks) according to the standard
MedDRA 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.
7
System Organ
Class
Adverse reactions reported in ≥ 1% of patients in clinical trials at the
recommended regimen [1.5
mg/m
2
, 24
hour infusion every 3 weeks ]
Investigations
Very Common
Blood creatine phosphokinase increased* (Grade 3-4 = 4%),
Blood creatinine increased*, Blood albumin decreased*
Common
Weight decreased
Blood and
Lymphatic System
Disorders
Very Common
Neutropenia* (Grade 3 = 26%, Grade 4 = 24%),
Thrombocytopenia* (Grade 3 = 11%, Grade 4 = 2%),
Anaemia* (Grade 3 = 10%, Grade 4 = 3%), Leukopenia*
Common
Febrile neutropenia
Nervous System
Disorders
Very Common
Headache
Common
Peripheral sensory neuropathy, Dysgeusia, Dizziness, Paraesthesia
Respiratory,
Thoracic and
Mediastinal
Disorders
Common
Dyspnoea (Grade 3-4 = 2%), Cough
Gastrointestinal
disorders
Very Common
Vomiting (Grade 3-4 = 6.5%), Nausea (Grade 3-4 = 6%),
Constipation (Grade 3-4 < 1%)
Common
Diarrhoea (Grade 3-4 < 1%), Stomatitis (Grade 3-4 < 1%), Abdominal pain,
Dyspepsia, Upper abdominal pain
Skin and
Subcutaneous
Tissue Disorders
Common
Alopecia
Musculoskeletal
and Connective
Tissue Disorders
Common
Myalgia, Arthralgia, Back pain
Metabolism and
Nutrition Disorders
Very Common
Anorexia (Grade 3-4 < 1%)
Common
Dehydration, Decreased appetite, Hypokalaemia
Common
Infection
Vascular Disorders
Common
Hypotension, Flushing
General Disorders
and Administration
Site Conditions
Very Common
Fatigue (Grade 3-4 = 9%), Asthenia (Grade 3-4 = 1%)
Common
Pyrexia, Oedema, Oedema peripheral, Injection site reaction
Hepatobiliary
Disorders
Very Common
Hyperbilirubinemia* (Grade 3 = 1%),
Alanine aminotransferase increased* (Grade 3 = 38%, Grade 4 = 3%),
Aspartate aminotransferase increased* (Grade 3 = 44%, Grade 4 = 7%),
Blood alkaline phosphatase increased*, Gamma-glutamyltransferase increased*
Psychiatric
Disorders
Common
Insomnia
* Derived from laboratory data
8
Infections and
Infestations
The table below provides the frequency and severity of undesirable effects considered possibly related
to study drug and reported in ≥ 5% of patients with ovarian cancer randomised to receive Yondelis
1.1 mg/m
2
/PLD 30 mg/m
2
or PLD 50 mg/m
2
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.
System Organ
Class
Adverse reactions reported in ≥ 5% of patients in clinical trial ET743-OVA-301
Yondelis+PLD
n=333
Frequency
Event
PLD
n=330
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
Investigations
Common
Blood creatine
phosphokinase
increased*
22.0
0.9
0.9
13.7
Blood and
lymphatic
system disorders
Very
common
Neutropenia*
91.6
29.7
42.3
73.5
19.7
9.8
Leukopenia*
94.9
44.7
17.7
81.8
16.0
4.0
Anaemia*
94.9
12.9
5.7
82.1
6.2
2.2
Thrombocytopenia*
63.7
12.3
10.8
27.4
2.5
1.8
Common
Febrile neutropenia*
6.9
4.5
2.4
2.1
1.8
0.3
Nervous system
disorders
Common
Headache
6.6
0.3
2.4
Dysgeusia
5.4
0.3
2.7
Respiratory,
thoracic and
mediastinal
disorders
Common
Dyspnoea
6.6
0.3
3.3
0.3
0.3
Gastrointestinal
disorders
Very
common
Nausea
70.9
8.7
37.6
2.4
Vomiting
51.7
9.9
0.3
23.9
2.1
Constipation
20.4
0.9
15.5
0.3
Stomatitis
19.2
0.9
31.2
4.8
0.3
Diarrhoea
17.1
2.1
10
1.2
Common
Abdominal pain
9.3
0.6
7
0.9
Dyspepsia
7.5
0.3
6.1
0.6
Skin and
subcutaneous
tissue disorders
Very
common
Palmar-plantar
erythrodysaesthesia
syndrome
24
3.9
53.6
18.5
1.2
Alopecia
12
13.3
0.3
Common
Rash
8.1
16.1
0.9
Skin
hyperpigmentation
5.4
7
Metabolism and
nutrition
disorders
Very
common
Anorexia
28.8
2.1
20
1.5
Common
Hypokalaemia
6.3
2.1
2.1
General
disorders and
administration
site conditions
Very
common
Fatigue
42.3
5.7
0.3
29.7
2.4
0.3
Asthenia
15.3
1.2
9.1
0.3
Mucosal
inflammation
11.4
2.1
18.8
5.8
Pyrexia
10.2
0.9
4.5
0.3
9
System Organ
Class
Adverse reactions reported in ≥ 5% of patients in clinical trial ET743-OVA-301
Yondelis+PLD
n=333
Frequency
Event
PLD
n=330
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
Hepatobiliary
disorders
Very
common
Hyperbilirubinaemia
*
(25.2)
(0.3)
(12.9)
(0.3)
Alanine
aminotransferase
increased*
96.1
45.6
4.5
36.0
2.2
Aspartate
aminotransferase
increased*
89.5
12.0
1.8
42.6
1.2
0.3
Blood alkaline
phosphatase
increased*
61.3
1.5
41.8
1.2
* Derived from laboratory data
The following reactions have been reported with a frequency below 5% in the combination arm, but
are included here for their clinical relevance: neutropenic infection (< 1%), neutropenic sepsis (< 1%),
pancytopenia (1.8%), bone marrow failure (1.5%), granulocytopenia (1.5%), dehydration, insomnia,
peripheral sensory neuropathy, syncope, left ventricular dysfunction (< 1%), pulmonary embolism
(1.2%), pulmonary edema (< 1%), cough, hepatotoxicity (< 1%), gamma-glutamyltransferase
increased, bilirubin conjugated increased, musculoskeletal pain, myalgia, blood creatinine increased,
oedema/peripheral oedema, catheter site reactions.
In the Yondelis+PLD arm, non-white (mainly Asian) patients had a higher incidence than white
patients in grade 3 or 4 adverse reactions (96%
versus
87%), and serious adverse reactions
(44%
versus
23% all grades). The differences were mainly observed in relation with neutropenia
(93%
versus
66%), anaemia (37%
versus
14%) and thrombocytopenia (41%
versus
19%). However,
the incidences of clinical complications related to haematological toxicity such as severe infections or
bleeding, or those leading to death or treatment termination, were similar in both subpopulations.
Most frequent adverse reactions
Blood and Lymphatic system disorders
Neutropenia:
Neutropenia 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.
10
Hepatobiliary disorders
AST/ALT increases:
The median time to reach the peak values was 5 days for both AST and ALT.
Most of the values had decreased to grade 1 or resolved by day 14-15 (see section 4.4). The analysis
per cycle performed in patients treated with the monotherapy regimen showed grade 3 elevations of
AST and ALT in 12% and 20% of cycles respectively. Grade 4 elevations of AST and ALT occurred
in 1% and 2% of cycles respectively. Most transaminase elevations improved to grade 1 or to pre-
retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25
days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less
severe elevations over time.
Hyperbilirubinemia:
Bilirubin peaks approximately a week after onset and resolves approximately two
weeks after onset.
Liver function tests predicting severe toxicity (meeting Hy´s law) and clinical manifestations of severe
hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms
including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in
less than 1% of patients in both regimens.
Other adverse reactions
CPK elevations and rhabdomyolysis:
CPK elevations of any grade were observed in 23-26% of
patients in both regimens. CPK increases in association with rhabdomyolysis were reported in less
than 1% of patients
.
Alopecia:
Alopecia was reported in approximately 3% of patients treated with the monotherapy
regimen, of which the majority was grade 1 alopecia.
Post-marketing experience
During post-marketing surveillance few cases of trabectedin extravasation with subsequent
tissue
necrosis
requiring debridement have been reported (see section 4.4).
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01.
Mechanism of action
Trabectedin binds to the minor groove of DNA, bending the helix to the major groove. This binding to
DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and
DNA repair pathways, resulting in perturbation of the cell cycle. Trabectedin has been shown to exert
antiproliferative
in vitro
and
in vivo
activity against a range of human tumour cell lines and
experimental tumours, including malignancies such as sarcoma, breast, non-small cell lung, ovarian
and melanoma.
11
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/m
2
as a 24-hour intravenous infusion every 3 weeks or at 0.58 mg/m
2
weekly as a
3-hour intravenous infusion for 3-weeks of a 4-week cycle. The protocol specified final time to
progression (TTP) analysis showed a 26.6% reduction in the relative risk of progression for patients
treated in the 24-h q3wk group [Hazard Ratio (HR)=0.734, CI: 0.554-0.974]. Median TTP values were
3.7 months (CI: 2.1-5.4 m) in the 24-h q3wk group and 2.3 months (CI: 2.0-3.5 m) in the 3-h qwk
group (p=0.0302). No significant differences were detected in overall survival (OS). Median OS with
the 24-h q3wk regimen was 13.9 months (CI: 12.5-18.6) and 60.2% of patients were alive at 1 year
(CI: 52.0-68.5%).
Additional efficacy data are available from 3 single-arm Phase II trials with similar populations treated
with the same regimen. These trials evaluated a total of 100 patients with lipo and leiomyosarcoma
and 83 patients with other types of sarcoma.
The efficacy of Yondelis/PLD combination in relapsed ovarian cancer is based on ET743-OVA-301, a
randomized phase 3 study of 672 patients who received either trabectedin (1.1 mg/m
2
) and PLD
(30 mg/m
2
) every 3 weeks or PLD (50 mg/m
2
) 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
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 (Interim analysis - n=419 events, 38% censoring)
All randomised
n=337
n=335
Median OS (95%
CI) (months)
22.4 (19.4-25.1)
19.5 (17.4-22.1)
0.85 (0.70-1.03)
0.0920
a
Overall Response Rate
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).
12
In the interim analysis, the effect of the Yondelis+PLD combination on overall survival was more
pronounced in patients with PFI ≥ 6 months (27.0
vs.
24.3 months, HR=0.82, CI: 0.63-1.06) than in
those with PFI < 6 months (14.2
vs.
12.4 months, HR=0.90, CI: 0.68-1.20).
In the multivariate analyses including PFI, treatment effect was statistically significant favouring the
Yondelis+PLD combination (PFS, p=0.0157; OS, p=0.0407).
No data are available comparing Yondelis+PLD to a platinum-based regimen in platinum-sensitive
patients.
No statistically significant differences were found between treatment arms in global measures of
Quality of Life.
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due
to the rarity of soft tissue sarcoma, it has not been possible to obtain complete information on Yondelis
in this indication.
The European Medicines Agency (EMEA) will review any new information which may become
available every year and this SPC will be updated as necessary.
5.2 Pharmacokinetic properties
Systemic exposure after intravenous administration as a constant rate infusion is dose proportional at
doses up to and including 1.8 mg/m
2
. 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 5000 l.
Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative
metabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute to
metabolism. Trabectedin does not induce or inhibit major cytochrome P450 enzymes.
Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half-life is
long (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelled
trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is
58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for
plasma clearance of trabectedin (30.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedin in
whole blood is approximately 35 l/h. This value is approximately one-half the rate of human hepatic
blood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter-patient
variability of the population estimate for plasma clearance of trabectedin was 49% and intra-patient
variability was 28%.
A population pharmacokinetic analysis showed that when administered in combination with PLD, the
plasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were not
influenced by the concomitant administration of trabectedin.
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 m
2
). An analysis made on a limited number of patients shows that race and
ethnicity are not expected to have clinically significant effects on trabectedin pharmacokinetics.
13
Impaired renal function
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
14
C-labelled trabectedin indicates that renal impairment has little influence on the elimination of
trabectedin or its metabolites.
Impaired hepatic function
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.
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 (C
max
values) in the range of those observed in the clinic. The plasma trabectedin levels
attained were 10.6 ± 5.4 (C
max
), higher than those reached in patients after infusion of 1500 μg/m
2
for
24 (C
max
of 1.8 ± 1.1 ng/ml) and similar to those reached after administration of the same dose by
3 hour infusion (C
max
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.
6.
6.1 List of excipients
Sucrose.
Potassium dihydrogen phosphate.
Phosphoric acid (for pH-adjustment).
Potassium hydroxide (for pH-adjustment).
14
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: 36 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 of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Yondelis is supplied in a Type I colourless glass vial with a bromobutyl rubber stopper covered with
an aluminium flip-off seal.
Each vial contains 0.25 mg of trabectedin.
Each outer carton contains one vial.
6.6 Special precautions for disposal and other handling
Preparation for intravenous infusion
Appropriate aseptic techniques must be used. Yondelis must be reconstituted and further diluted prior
to infusion. When used in combination the intravenous line should be flushed well with
50 mg/ml (5%) glucose solution for
infusion after administration of PLD and before administration of
Yondelis. The use of any diluent other than 50 mg/ml (5%) glucose solution for infusion may cause
precipitation of PLD. (See also PLD Summary Product Characteristics for specific handling
instructions)
Each vial containing 0.25 mg of trabectedin is reconstituted with 5 ml of sterile water for injections.
The solution obtained has a concentration of 0.05 mg/ml and is for single-use only.
Instructions for reconstitution
A syringe is used to inject 5 ml 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.
15
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:
Volume (ml) =
BSA
(m
2
) x individual dose (mg/m
2
)
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.
Any unused product or waste material should be disposed of in accordance with local requirements for
cytotoxic medicinal products.
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.
7.
Pharma Mar, S.A.
Avda. de los Reyes 1, Polígono Industrial La Mina
28770 Colmenar Viejo (Madrid)
Spain
8.
EU/1/07/417/001
9.
16
1.
Yondelis 1 mg powder for concentrate for solution for infusion.
2.
Each vial contains 1 mg of trabectedin.
1 ml of reconstituted solution contains 0.05 mg of trabectedin.
Excipients:
Each vial contains 8 mg of potassium and 0.4 g of sucrose.
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
White to off-white powder.
4.
Yondelis is indicated for the treatment of 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.
Yondelis must be administered under the supervision of a physician experienced in the use of
chemotherapy. Its use should be confined to qualified oncologists or other health professionals
specialised in the administration of cytotoxic agents.
For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m
2
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/m
2
, immediately after PLD 30 mg/m
2
. To minimize the risk of PLD infusion
reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction
is observed, subsequent PLD infusions may be administered over a 1-hour period. (See also PLD
Summary Product Characteristics for specific administration advice).
Administration through a central venous line is strongly recommended (see section 6.6).
All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior
to PLD (in combination therapy) or Yondelis (in monotherapy); not only as anti-emetic prophylaxis,
but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be
administered as needed.
18
The following criteria are required to allow treatment with Yondelis:
-
Absolute neutrophil count (ANC) ≥ 1,500/mm
3
-
Platelet count ≥ 100,000/mm
3
-
Bilirubin ≤ upper limit of normal (ULN)
-
Alkaline phosphatase ≤ 2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or GGT, if the
elevation could be osseous in origin).
-
Albumin ≥ 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/mm
3
lasting for more than 5 days or associated with fever or infection
-
Thrombocytopenia < 25,000/mm
3
-
Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN
-
Increase of aminotransferases (AST or ALT) > 2.5 x ULN (monotherapy) or > 5 x ULN
(combination therapy), which has not recovered by day 21
-
Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)
Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not
recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical
benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered
for hematologic toxicity according to local standard practice.
Table 1 Dose modification table for Yondelis (as single agent for STS or
in combination for ovarian cancer) and PLD
Soft Tissue Sarcoma
Ovarian Cancer
Yondelis
Yondelis
PLD
Starting dose
1.5 mg/m
2
1.1 mg/m
2
30 mg/m
2
First reduction
1.2 mg/m
2
0.9 mg/m
2
25 mg/m
2
Second reduction
1 mg/m
2
0.75 mg/m
2
20 mg/m
2
See the PLD SPC for more detailed information on PLD dose adjustments.
In the event that further dose reductions are necessary, treatment discontinuation should be considered.
Duration of treatment
19
In clinical trials, there were no pre-defined limits to the number of cycles administered. Treatment
continued whilst clinical benefit was noted. Yondelis has been administered for 6 or more cycles in
29.5% and 52% of patients treated with the monotherapy and combination dose and schedule
respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles
respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.
Special patient populations
Paediatric patients
The safety and efficacy of trabectedin in paediatric patients have not yet been established. Therefore,
this medicinal product must not be used in children and adolescents until further data become
available.
Elderly patients
No specific studies in elderly patients have been performed. Overall 20% of the 1164 patients in the
integrated safety analysis of monotherapy clinical trials were over 65 years. Of the 333 patients with
ovarian cancer who received trabectedin in combination with PLD, 24% were 65 years of age or older
and 6% were over 75 years. No relevant differences in the safety profile were seen in this patient
population. It seems that plasma clearance and distribution volume of trabectedin are not influenced
by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.
Patients with impaired hepatic function
No studies with the proposed regimen have been conducted in patients with liver dysfunction. Thus,
data are not available to recommend a lower starting dose in patients with hepatic impairment.
However, special caution is advised and dose adjustments may be necessary in these patients since
systemic exposure is probably increased and the risk of hepatotoxicity might be increased. Patients
with elevated bilirubin must not be treated with Yondelis (see section 4.4).
Patients with impaired renal function
Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the
monotherapy, and < 60 ml/min for the combination regimen) have not been conducted and therefore
Yondelis must not be used in this patient population (see section 4.4). Considering the
pharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted in
patients with mild or moderate renal impairment.
For instructions on reconstitution and dilution of the medicinal product before administration, see
section 6.6.
-
Hypersensitivity to trabectedin or to any of the excipients
-
Concurrent serious or uncontrolled infection
-
Combination with yellow fever vaccine (see section 4.4)
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
20
-
Breast-feeding (see section 4.6)
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/mm
3
and platelets count of less than 100,000 cells/mm
3
. If severe neutropenia
(ANC < 500 cells/mm
3
) 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.
21
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).
Men in fertile age and women of childbearing potential must use effective contraception during
treatment and 3 months thereafter for women and immediately inform the treating physician if a
pregnancy occurs, and 5 months after treatment for men (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.
Effects of other substances on trabectedin
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, phenorbarbital,
Saint John’s Wort) may decrease the systemic exposure to trabectedin.
Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of
the medicinal product (see section 4.4).
Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration
of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or
elimination. The relevance of this interaction e.g. CNS toxicity has not been established. Caution
should be taken in such situations.
Pregnancy
No sufficient clinical data on exposed pregnancies are available. However, based on its known
mechanism of action, trabectedin may cause serious birth defects when administered during
pregnancy. Trabectedin should not be used during pregnancy unless clearly necessary. If it is used
during pregnancy, the patient must be informed of the potential risk to the foetus (see section 5.3) and
be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions
should be monitored carefully in the newborns.
Fertility
22
Men in fertile age and women of childbearing potential must use effective contraception during
treatment and 3 months thereafter for women and immediately inform the treating physician if a
pregnancy occurs (see section 5.3) and 5 months after treatment for men (see section 4.4).
Trabectedin can have genotoxic effects. Advice on conservation of sperm should be sought prior to
treatment because of the possibility of irreversible infertility due to therapy with Yondelis.
If pregnancy occurs during treatment the possibility of genetic counselling should be considered.
Genetic counselling is also recommended for patients wishing to have children after therapy.
Lactation
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).
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 events during therapy must not drive or operate machines.
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.
The frequencies of the adverse reactions reported below are classified as very common (≥ 1/10),
common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 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/m
2
, 24 hour infusion every 3 weeks) according to the standard
MedDRA 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.
23
System Organ
Class
Adverse reactions reported in ≥ 1% of patients in clinical trials at the
recommended regimen [1.5
mg/m
2
, 24
hour infusion every 3 weeks]
Investigations
Very Common
Blood creatine phosphokinase increased* (Grade 3-4 = 4%),
Blood creatinine increased*, Blood albumin decreased*
Common
Weight decreased
Blood and
Lymphatic System
Disorders
Very Common
Neutropenia* (Grade 3 = 26%, Grade 4 = 24%),
Thrombocytopenia* (Grade 3 = 11%, Grade 4 = 2%),
Anaemia* (Grade 3 = 10%, Grade 4 = 3%), Leukopenia*
Common
Febrile neutropenia
Nervous System
Disorders
Very Common
Headache
Common
Peripheral sensory neuropathy, Dysgeusia, Dizziness, Paraesthesia
Respiratory,
Thoracic and
Mediastinal
Disorders
Common
Dyspnoea (Grade 3-4 = 2%), Cough
Gastrointestinal
disorders
Very Common
Vomiting (Grade 3-4 = 6.5%), Nausea (Grade 3-4 = 6%),
Constipation (Grade 3-4 < 1%)
Common
Diarrhoea (Grade 3-4 < 1%), Stomatitis (Grade 3-4 <1%), Abdominal pain,
Dyspepsia, Upper abdominal pain
Skin and
Subcutaneous
Tissue Disorders
Common
Alopecia
Musculoskeletal
and Connective
Tissue Disorders
Common
Myalgia, Arthralgia, Back pain
Metabolism and
Nutrition Disorders
Very Common
Anorexia (Grade 3-4 < 1%)
Common
Dehydration, Decreased appetite, Hypokalaemia
Common
Infection
Vascular Disorders
Common
Hypotension, Flushing
General Disorders
and Administration
Site Conditions
Very Common
Fatigue (Grade 3-4 = 9%), Asthenia (Grade 3-4 = 1%)
Common
Pyrexia, Oedema, Oedema peripheral, Injection site reaction
Hepatobiliary
Disorders
Very Common
Hyperbilirubinemia* (Grade 3 = 1%),
Alanine aminotransferase increased* (Grade 3 = 38%, Grade 4 = 3%),
Aspartate aminotransferase increased* (Grade 3 = 44%, Grade 4 = 7%),
Blood alkaline phosphatase increased*, Gamma-glutamyltransferase increased*
Psychiatric
Disorders
Common
Insomnia
* Derived from laboratory data
24
Infections and
Infestations
The table below provides the frequency and severity of undesirable effects considered possibly related
to study drug and reported in ≥ 5% of patients with ovarian cancer randomised to receive Yondelis
1.1 mg/m
2
/PLD 30 mg/m
2
or PLD 50 mg/m
2
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.
System Organ
Class
Adverse reactions reported in ≥ 5% of patients in clinical trial ET
743-OVA-301
Yondelis+PLD
n=333
Frequency
Event
PLD
n=330
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade
3
(%)
Grade
4
(%)
Investigations
Common
Blood creatine
phosphokinase
increased*
22.0
0.9
0.9
13.7
Blood and
lymphatic
system disorders
Very
common
Neutropenia*
91.6
29.7
42.3
73.5
19.7
9.8
Leukopenia*
94.9
44.7
17.7
81.8
16.0
4.0
Anaemia*
94.9
12.9
5.7
82.1
6.2
2.2
Thrombocytopenia*
63.7
12.3
10.8
27.4
2.5
1.8
Common
Febrile neutropenia*
6.9
4.5
2.4
2.1
1.8
0.3
Nervous system
disorders
Common
Headache
6.6
0.3
2.4
Dysgeusia
5.4
0.3
2.7
Respiratory,
thoracic and
mediastinal
disorders
Common
Dyspnoea
6.6
0.3
3.3
0.3
0.3
Gastrointestinal
disorders
Very
common
Nausea
70.9
8.7
37.6
2.4
Vomiting
51.7
9.9
0.3
23.9
2.1
Constipation
20.4
0.9
15.5
0.3
Stomatitis
19.2
0.9
31.2
4.8
0.3
Diarrhoea
17.1
2.1
10
1.2
Common
Abdominal pain
9.3
0.6
7
0.9
Dyspepsia
7.5
0.3
6.1
0.6
Skin and
subcutaneous
tissue disorders
Very
common
Palmar-plantar
erythrodysaesthesia
syndrome
24
3.9
53.6
18.5
1.2
Alopecia
12
13.3
0.3
Common
Rash
8.1
16.1
0.9
Skin
hyperpigmentation
5.4
7
Metabolism and
nutrition
disorders
Very
common
Anorexia
28.8
2.1
20
1.5
Common
Hypokalaemia
6.3
2.1
2.1
General
disorders and
administration
site conditions
Very
common
Fatigue
42.3
5.7
0.3
29.7
2.4
0.3
Asthenia
15.3
1.2
9.1
0.3
Mucosal
inflammation
11.4
2.1
18.8
5.8
Pyrexia
10.2
0.9
4.5
0.3
25
System Organ
Class
Adverse reactions reported in ≥ 5% of patients in clinical trial ET
743-OVA-301
Yondelis+PLD
n=333
Frequency
Event
PLD
n=330
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade
3
(%)
Grade
4
(%)
Hepatobiliary
disorders
Very
common
Hyperbilirubinaemia
*
(25.2)
(0.3)
(12.9)
(0.3)
Alanine
aminotransferase
increased*
96.1
45.6
4.5
36.0
2.2
Aspartate
aminotransferase
increased*
89.5
12.0
1.8
42.6
1.2
0.3
Blood alkaline
phosphatase
increased*
61.3
1.5
41.8
1.2
* Derived from laboratory data
The following reactions have been reported with a frequency below 5% in the combination arm, but
are included here for their clinical relevance: neutropenic infection (<
1%), neutropenic sepsis (<
1%),
pancytopenia (1.8%), bone marrow failure (1.5%), granulocytopenia (1.5%), dehydration, insomnia,
peripheral sensory neuropathy, syncope, left ventricular dysfunction (<
1%), pulmonary embolism
(1.2%), pulmonary edema (<
1%), cough, hepatotoxicity (<
1%), gamma-glutamyltransferase
increased, bilirubin conjugated increased, musculoskeletal pain, myalgia, blood creatinine increased,
oedema/peripheral oedema, catheter site reactions.
In the Yondelis+PLD arm, non-white (mainly Asian) patients had a higher incidence than white
patients in grade 3 or 4 adverse reactions (96%
versus
87%), and serious adverse reactions
(44%
versus
23% all grades). The differences were mainly observed in relation with neutropenia
(93%
versus
66%), anaemia (37%
versus
14%) and thrombocytopenia (41%
versus
19%). However,
the incidences of clinical complications related to haematological toxicity such as severe infections or
bleeding, or those leading to death or treatment termination, were similar in both subpopulations.
Most frequent adverse reactions
Blood and Lymphatic system disorders
Neutropenia:
Neutropenia 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.
26
Hepatobiliary disorders
AST/ALT increases:
The median time to reach the peak values was 5 days for both AST and ALT.
Most of the values had decreased to grade 1 or resolved by day 14-15 (see section 4.4). The analysis
per cycle performed in patients treated with the monotherapy regimen showed grade 3 elevations of
AST and ALT in 12% and 20% of cycles respectively. Grade 4 elevations of AST and ALT occurred
in 1% and 2% of cycles respectively. Most transaminase elevations improved to grade 1 or to pre-
retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25
days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less
severe elevations over time.
Hyperbilirubinemia:
Bilirubin peaks approximately a week after onset and resolves approximately two
weeks after onset.
Liver function tests predicting severe toxicity (meeting Hy´s law) and clinical manifestations of severe
hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms
including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in
less than 1% of patients in both regimens.
Other adverse reactions
CPK elevations and rhabdomyolysis:
CPK elevations of any grade were observed in 23-26% of
patients in both regimens. CPK increases in association with rhabdomyolysis were reported in less
than 1% of patients
.
Alopecia:
Alopecia was reported in approximately 3% of patients treated with the monotherapy
regimen, of which the majority was grade 1 alopecia.
Post-marketing experience
During post-marketing surveillance few cases of trabectedin extravasation with subsequent
tissue
necrosis
requiring debridement have been reported (see section 4.4).
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agent, ATC code: L01CX01.
Mechanism of action
Trabectedin binds to the minor groove of DNA, bending the helix to the major groove. This binding to
DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and
DNA repair pathways, resulting in perturbation of the cell cycle. Trabectedin has been shown to exert
antiproliferative
in vitro
and
in vivo
activity against a range of human tumour cell lines and
experimental tumours, including malignancies such as sarcoma, breast, non-small cell lung, ovarian
and melanoma.
27
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/m
2
as a 24-hour intravenous infusion every 3 weeks or at 0.58 mg/m
2
weekly as a
3-hour intravenous infusion for 3-weeks of a 4-week cycle. The protocol specified final time to
progression (TTP) analysis showed a 26.6% reduction in the relative risk of progression for patients
treated in the 24-h q3wk group [Hazard Ratio (HR)=0.734, CI: 0.554-0.974]. Median TTP values were
3.7 months (CI: 2.1-5.4 m) in the 24-h q3wk group and 2.3 months (CI: 2.0-3.5 m) in the 3-h qwk
group (p=0.0302). No significant differences were detected in overall survival (OS). Median OS with
the 24-h q3wk regimen was 13.9 months (CI: 12.5-18.6) and 60.2% of patients were alive at 1 year
(CI: 52.0-68.5%).
Additional efficacy data are available from 3 single-arm Phase II trials with similar populations treated
with the same regimen. These trials evaluated a total of 100 patients with lipo and leiomyosarcoma
and 83 patients with other types of sarcoma.
The efficacy of Yondelis/PLD combination in relapsed ovarian cancer is based on ET743-OVA-301, a
randomized phase 3 study of 672 patients who received either trabectedin (1.1 mg/m
2
) and PLD
(30 mg/m
2
) every 3 weeks or PLD (50 mg/m
2
) 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
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 (Interim analysis - n=419 events, 38% censoring)
All randomised
n=337
n=335
Median OS (95%
CI) (months)
22.4 (19.4-25.1)
19.5 (17.4-22.1)
0.85 (0.70-1.03)
0.0920
a
Overall Response Rate
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).
28
In the interim analysis, the effect of the Yondelis+PLD combination on overall survival was more
pronounced in patients with PFI ≥ 6 months (27.0
vs.
24.3 months, HR=0.82, CI: 0.63-1.06) than in
those with PFI < 6 months (14.2
vs.
12.4 months, HR=0.90, CI: 0.68-1.20).
In the multivariate analyses including PFI, treatment effect was statistically significant favouring the
Yondelis+PLD combination (PFS, p=0.0157; OS, p=0.0407).
No data are available comparing Yondelis+PLD to a platinum-based regimen in platinum-sensitive
patients.
No statistically significant differences were found between treatment arms in global measures of
Quality of Life.
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due
to the rarity of soft tissue sarcoma, it has not been possible to obtain complete information on Yondelis
in this indication.
The European Medicines Agency (EMEA) will review any new information which may become
available every year and this SPC will be updated as necessary.
5.2 Pharmacokinetic properties
Systemic exposure after intravenous administration as a constant rate infusion is dose proportional at
doses up to and including 1.8 mg/m
2
. 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 5000 l.
Cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for the oxidative
metabolism of trabectedin at clinically relevant concentrations. Other P450 enzymes may contribute to
metabolism. Trabectedin does not induce or inhibit major cytochrome P450 enzymes.
Renal elimination of unchanged trabectedin in humans is low (less than 1%). The terminal half-life is
long (population value of the terminal elimination phase: 180-hr). After a dose of radiolabelled
trabectedin administered to cancer patients, faecal mean (SD) recovery of total radioactivity is
58% (17%), and urinary mean (SD) recovery is 5.8% (1.73%). Based on the population estimate for
plasma clearance of trabectedin (30.9 l/h) and blood/plasma ratio (0.89), the clearance of trabectedin in
whole blood is approximately 35 l/h. This value is approximately one-half the rate of human hepatic
blood flow. Thus the trabectedin extraction ratio can be considered moderate. The inter-patient
variability of the population estimate for plasma clearance of trabectedin was 49% and intra-patient
variability was 28%.
A population pharmacokinetic analysis showed that when administered in combination with PLD, the
plasma clearance of trabectedin was decreased by 31%; the plasma pharmacokinetics of PLD were not
influenced by the concomitant administration of trabectedin.
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 m
2
). An analysis made on a limited number of patients shows that race and
ethnicity are not expected to have clinically significant effects on trabectedin pharmacokinetics.
29
Impaired renal function
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
14
C-labelled trabectedin indicates that renal impairment has little influence on the elimination of
trabectedin or its metabolites.
Impaired hepatic function
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.
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 (C
max
values) in the range of those observed in the clinic. The plasma trabectedin levels
attained were 10.6 ± 5.4 (C
max
), higher than those reached in patients after infusion of 1500 μg/m
2
for
24 (C
max
of 1.8 ± 1.1 ng/ml) and similar to those reached after administration of the same dose by
3 hour infusion (C
max
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.
6.
6.1 List of excipients
Sucrose.
Potassium dihydrogen phosphate.
Phosphoric acid (for pH-adjustment).
Potassium hydroxide (for pH-adjustment).
30
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: 36 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 of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Yondelis is supplied in a Type I colourless glass vial with a bromobutyl rubber stopper covered with
an aluminium flip-off seal.
Each vial contains 1 mg of trabectedin.
Each outer carton contains one vial.
6.6 Special precautions for disposal and other handling
Preparation for intravenous infusion
Appropriate aseptic techniques must be used. Yondelis must be reconstituted and further diluted prior
to infusion. When used in combination the intravenous line should be flushed well with
50 mg/ml (5%) glucose solution for infusion
after administration of PLD and before administration of
Yondelis. The use of any diluent other than 50 mg/ml (5%) glucose solution for infusion may cause
precipitation of PLD. (See also PLD Summary Product Characteristics for specific handling
instructions)
Each vial containing 1 mg of trabectedin is reconstituted with 20 ml of sterile water for injections. The
solution obtained has a concentration of 0.05 mg/ml and is for single-use only.
Instructions for reconstitution
A syringe is used to inject 20 ml 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.
31
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:
Volume (ml) =
BSA
(m
2
) x individual dose (mg/m
2
)
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.
Any unused product or waste material should be disposed of in accordance with local requirements for
cytotoxic medicinal products.
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.
7.
Pharma Mar, S.A.
Avda. de los Reyes 1, Polígono Industrial La Mina
28770 Colmenar Viejo (Madrid)
Spain
8.
EU/1/07/417/002
9.
32
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
C.
34
A. MANUFACTURING AUTHORISATION HOLDER 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 OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 3.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 6.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities.
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached.
•
At the request of the EMEA
35
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
Clinical aspects:
To conduct further investigations in order to elucidate whether predictors of response to
Yondelis in patients with soft tissue sarcoma can be identified. The final study report will be
submitted by 30 June 2011.
36
ANNEX III
LABELLING AND PACKAGE LEAFLET
37
A. LABELLING
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton
– 0.25 mg vial
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP: {MM/YYYY}
39
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. For storage conditions for the reconstituted and diluted solutions, see the
package leaflet.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cytotoxic product. Discard any unused product or waste material in accordance with local
requirements.
Pharma Mar, S.A.
Avda. de los Reyes 1
Pol. Ind. La Mina
28770 Colmenar Viejo (Madrid)
Spain
EU/1/07/417/001
13. BATCH NUMBER
Lot: {number}
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.
40
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label
– 0.25 mg vial
1.
Yondelis 0.25 mg powder for concentrate for solution for infusion
Trabectedin
IV use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.25 mg trabectedin
6.
OTHER
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton
– 1 mg vial
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP: {MM/YYYY}
42
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator. For storage conditions for the reconstituted and diluted solutions, see the
package leaflet.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cytotoxic product. Discard any unused product or waste material in accordance with local
requirements.
Pharma Mar, S.A.
Avda. de los Reyes 1
Pol. Ind. La Mina
28770 Colmenar Viejo (Madrid)
Spain
EU/1/07/417/002
13. BATCH NUMBER
Lot: {number}
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.
43
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial label
– 1 mg vial
1.
Yondelis 1 mg powder for concentrate for solution for infusion
Trabectedin
IV use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP: {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 mg trabectedin
6.
OTHER
44
B. PACKAGE LEAFLET
45
PACKAGE LEAFLET: INFORMATION FOR THE USER
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.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1.
What Yondelis is and what it is used for
3.
How to use Yondelis
4.
Possible side effects
5.
How to store Yondelis
6.
Further information
1.
WHAT YONDELIS IS AND WHAT IT IS USED FOR
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 platinum based anti-cancer medicines.
2.
BEFORE YOU ARE GIVEN YONDELIS
Do not use Yondelis:
-
if you are allergic (hypersensitive) to trabectedin or any of the other ingredients of Yondelis.
-
if you have any serious infections.
-
if you are breast-feeding.
-
if you will receive yellow fever vaccine.
Take special care with Yondelis:
Yondelis or its combination with PLD must not be used if you have severe liver or kidney damage.
Tell your doctor if you know or suspect that you have any liver or kidney problems before starting the
treatment with Yondelis.
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.
46
2.
Before you are given Yondelis
•
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.
Yondelis must not be used in children and adolescents since safety and efficacy have not yet been
studied in this age group.
Using other medicines
Please tell your doctor if you plan to take, are taking or have recently taken any other medicines,
including medicines obtained without a prescription, vaccines and herbal 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 other medicines, you may need to be closely monitored as the effects of Yondelis might be
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
HIV infection), clarithromycin (for 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)) as a result.
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,
when using Yondelis together with this medicine, as there could be an increased risk of damage.
Medicines containing statins (for lowering cholesterol levels and preventing cardiovascular disease) is
an example of medicines that may cause muscle damage.
Using Yondelis with food and drink
Alcohol consumption must be avoided during treatment with Yondelis as this may harm the liver.
Pregnancy and breast-feeding
Pregnancy
You should not use Yondelis if you are pregnant or if you are trying to become pregnant as Yondelis
may harm the unborn baby. If you are pregnant or you think you may be pregnant, you must tell your
doctor immediately. The doctor may prescribe Yondelis during pregnancy in certain circumstances.
Adequate contraceptive precautions must be used by men in fertile age and women of childbearing
potential when receiving Yondelis and for 3 months following the end of treatment for women and 5
months following the end of treatment for men. If a pregnancy should occur you must tell your doctor
immediately and genetic counselling is recommended since Yondelis can cause genetic damage.
Genetic counselling is also recommended for patients wishing to have children after therapy. Male
patients should seek advice on sperm conservation prior to treatment because of the risk of irreversible
infertility due to therapy with Yondelis.
47
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.
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.
Important information about some of the ingredients of Yondelis
This medicine contains potassium, less than 1 mmol (39 mg) per vial, and can therefore be considered
as essentially “potassium-free”.
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/m
2
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.
For the treatment of ovarian cancer, the usual dose is 1.1 mg/m
2
body surface area after the
administration of 30 mg/m
2
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 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 dosage 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, Yondelis 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.
48
Side effects caused by the single treatment with Yondelis:
Very common (occurring in at least 1 in 10 patients):
•
You may:
•
feel tired
•
feel short of breath (dyspnoea)
•
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.
•
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 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).
•
You may experience headache and a loss of strength.
•
You may also lose your appetite, feel sick (nausea) or vomit, and become constipated.
If you
still feel sick, vomit or are unable to drink fluids and therefore pass less urine, despite being
given anti-sickness medication, you should immediately seek medical help.
•
Your doctor will order regular blood tests to detect any abnormalities in the blood.
Common (occurring in at least 1 in 100 patients):
•
You may have fever.
If you have a raised temperature you should seek medical attention
immediately.
•
You could also feel pain in your back, muscles and joints. There could 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 experience diarrhoea, loss of water from the body, inflammation of the mouth
(stomatitis), pain in the abdomen, weight loss, digestive discomfort and a change in your sense
of taste.
•
You could have coughing.
•
You may lose hair (alopecia).
•
You could also experience dizziness, sleeping problems, low blood pressure and flushing.
•
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 “Take special care with Yondelis”) which may
require surgery.
Other side effects that may occur with the combination of Yondelis and PLD:
When Yondelis is used in combination with PLD some of these side effects are more likely to occur
and some may occcur in a more severe way.
49
Very common (occurring in at least 1 in 10 patients):
•
You may 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 swelling and violaceous. The lesions may either dry out
and desquamate, or blister with ulceration.
Common (occurring in at least 1 in 100 patients):
•
You may have a higher skin pigmentation and rash.
•
You could have mucosal inflammation as a swelling redness of the inside of the mouth leading
to painful ulcers and mouth sores or as an inflammation of the gastrointestinal tract.
•
You may also have blood infections (neutropenic infection and neutropenic sepsis). Your doctor
will order regular blood tests to detect any abnormalities in the blood.
•
You may have syncope also called fainting.
•
You could have a weakness in the ventricles, the heart's major pumping chambers (left
ventricular dysfunction),
sudden blockage in a lung artery (
pulmonary embolism) and
an
abnormal build up of fluid in the lungs, which leads to swelling
(pulmonary oedema).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE YONDELIS
Keep out of the reach and sight of children.
Do not use Yondelis 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.
6.
FURTHER INFORMATION
What Yondelis contains:
-
The active substance is trabectedin.
Yondelis 0.25 mg: Each vial contains 0.25 mg of trabectedin.
Yondelis 1 mg: Each vial 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.
50
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.
This leaflet was last approved in
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 Yondelis
in this indication.
The European Medicines Agency (EMEA) will review any new information on the medicine every
year and this leaflet will be updated as necessary.
The following information is intended for medical or 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 Products Characteristics for specific handling
instructions).
Instructions for reconstitution:
Yondelis 0.25 mg:
Inject 5 ml of sterile water for injections into the vial.
51
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:
Volume (ml) =
BSA (m
2
) x individual dose (mg/m
2
)
0.05 mg/ml
BSA = Body Surface Area
Withdraw the appropriate amount of reconstituted solution from the vial. If 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 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.
52
ANNEX IV
SCIENTIFIC CONCLUSION AND GROUNDS FOR REFUSAL OF AN ADDITIONAL YEAR
OF MARKETING PROTECTION AS PRESENTED BY THE EMEA
53
SCIENTIFIC CONCLUSION AND GROUNDS FOR REFUSAL OF AN ADDITIONAL YEAR
OF MARKETING PROTECTION AS PRESENTED BY THE EMEA
1
.
Introduction
Yondelis (trabectedin) is an antineoplastic agent that binds to the minor groove of DNA, bending the
helix to the major groove. This binding to DNA triggers a cascade of events affecting several
transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the
cell cycle. Trabectedin has been shown to exert antiproliferative
in vitro
and
in vivo
activity against a
range of human tumour cell lines and experimental tumours, including malignancies such as sarcoma,
breast, non-small cell lung, ovarian and melanoma.
Yondelis (trabectedin), formerly known as ecteinascidin 743 (ET-743) was granted orphan designation
(EU/3/01/039) by the European Commission on 30 May 2001 for the treatment of soft tissue sarcoma.
Subsequently, an orphan designation (EU/3/03/171) was granted by the European Commission for
trabectedin for the treatment of ovarian cancer.
Yondelis was granted a marketing authorisation in the European Union on 17 September 2007.
Yondelis is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of
anthracyclines and ifosfamide, or who are unsuited to receive these agents.
On 4 December 2008, the Marketing Authorisation Holder (MAH) submitted an application for a
Type II variation concerning the addition of a new indication of Yondelis in combination with
pegylated liposomal doxorubicin (PLD) in the treatment of patients with relapsed platinum-sensitive
ovarian cancer (EMEA/H/C/773/II/08).
In accordance with the provisions of Article 14(11) of Regulation 726/2004, the MAH also applied for
an additional one year marketing protection period for Yondelis in the context of this Type II variation
(EMEA/H/C/773/II/08). The MAH’s position was provided in line with the “Guidance on elements
required to support the significant clinical benefit in comparison with existing therapies of a new
therapeutic indication in order to benefit from an extended (11-year) marketing protection period
(Nov. 2007)”.
2. Justification of significant clinical benefit as presented by the applicant (summary)
The MAH aimed to justify that Yondelis, in the proposed indication, provides significant clinical
benefit compared with existing therapies. The benefits of the proposed combination over single agent
PLD have been demonstrated by the results from the pivotal study ET743-OVA-301 (abbreviated as
OVA-301 in this document) carried out in patients with ovarian cancer after failure of a first-line
platinum-based chemotherapy regimen.
The claim of a clinically relevant advantage over other existing therapeutic options is based on a
review of relevant scientific literature on these products, used either as single agents or in combination
in a similar patient population.
The main treatment goal for patients with advanced, relapsed ovarian cancer is to achieve effective
palliation. New therapeutic alternatives must offer clinically relevant patient benefit with predictable
and manageable toxicity without a quality of life (QoL) deterioration. The management of advanced,
relapsed ovarian cancer is complex and no global consensus exists on the various existing treatment
options. PLD is a well established, approved therapy for this patient population and, therefore, is an
appropriate control in order to evaluate the merits of a new medical intervention in this setting. In fact,
PLD prolongs both PFS and OS as compared to topotecan, another established and approved therapy
in platinum pre-treated patients.
OVA-301 is the largest and most rigorously conducted randomised trial in advanced, relapsed ovarian
cancer after failure of platinum-based chemotherapy. The combination of trabectedin plus PLD
54
provides significant benefit in this disease setting because it shows increased efficacy over PLD alone,
without substantial worsening of clinical safety. As an additional benefit, improvement in PFS is
achieved without any decline in the quality of life of patients.
Recently, carboplatin-based combinations (namely with paclitaxel or gemcitabine) have become a new
standard of care for chemotherapy in relapsed, platinum-sensitive ovarian cancer. Combination
chemotherapy appears to decrease tumour burden more rapidly than single agents. Moreover, PFS and
OS have been found significantly longer with combinations in randomised trials in the platinum-
sensitive population. However, the cumulative toxicities of available carboplatin-based combinations
(debilitating residual neurotoxicity, myelosuppression, particularly thrombocytopenia, or
hypersensitivity reactions) represent barriers to the long-term use of these combinations or for
retreatment in patients with relapsed disease. Therefore, the identification of efficacious non-platinum-
based combinations is important in relapsed ovarian cancer.
In conclusion, the combination of trabectedin plus PLD represents a significant advance in comparison
to the approved standard PLD therapy. Furthermore, trabectedin plus PLD provides efficacy outcomes
that compare favourably with those obtained with carboplatin-based combinations. An additional
advantage of trabectedin plus PLD is the lack of cumulative toxicities. This new combination
constitutes an alternative treatment that can be given to patients during prolonged periods of time
while they derive clinical benefit. Therefore, the combination of trabectedin and PLD is a new
valuable treatment option for patients with relapsed ovarian cancer after failure of platinum-based
chemotherapy.
3. Assessment of the applicant’s justification of significant clinical benefit
In a well-conducted phase III trial (OVA-301) comparing PLD with PLD/trabectedin in 663 patients
with relapsed ovarian cancer, the primary efficacy endpoint PFS showed a clear advantage for the
combination therapy whichever dataset was used. With the most conservative assessment (independent
radiology in patients with measurable disease) a 21% risk reduction for the PFS endpoint could be
considered evidence of activity of trabectedin (this is also supported by phase II data). However, the
absolute magnitude of PFS prolongation (about 1.5 months) from 5.8 months to 7.3 months may not
be impressive but within the expected range in this particular cancer.
PLD is a well established,
approved therapy for this patient population and, therefore, it is an appropriate control to evaluate the
merits of a new medical intervention in this setting.
However, the PFS endpoint needs further support by mature OS data. The protocol-specified interim
analysis of overall survival (OS) was carried out with 300 events, and even though the data are clearly
immature, a favourable trend appears for the combination (HR=0.85) and survival curves remain
separated throughout the entire observation period. Following a specific request by the FDA and the
CHMP, an
ad hoc
interim analysis of the secondary endpoint OS has been conducted with a
prospectively established cut off date of 31 May 2009.
At the 31 May 2009 cut-off, a total of 419 death events (215 in the PLD monotherapy arm and 204 in
the trabectedin + PLD combination arm) had occurred. This represents 81% of the 520 death events
required for the final OS analysis, or 62% of the 672 randomised population. Current follow-up ranges
from April 2005 to May 2009. The trabectedin + PLD combination resulted in a 15% decrease in the
risk of death compared with PLD alone [HR=0.85 (95% CI, 0.70-1.03); p=0.0920]. The median OS
was 19.5 months (95% CI, 17.4-22.1) in the PLD monotherapy arm and 22.4 months (95% CI, 19.4-
25.1) in the combination arm.
The study OVA 301 was not powered to detect differences in outcome according to platinum-
resistance status. This result of a multivariate analysis indicates that treatment effect and platinum
sensitivity acted as independent factors with influence on PFS. Although a long platinum-free interval
points to a better outcome in terms of PFS as compared to a short interval (platinum-resistance) the
CHMP agree that the potential benefit in the platinum-resistant subset cannot be ruled out. In an
updated analysis the survival benefit appears enhanced in the stratum of platinum-sensitive patients,
55
where PFS HR was 0.73 (p=0.0170) and OS HR was 0.82 (p=0.1259) in the updated analysis. Of
interest, in the subpopulation of patients with intermediate platinum-sensitivity (PFI 6-12 months), an
exploratory analysis shows the largest differential effect favouring the trabectedin combination with a
41% reduction in the risk of death (HR=0.59; p=0.0015) and a 6 month increase in median survival.
The overall clinical safety assessment of the proposed combination of trabectedin + PLD does not
cause any major concern per se since the toxicity profile is predictable from the known safety profiles
of both substances and such toxicity is routine management in oncology centres. The most important
additive toxicity is neutropenia and infection-related adverse events due to neutropenia with increasing
frequency and severity with the combination as compared to both agents used as monotherapy. Any
potential safety concern of the combination should be evaluated in the context of risk/benefit. Two
percent (2%) of subjects in the PLD arm developed Grade 3 or 4 febrile neutropenia versus 8% in the
trabectedin + DOXIL arm. Sepsis, septic shock, or sepsis syndrome were reported in 4 subjects (1.2%)
in the PLD monotherapy arm and 2 subjects (0.6%) in the trabectedin + PLD arm.
Other risks of concern are more thrombocytopenia with the combination, more elevations in liver
transaminases and more elevations in CPK (and Rhabdomyolysis in rare cases) due to the toxicity of
trabectedin.
Therefore, the benefit-risk of Yondelis in combination with pegylated liposomal doxorubicin (PLD) in
the treatment of patients with relapsed platinum-sensitive ovarian cancer, is considered positive.
The
combination of trabectedin plus PLD shows increased efficacy over PLD alone, a recognised and
approved therapy, without substantial worsening of clinical safety. As an additional benefit,
improvement in PFS is achieved without decline in the quality of life of patients.
However, as expected the efficacy of the combination in patients with relapsed ovarian cancer is most
pronounced in patients with platinum-sensitive or platinum intermedium sensitive disease and for
these patients other therapeutic options are available. These patients may be retreated with platinum
based regimens, in particular the combinations of carboplatin + gemcitabine or paclitaxel.
The safety profiles of these treatment options differ; Carboplatin + paclitaxel is associated with
significant neurotoxicity and carboplatin + gemcitabine is primarily a myelotoxic combination.
Another risk of carboplatin is severe hypersensitivity reactions.
However, the relative efficacy and safety of these standard regimens as compared to trabectidin + PLD
remain unknown since no head-to-head comparisons are available. Therefore, based on HR and PFS
estimations the efficacy may be comparable, but there is also a possibility that the efficacy of the
combination trabectidin + PLD is inferior to that of platinum-based regimens.
In conclusion, the benefit-risk of the combination trabectidin + PLD in the treatment of patients with
relapsed platinum-sensitive ovarian cancer, is considered positive. The differential toxicity of the new
combination may be regarded as an advantage. However, since the relative safety and efficacy in
comparison with platinum based regimens is unknown due to the fact that no head-to-head comparison
has been performed, the CHMP is of the view that the applicant’s justification for one additional year
of marketing protection is insufficient.
4. CHMP Conclusion
Following the overall assessment of the efficacy and safety data provided, the CHMP concluded that
the benefit/risk ratio of Yondelis is positive for the treatment of patients with relapsed platinum-
sensitive ovarian cancer.
Taking into account the absence of a significant clinical benefit based on improved efficacy, safety
and contribution to patient care in comparison with existing therapies, the CHMP concluded that the
justification for one additional year of marketing protection was insufficient.
56
5. Outcome
The CHMP reviewed the data submitted by the applicant taking into account the provisions of Article
14(11) of Regulation (EC) No. 726/2004, and taking into account the provisions of the “
Guidance on
elements required to support the significant clinical benefit in comparison with existing therapies of a
new therapeutic indication in order to benefit from an extended (11-year) marketing protection period
(November 2007)
”, and did not consider that the new therapeutic indication brings significant clinical
benefit in comparison with existing therapies.
57
Source: European Medicines Agency
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