Yondelis
Generic Name: trabectedin
Dosage Form: injection, powder, lyophilized, for solution
Indications and Usage for Yondelis
Yondelis® is indicated for the
treatment of patients with unresectable or metastatic liposarcoma or
leiomyosarcoma who received a prior anthracycline-containing regimen [see Clinical Studies (14)].
Yondelis Dosage and AdministrationRecommended
Dose and Schedule
The recommended dose is 1.5
mg/m2 administered
as an intravenous infusion over 24 hours through a central venous line every 21
days (3 weeks), until disease progression or unacceptable toxicity, in patients
with normal bilirubin and AST or ALT less than or equal to 2.5 times the upper
limit of normal.
Hepatic Impairment: The recommended dose is 0.9 mg/m2 in
patients with moderate hepatic impairment (bilirubin levels 1.5 times to 3
times the upper limit of normal, and AST and ALT less than 8 times the upper
limit of normal). Do not administer Yondelis to patients with severe hepatic
impairment (bilirubin levels above 3 times to 10 times the upper limit of
normal, and any AST and ALT) [see Warnings and
Precautions (5.3), Use in
Specific Populations (8.6), and Clinical Pharmacology
(12.3)].
Premedication
Administer dexamethasone 20 mg
intravenously 30 minutes prior to each dose of Yondelis.
Dose
Modifications
Permanently discontinue
Yondelis for:
·
Persistent adverse reactions
requiring a delay in dosing of more than 3 weeks.
· Adverse reactions requiring dose reduction
following Yondelis administered at 1.0 mg/m2 for
patients with normal hepatic function or at 0.3 mg/m2 for
patients with pre-existing moderate hepatic impairment.
· Severe liver dysfunction all of the
following: bilirubin two times the upper limit of normal and AST or ALT three
times the upper limit of normal with alkaline phosphatase less than two times
the upper limit of normal in the prior treatment cycle for patients with normal
liver function at baseline.
· Exacerbation of liver dysfunction in
patients with pre-existing moderate hepatic impairment.
The recommended dose modifications for
adverse reactions are listed in Table 1. Once reduced, the dose of Yondelis
should not be increased in subsequent treatment cycles.
Table 1:
Recommended Dose Modification
|
|
Laboratory
Result or Adverse Reaction
|
DELAY next dose of Yondelis for up to 3
weeks
|
REDUCE next dose of Yondelis by one dose
level for adverse reaction(s) during prior cycle
|
|
Table 1: Recommended Dose
ModificationLaboratory Result or Adverse ReactionDELAY next dose of Yondelis
for up to 3 weeksREDUCE next dose of Yondelis by one dose level for adverse
reaction(s) during prior cyclePlateletsLess than 100,000
platelets/microliterLess than 25,000 platelets/microliterAbsolute neutrophil
countLess than 1,500 neutrophils/microliterLess than 1,000
neutrophils/microliter with fever/infectionLess than 500
neutrophils/microliter lasting more than 5 daysTotal bilirubin
*
Permanently
discontinue Yondelis when liver dysfunction is exacerbated for patients with
pre-existing moderate hepatic impairment.
Greater than the upper limit of normalGreater than
the upper limit of normalAspartate aminotransferase (AST) or alanine
aminotransferase (ALT)More than 2.5 times the upper limit of normalMore than
5 times the upper limit of normalAlkaline phosphatase (ALP)More than 2.5
times the upper limit of normalMore than 2.5 times the upper limit of
normalCreatine phosphokinaseMore than 2.5 times the upper limit of normalMore
than 5 times the upper limit of normalDecreased left ventricular ejection
fractionLess than lower limit of normal; orClinical evidence of
cardiomyopathyAbsolute decrease of 10% or more from baseline and less than
lower limit of normal; orClinical evidence of cardiomyopathyOther
non-hematologic adverse reactionsGrade 3 or 4Grade 3 or 4
|
|
Platelets
|
Less than 100,000 platelets/microliter
|
Less than 25,000 platelets/microliter
|
|
Absolute
neutrophil count
|
Less than 1,500 neutrophils/microliter
|
· Less
than 1,000 neutrophils/microliter with fever/infection
· Less
than 500 neutrophils/microliter lasting more than 5 days
|
|
Total
bilirubin*
|
Greater than the upper limit of normal
|
Greater than the upper limit of normal
|
|
Aspartate
aminotransferase (AST) or alanine aminotransferase (ALT)*
|
More than 2.5 times the upper limit of
normal
|
More than 5 times the upper limit of
normal
|
|
Alkaline
phosphatase (ALP)*
|
More than 2.5 times the upper limit of
normal
|
More than 2.5 times the upper limit of
normal
|
|
Creatine
phosphokinase
|
More than 2.5 times the upper limit of
normal
|
More than 5 times the upper limit of
normal
|
|
Decreased
left ventricular ejection fraction
|
· Less
than lower limit of normal; or
· Clinical
evidence of cardiomyopathy
|
· Absolute
decrease of 10% or more from baseline and less than lower limit of normal; or
· Clinical
evidence of cardiomyopathy
|
|
Other
non-hematologic adverse reactions
|
Grade 3 or 4
|
Grade 3 or 4
|
The recommended starting doses and dose
reductions for Yondelis are listed in Table 2:
Table 2:
Recommended Starting Doses and Dose Reductions
|
|
Starting
Dose and Dose Reduction
|
For patients with normal hepatic
function or mild hepatic impairment* prior to initiation of Yondelis
treatment
|
For patients with moderate hepatic
impairment prior to initiation of Yondelis treatment
|
|
Table 2: Recommended Starting Doses and
Dose ReductionsStarting Dose and Dose ReductionFor patients with normal
hepatic function or mild hepatic impairment
*
Including
patients with bilirubin 1 to 1.5 times the upper limit of normal, and any AST
or ALT.
prior to initiation of Yondelis treatmentFor patients
with moderate hepatic impairment prior to initiation of Yondelis
treatmentStarting Dose1.5 mg/m20.9 mg/m2Dose Reduction First dose
reduction1.2 mg/m20.6 mg/m2 Second dose reduction1.0 mg/m20.3
mg/m2
|
|
Starting
Dose
|
1.5 mg/m2
|
0.9 mg/m2
|
|
Dose
Reduction
|
|
|
First
dose reduction
|
1.2 mg/m2
|
0.6 mg/m2
|
|
Second
dose reduction
|
1.0 mg/m2
|
0.3 mg/m2
|
Preparation
for AdministrationYondelis is a cytotoxic drug. Follow applicable
special handling and disposal procedures.
1Using aseptic technique, inject 20 mL of Sterile
Water for Injection, USP into the vial. Shake the vial until complete
dissolution. The reconstituted solution is clear, colorless to pale
brownish-yellow, and contains 0.05 mg/mL of trabectedin.Inspect for particulate matter and discoloration prior
to further dilution. Discard vial if particles or discoloration are
observed.Immediately following reconstitution, withdraw the
calculated volume of trabectedin and further dilute in 500 mL of 0.9%
Sodium Chloride, USP or 5% Dextrose Injection, USP.Do not mix Yondelis with other drugs.Discard any remaining solution within 30 hours of
reconstituting the lyophilized powder.Yondelis diluted solution is compatible with Type I
colorless glass vials, polyvinylchloride (PVC) and polyethylene (PE) bags
and tubing, PE and polypropylene (PP) mixture bags, polyethersulfone (PES)
in-line filters, titanium, platinum or plastic ports, silicone and
polyurethane catheters, and pumps having contact surfaces made of PVC, PE,
or PE/PP.AdministrationInfuse the reconstituted, diluted solution over 24
hours through a central venous line using an infusion set with a 0.2
micron polyethersulfone (PES) in-line filter to reduce the risk of
exposure to adventitious pathogens that may be introduced during solution
preparation.Complete infusion within 30 hours of initial
reconstitution. Discard any unused portion of the reconstituted product or
of the infusion solution.Dosage Forms and Strengths
For injection: 1 mg,
lyophilized powder in single-dose vial for reconstitution.
Contraindications
Yondelis is contraindicated in
patients with known severe hypersensitivity, including anaphylaxis, to
trabectedin.
Warnings and PrecautionsNeutropenic
Sepsis
Neutropenic sepsis, including
fatal cases, can occur with Yondelis. In Trial 1, the incidence of Grade 3 or 4
neutropenia, based on laboratory values, in patients receiving Yondelis was 43%
(161/378). The median time to the first occurrence of Grade 3 or 4 neutropenia
was 16 days (range: 8 days to 9.7 months); the median time to complete
resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile
neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18
patients (5%) treated with Yondelis. Ten patients (2.6%) experienced
neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4
patients (1.1%).
Assess neutrophil count prior
to administration of each dose of Yondelis and periodically throughout the
treatment cycle. Withhold Yondelis for neutrophil counts of less than 1,500
cells/microliter on the day of dosing. Permanently reduce the dose of Yondelis
for life-threatening or prolonged, severe neutropenia in the preceding
cycle [see Dosage and
Administration (2.3)].
Rhabdomyolysis
Yondelis can cause
rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading
to death occurred in 3 (0.8%) of the 378 patients receiving Yondelis.
Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378
patients receiving Yondelis, including Grade 3 or 4 CPK elevation in 24
patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine
with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation.
Among the 24 patients receiving Yondelis with Grade 3 or 4 CPK elevation, renal
failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of
renal failure occurred in 4 of these 11 patients (1.1%). The median time to
first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5
months). The median time to complete resolution was 14 days (range: 5 days to 1
month).
Assess CPK levels prior to
each administration of Yondelis. Withhold Yondelis for serum CPK levels more
than 2.5 times the upper limit of normal. Permanently discontinue Yondelis for
rhabdomyolysis [see Dosage
and Administration (2.3)].
Hepatotoxicity
Hepatotoxicity, including hepatic failure,
can occur with Yondelis. Patients with serum bilirubin levels above the upper
limit of normal or AST or ALT levels >2.5 × upper limit of normal were not
enrolled in Trial 1. In Trial 1, the incidence of Grade 3–4 elevated liver
function tests (LFTs; defined as elevations in ALT, AST, total bilirubin, or
alkaline phosphatase) was 35% (134/378) in patients receiving Yondelis. The
median time to development of Grade 3–4 elevation in ALT or AST was 29 days
(range: 3 days to 11.5 months). Of the 134 patients with Grade 3–4 elevations
in LFTs, 114 (85%) experienced complete resolution with the median time to
complete resolution of 13 days (range: 4 days to 4.4 months).
In Trial 1, the incidence of drug-induced
liver injury (defined as concurrent elevation in ALT or AST of more than three
times the upper limit of normal, alkaline phosphatase less than two times the
upper limit of normal, and total bilirubin at least two times the upper limit
of normal) was 1.3% (5/378) in patients receiving Yondelis. ALT or AST
elevation greater than eight times the upper limit of normal occurred in 18%
(67/378) of patients receiving Yondelis.
Assess LFTs prior to each administration
of Yondelis and as clinically indicated based on underlying severity of
pre-existing hepatic impairment. Manage elevated LFTs with treatment
interruption, dose reduction, or permanent discontinuation based on severity
and duration of LFT abnormality [see Dosage and
Administration (2.3) and Use in Specific
Populations (8.6)].
Cardiomyopathy
Cardiomyopathy including
cardiac failure, congestive heart failure, ejection fraction decreased,
diastolic dysfunction, or right ventricular dysfunction can occur with
Yondelis. In Trial 1, patients with a history of New York Heart Association
Class II to IV heart failure or abnormal left ventricular ejection fraction
(LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23
patients (6%) receiving Yondelis and in four patients (2.3%) receiving
dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving
Yondelis and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to
death occurred in 1 patient (0.3%) receiving Yondelis and in none of the
patients receiving dacarbazine. The median time to development of Grade 3 or 4
cardiomyopathy in patients receiving Yondelis was 5.3 months (range: 26 days to
15.3 months).
Assess LVEF by echocardiogram
or multigated acquisition (MUGA) scan before initiation of Yondelis and at 2-
to 3-month intervals thereafter until Yondelis is discontinued. Withhold
Yondelis for LVEF below lower limit of normal. Permanently discontinue Yondelis
for symptomatic cardiomyopathy or persistent left ventricular dysfunction that
does not recover to lower limit of normal within 3 weeks [see Dosage and
Administration (2.3)].
Capillary
Leak Syndrome
Capillary leak syndrome (CLS)
characterized by hypotension, edema, and hypoalbuminemia has been reported with
Yondelis, including serious CLS resulting in death. Monitor for signs and
symptoms of CLS. Discontinue Yondelis and promptly initiate standard management
for patients with CLS, which may include a need for intensive care [see Adverse Reactions (6.2)].
Extravasation
Resulting in Tissue Necrosis
Extravasation of Yondelis,
resulting in tissue necrosis requiring debridement, can occur. Evidence of
tissue necrosis can occur more than 1 week after the extravasation. There is no
specific antidote for extravasation of Yondelis. Administer Yondelis through a
central venous line [see Dosage
and Administration (2.5)].
Embryofetal
Toxicity
Based on its mechanism of
action, Yondelis can cause fetal harm when administered to a pregnant woman.
Advise females of reproductive potential to use effective contraception during
therapy and for at least 2 months after the last dose of Yondelis. Advise males
with female partners of reproductive potential to use effective contraception
during therapy and for at least 5 months after the last dose of Yondelis [see Use in Specific
Populations (8.1, 8.3)].
Adverse Reactions
The following adverse
reactions are discussed in more detail in other sections of the labeling:
Anaphylaxis [see Contraindications
(4)]Neutropenic Sepsis [see Warnings
and Precautions (5.1)]Rhabdomyolysis [see Warnings
and Precautions (5.2)]Hepatotoxicity [see Warnings
and Precautions (5.3)]Cardiomyopathy [see Warnings
and Precautions (5.4)]Capillary Leak Syndrome [see Warnings
and Precautions (5.5)]Extravasation Resulting in Tissue Necrosis [see Warnings
and Precautions (5.6)]Adverse Reactions
in Clinical Trials
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
The data described below
reflect exposure to Yondelis in 755 patients with soft tissue sarcoma including
197 (26%) patients exposed to Yondelis for greater than or equal to 6 months
and 57 (8%) patients exposed to Yondelis for greater than or equal to 1 year.
The safety of Yondelis was evaluated in six open-label, single-arm trials, in
which 377 patients received Yondelis and one open-label, randomized,
active-controlled clinical trial in which 378 patients received Yondelis (Trial
1). All patients received Yondelis at the recommended dosing regimen of 1.5
mg/m2 administered
as an intravenous infusion over 24 hours once every 3 weeks (q3wk, 24-h). The
median age was 54 years (range: 18 to 81 years), 63% were female, and all
patients had metastatic soft tissue sarcoma.
Tables 3 and 4 present
selected adverse reactions and laboratory abnormalities, respectively, observed
in Trial 1, an open-label, randomized (2:1), active-controlled trial in which
550 patients with previously treated leiomyosarcoma or liposarcoma
(dedifferentiated, myxoid round cell, or pleomorphic) received Yondelis 1.5
mg/m2 intravenous
infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2 intravenous infusion
over 20 to 120 minutes once every 3 weeks (n=172) [see Clinical
Studies (14)]. All patients treated with Yondelis were required to receive
dexamethasone 20 mg intravenous injection 30 minutes prior to start of the
Yondelis infusion.
In Trial 1, patients had been
previously treated with an anthracycline- and ifosfamide-containing regimen or
with an anthracycline-containing regimen and one additional cytotoxic
chemotherapy regimen. The trial excluded patients with known central nervous
system metastasis, elevated serum bilirubin or significant chronic liver
disease, such as cirrhosis or active hepatitis, and history of myocardial
infarction within 6 months, history of New York Heart Association Class II to
IV heart failure, or abnormal left ventricular ejection fraction at baseline.
The median age of patients in Trial 1 was 57 years (range: 17 to 81 years),
with 69% female, 77% White, 12% Black or African American, 4% Asian, and <1%
American Indian or Alaska Native. The median duration of exposure to
trabectedin was 13 weeks (range: 1 to 127 weeks) with 30% of patients exposed
to Yondelis for greater than 6 months and 7% of patients exposed to Yondelis
for greater than 1 year.
In Trial 1, adverse reactions
resulting in permanent discontinuation of Yondelis occurred in 26% (98/378) of
patients; the most common were increased liver tests (defined as ALT, AST,
alkaline phosphatase, bilirubin) (5.6%), thrombocytopenia (3.4%), fatigue
(1.6%), increased creatine phosphokinase (1.1%), and decreased ejection
fraction (1.1%). Adverse reactions that led to dose reductions occurred in 42%
(158/378) of patients treated with Yondelis; the most common were increased
liver tests (24%), neutropenia (including febrile neutropenia) (8%), thrombocytopenia
(4.2%), fatigue (3.7%), increased creatine phosphokinase (2.4%), nausea (1.1%),
and vomiting (1.1%). Adverse reactions led to dose interruptions in 52%
(198/378) of patients treated with Yondelis; the most common were neutropenia
(31%), thrombocytopenia (15%), increased liver tests (6%), fatigue (2.9%),
anemia (2.6%), increased creatinine (1.1%), and nausea (1.1%).
The most common adverse
reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased
appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common
laboratory abnormalities (≥20%) were increases in AST or ALT, increased
alkaline phosphatase, hypoalbuminemia, increased creatinine, increased creatine
phosphokinase, anemia, neutropenia, and thrombocytopenia.
Table 3: Selected Adverse Reactions* Occurring in ≥10% of Patients
Receiving Yondelis and at a Higher Incidence than in the Control Arm - Trial
1
|
|
|
Yondelis
(N=378)
|
Dacarbazine
(N=172)
|
|
System Organ
Class
Adverse Reaction
|
All Grades†
(%)
|
Grades 3–4
(%)
|
All Grades
(%)
|
Grades 3–4
(%)
|
|
*
Limited to
adverse reactions at a rate of ≥10% in the trabectedin arm and at a rate
higher in the trabectedin arm compared with dacarbazine arm by ≥5% in overall
incidence or by ≥2% for Grade 3–4 adverse reactions.
†
Toxicity grade
is based on NCI common toxicity criteria, version 4.0.
‡
Fatigue is a composite of the following adverse event
terms: fatigue, asthenia, and malaise.
|
|
Gastrointestinal disorders
|
|
Nausea
|
75
|
7
|
50
|
1.7
|
|
Vomiting
|
46
|
6
|
22
|
1.2
|
|
Constipation
|
37
|
0.8
|
31
|
0.6
|
|
Diarrhea
|
35
|
1.6
|
23
|
0
|
|
General disorders and administration site conditions
|
|
Fatigue‡
|
69
|
8
|
52
|
1.7
|
|
Peripheral
edema
|
28
|
0.8
|
13
|
0.6
|
|
Metabolism and nutrition disorders
|
|
Decreased
appetite
|
37
|
1.9
|
21
|
0.6
|
|
Respiratory, thoracic and mediastinal disorders
|
|
Dyspnea
|
25
|
4.2
|
20
|
1.2
|
|
Nervous system disorders
|
|
Headache
|
25
|
0.3
|
19
|
0
|
|
Musculoskeletal and connective tissue disorders
|
|
Arthralgia
|
15
|
0
|
8
|
1.2
|
|
Myalgia
|
12
|
0
|
6
|
0
|
|
Psychiatric disorders
|
|
Insomnia
|
15
|
0.3
|
9
|
0
|
Other clinically important
adverse reactions observed in <10% of patients (N=755) with soft tissue
sarcoma receiving Yondelis were:
Nervous
system disorders: peripheral neuropathy,
paresthesia, hypoesthesia.
Respiratory,
thoracic, and mediastinal disorders:
pulmonary embolism.
Table 4: Incidence of Selected Treatment-Emergent Laboratory
Abnormalities* - Trial 1
|
|
|
Laboratory
Abnormalities
|
Yondelis
|
Dacarbazine
|
|
|
All Grades
(%)
|
Grades 3–4
(%)
|
All Grades
(%)
|
Grades 3–4
(%)
|
|
|
Yondelis group
(range: 373 to 377 patients) and dacarbazine group (range: 166 to 168
patients).
|
|
|
*
Treatment-emergent laboratory abnormalities including
those higher in the trabectedin arm compared with the dacarbazine arm by ≥5%
(all Grades) or by ≥2% (Grade 3–4). Incidence based on number of patients who
had both baseline and at least one on-study laboratory measurement.
|
|
|
Chemistry
|
|
|
|
|
|
|
Increased
ALT
|
90
|
31
|
33
|
0.6
|
|
|
Increased
AST
|
84
|
17
|
32
|
1.2
|
|
|
Increased
alkaline phosphatase
|
70
|
1.6
|
60
|
0.6
|
|
|
Hypoalbuminemia
|
63
|
3.7
|
51
|
3.0
|
|
|
Increased
creatinine
|
46
|
4.2
|
29
|
1.2
|
|
|
Increased
creatine phosphokinase
|
33
|
6.4
|
9
|
0.6
|
|
|
Hyperbilirubinemia
|
13
|
1.9
|
5
|
0.6
|
|
|
Hematology
|
|
|
|
|
|
|
Anemia
|
96
|
19
|
79
|
12
|
|
|
Neutropenia
|
66
|
43
|
47
|
26
|
|
|
Thrombocytopenia
|
59
|
21
|
57
|
20
|
|
Postmarketing
Experience
The following adverse
reactions have been identified during post-approval use of Yondelis. Because
these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Vascular disorders: capillary
leak syndrome [see Warnings
and Precautions (5.5)].
Drug InteractionsEffect of
Cytochrome CYP3A Inhibitors
Coadministration of Yondelis
with ketoconazole, a strong CYP3A inhibitor, increased systemic exposure of
trabectedin by 66%. Avoid using strong CYP3A inhibitors (e.g., oral
ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin,
telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir,
saquinavir, telaprevir, nefazodone, conivaptan) in patients taking Yondelis. If
a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be
used, administer the strong CYP3A inhibitor 1 week after the Yondelis infusion,
and discontinue it the day prior to the next Yondelis infusion [see Clinical Pharmacology
(12.3)].
Effect of
Cytochrome CYP3A Inducers
Coadministration of Yondelis
with rifampin, a strong CYP3A inducer, decreased systemic exposure of
trabectedin by 31%. Avoid using strong CYP3A inducers (e.g., rifampin,
phenobarbital, St. John's wort) in patients taking Yondelis [see Clinical Pharmacology
(12.3)].
USE IN SPECIFIC POPULATIONSPregnancy
Risk
Summary
Based on its mechanism of
action, trabectedin can cause fetal harm when administered during
pregnancy [see Clinical
Pharmacology (12.1)]. There are no available data
with the use of Yondelis during pregnancy. Animal reproductive and
developmental studies at relevant doses have not been conducted with
trabectedin; however, placental transfer of trabectedin was demonstrated in
pregnant rats. Advise pregnant woman of the potential risk to a fetus. The
background risk of major birth defects and miscarriage for the indicated
population are unknown; however, the background risk in the U.S. general
population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of
clinically recognized pregnancies.
Lactation
Risk
Summary
There are no data on the
presence of trabectedin in human milk, the effects on the breastfed infant, or
the effects on milk production. Because of the potential for serious adverse
reactions from Yondelis in breastfed infants, advise a nursing woman to
discontinue nursing during treatment with Yondelis.
Females and
Males of Reproductive Potential
Contraception
Females
Advise female patients of
reproductive potential to use effective contraception during and for 2 months
after the last dose of Yondelis [see Use in
Specific Populations (8.1)].
Males
Yondelis may damage
spermatozoa, resulting in possible genetic and fetal abnormalities. Advise
males with a female sexual partner of reproductive potential to use effective
contraception during and for 5 months after the last dose of Yondelis [see Nonclinical Toxicology
(13.1)].
Infertility
Yondelis may result in
decreased fertility in males and females [see Nonclinical
Toxicology (13.1)].
Pediatric Use
Safety and effectiveness in
pediatric patients have not been established.
Geriatric Use
Clinical studies of Yondelis
did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.
Hepatic
Impairment
The mean trabectedin exposure
was (97%) higher in patients with moderate (bilirubin levels 1.5 to 3.0 times
the upper limit of normal, and AST and ALT less than 8 times the upper limit of
normal) hepatic impairment compared to patients with normal (total bilirubin ≤
the upper limit of normal, and AST and ALT ≤ the upper limit of normal) liver
function. Reduce Yondelis dose in patients with moderate hepatic
impairment [see Dosage
and Administration (2.1) and Clinical Pharmacology
(12.3)].
Do not administer Yondelis to
patients with severe hepatic impairment (bilirubin levels above 3 times to 10
times the upper limit of normal, and any AST and ALT) [see Warnings
and Precautions (5.3)].
Renal
Impairment
No dose adjustment is
recommended in patients with mild [creatinine clearance (CLcr) 60–89 mL/min] or
moderate (CLcr of 30–59 mL/min) renal impairment.
The pharmacokinetics of
trabectedin has not been evaluated in patients with severe renal impairment
(CLcr <30 mL/min) or end stage renal disease [see Clinical
Pharmacology (12.3)].
Overdosage
There is no specific antidote
for Yondelis. Hemodialysis is not expected to enhance the elimination of
Yondelis because trabectedin is highly bound to plasma proteins (97%) and not
significantly renally excreted.
Yondelis Description
Trabectedin is an alkylating
agent with the chemical name (1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8,14-trihydroxy-7',9-dimethoxy-4,10,23-trimethyl-spiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]-19-one. The molecular formula is C39H43N3O11S. The molecular weight is
761.84 daltons. The chemical structure is shown below:
Trabectedin is hydrophobic and
has a low solubility in water.
Yondelis (trabectedin) for
injection is supplied as a sterile lyophilized white to off-white powder/cake
in a single-dose vial. Each single-dose vial contains 1 mg of trabectedin, 27.2
mg potassium dihydrogen phosphate, 400 mg sucrose, and phosphoric acid and
potassium hydroxide (for pH adjustment to 3.6 – 4.2).
Yondelis - Clinical PharmacologyMechanism of
Action
Trabectedin is an alkylating
drug that binds guanine residues in the minor groove of DNA, forming adducts
and resulting in a bending of the DNA helix towards the major groove. Adduct
formation triggers a cascade of events that can affect the subsequent activity
of DNA binding proteins, including some transcription factors, and DNA repair
pathways, resulting in perturbation of the cell cycle and eventual cell death.
Pharmacodynamics
Cardiac
Electrophysiology
The effect of trabectedin on
the QT/QTc interval was evaluated in 75 patients who received placebo on day 1
and trabectedin (1.3 mg/m2) as a 3-hour intravenous infusion on day 2. No patients in the
study showed a QTc interval exceeding 500 msec or more than 60 msec increase
from baseline, and no large changes in the mean QTc interval (i.e., >20
msec) were observed.
Pharmacokinetics
The pharmacokinetics of
trabectedin is characterized by a rapid decline phase at the end of the
infusion and slower exponential phases. Population pharmacokinetic analyses
suggest that the pharmacokinetics of trabectedin is dose-proportional (over the
dose range of 0.024 to 1.8 mg/m2) and exposure is time-independent. No accumulation of
trabectedin in plasma is observed upon repeated administrations every 3 weeks.
Distribution
Binding of trabectedin to
human plasma proteins was approximately 97%, independent of trabectedin
concentrations ranging from 10 ng/mL to 100 ng/mL. Steady state volume of
distribution of trabectedin exceeds 5000 L.
Elimination
The estimated mean (%
coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the
terminal elimination half-life is approximately 175 hours.
Metabolism
CYP3A is the predominant CYP
enzyme responsible for the hepatic metabolism of trabectedin.
Trabectedin was extensively
metabolized with negligible unchanged drug in urine and feces following
administration of trabectedin to humans.
Excretion
In patients with solid tumors,
following a 3-hour or a 24-hour intravenous infusion of 14C-labeled trabectedin, 64% of
the total administered radioactive dose was recovered in 24 days, with 58% in
feces and 6% in urine.
Specific
Populations
The following population
characteristics are not associated with a clinically significant effect on the
pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to
148 kg), body surface area (0.9 to 2.8 m2), mild hepatic impairment, or
mild to moderate renal impairment. The effects of severe hepatic impairment,
severe renal impairment or end stage renal disease on trabectedin exposure are
unknown.
Hepatic Impairment
The geometric mean dose
normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in
patients with moderate hepatic impairment following administration of a single
Yondelis dose of 0.58 mg/m2 or 0.9 mg/m2 compared to patients with normal liver function following
administration of a single Yondelis dose of 1.3 mg/m2 [see Dosage
and Administration (2.1) and Use in Specific
Populations (8.6)].
Drug
Interactions
Effect of Strong CYP3A Inhibitors on Trabectedin
Coadministration of multiple
doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of
Yondelis (0.58 mg/m2) on day 1 increased trabectedin dose-normalized AUC by 66% and
Cmax by
22% compared to a single Yondelis dose (1.3 mg/m2) given alone.
Effect of Strong CYP3A Inducers on Trabectedin
Coadministration of multiple
doses of rifampin (600 mg daily for 6 days) with a single Yondelis dose (1.3
mg/m2) on
day 6 decreased trabectedin AUC by 31% and Cmax by 21% compared to a
single Yondelis dose (1.3 mg/m2) given alone.
Effect of Trabectedin on CYP Enzymes
In
vitro, trabectedin has limited inhibition or
induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6,
2E1, and 3A4).
Nonclinical ToxicologyCarcinogenesis,
Mutagenesis, Impairment of Fertility
Trabectedin is genotoxic in
both in vitro and in vivo studies. Long-term carcinogenicity
studies have not been performed.
Fertility studies with
trabectedin were not performed. In male rats there were limited
histopathological signs of hemorrhage and degeneration in the testes following
repeated administration of trabectedin at doses approximately 0.2 times the 1.5
mg/m2 human
dose based on body surface area.
Clinical Studies
The clinical efficacy and
safety of Yondelis in patients with metastatic or recurrent leiomyosarcoma or
liposarcoma were demonstrated in Trial 1, a randomized (2:1), open-label,
active-controlled trial comparing treatment with Yondelis 1.5 mg/m2 as a 24-hour continuous
intravenous infusion once every 3 weeks to dacarbazine 1000 mg/m2 intravenous infusion (20
to 120 minutes) once every 3 weeks. Treatment continued in both arms until
disease progression or unacceptable toxicity; all patients in the Yondelis arm
were required to receive dexamethasone 20 mg intravenous injection prior to
each Yondelis infusion. Patients were required to have unresectable, locally
advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid
round cell, or pleomorphic) and previous treatment with an anthracycline- and
ifosfamide-containing regimen or an anthracycline-containing regimen and one
additional cytotoxic chemotherapy regimen. Randomization was stratified by
subtype of soft tissue sarcoma (leiomyosarcoma vs. liposarcoma), ECOG
performance status (0 vs. 1), and number of prior chemotherapy regimens (1 vs.
≥2). The efficacy outcome measures were investigator-assessed progression-free
survival (PFS) according to the Response Evaluation Criteria in Solid Tumors
(RECIST v1.1), overall survival (OS), objective response rate (ORR), and
duration of response (DOR). Patients in the dacarbazine arm were not offered
Yondelis at the time of disease progression.
A total of 518 patients were
randomized, 345 to the Yondelis arm and 173 patients to the dacarbazine arm.
The median patient age was 56 years (range: 17 to 81); 30% were male; 76%
White, 12% Black, and 4% Asian; 73% had leiomyosarcomas and 27% liposarcomas;
49% had an ECOG PS of 0; and 89% received ≥2 prior chemotherapy regimens. The
most common (≥20%) pre-study chemotherapeutic agents administered were
doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%).
Approximately 10% of patients had received pazopanib.
Trial 1 demonstrated a
statistically significant improvement in PFS. An exploratory analysis of
independent radiology committee-determined PFS, in a subgroup consisting of
approximately 60% of the total population, provided similar results to the
investigator-determined PFS. Efficacy results from Trial 1 are presented in the
table below.
Table 5: Efficacy Results for Trial 1
|
|
Efficacy
Endpoint
|
Yondelis
N=345
|
Dacarbazine
N=173
|
|
CR=Complete
Response; PR=Partial Response; CI=Confidence Interval, HR=hazard ratio,
NE=not estimable.
|
|
*
Cox proportional
hazards model with treatment group as the only covariate.
†
Unstratified log
rank test.
‡
Based on 384
patients randomized to Yondelis arm and 193 patients randomized to
dacarbazine.
§
Fisher's exact CI.
|
|
Progression-free survival
|
|
PFS
Events, n (%)
|
217 (63%)
|
112 (65%)
|
|
Disease
progression
|
204
|
109
|
|
Death
|
13
|
3
|
|
Median
(95% CI) (months)
|
4.2 (3.0, 4.8)
|
1.5 (1.5, 2.6)
|
|
HR
(95% CI)*
|
0.55 (0.44, 0.70)
|
|
p-value†
|
<0.001
|
|
Overall survival‡
|
|
|
Events,
n (%)
|
258 (67%)
|
123 (64%)
|
|
Median
(95% CI) (months)
|
13.7 (12.2, 16.0)
|
13.1 (9.1, 16.2)
|
|
HR
(95% CI)*
|
0.93 (0.75, 1.15)
|
|
p-value†
|
0.49
|
|
Objective Response Rate (ORR: CR+PR)
|
|
Number
of patients (%)
|
23 (7%)
|
10 (6%)
|
|
95%
CI§
|
(4.3, 9.8)
|
(2.8, 10.4)
|
|
Duration of Response (CR+ PR)
|
|
Median
(95% CI) (months)
|
6.9 (4.5, 7.6)
|
4.2 (2.9, NE)
|
Figure
1: Kaplan-Meier Curves of Progression-Free Survival in Trial 1
REFERENCES
1.
"Hazardous
Drugs", OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html
How Supplied/Storage
and HandlingHow Supplied
Yondelis
is supplied in a glass vial containing 1 mg trabectedin. Each carton contains
one vial (NDC: 59676-610-01).
Storage and Handling
Store
Yondelis vials in a refrigerator at 2°C to 8°C (36°F to 46°F).
Yondelis
is a cytotoxic drug. Follow applicable special handling and disposal
procedures.1
Patient Counseling
Information
Advise
the patient to read the FDA-approved patient labeling (Patient Information).
Myelosuppression:
Inform patients of the risks of myelosuppression. Instruct patients to
immediately contact their healthcare provider for fever or unusual bruising,
bleeding, tiredness, or paleness.
Rhabdomyolysis:
Advise patients to contact their healthcare provider if they experience severe
muscle pain or weakness.
Hepatotoxicity:
Advise patients to contact their healthcare provider immediately for yellowing
of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or
vomiting, difficulty in concentrating, disorientation, or confusion.
Cardiomyopathy:
Advise patients to contact their healthcare provider for new onset chest pain,
shortness of breath, fatigue, lower extremity edema, or heart palpitations.
Hypersensitivity:
Advise patients to seek immediate medical attention for symptoms of allergic
reactions including difficulty breathing, chest tightness, wheezing, severe
dizziness or light-headedness, swelling of the lips or skin rash.
Extravasation:
Inform patients of the risks of extravasation and to notify their healthcare
provider for redness, swelling, itchiness and discomfort or leakage at the
injection site.
Capillary leak syndrome:
Advise patients to report symptoms such as edema with or without
hypotension [see Warnings
and Precautions (5.5)].
Embryofetal toxicity:
Advise pregnant women of the potential risk to a fetus. Advise females to
contact their healthcare provider if they become pregnant, or if pregnancy is
suspected, during treatment with Yondelis [see Warnings
and Precautions (5.7) and Use in Specific
Populations (8.1)].
Females and males of reproductive potential: Advise females of reproductive potential to use effective
contraception during treatment with Yondelis and for at least 2 months after
last dose. Advise males with female partners of reproductive potential to use
effective contraception during treatment with Yondelis and for at least 5
months after the last dose [see Warnings
and Precautions (5.7) and Use in Specific
Populations (8.3)].
Lactation: Advise females not to
breastfeed during treatment with Yondelis [see Use in
Specific Populations (8.2)].
Manufactured
by:
Baxter Oncology GmbH
Halle/Westfalen Germany
Manufactured
for:
Janssen Products, LP
Horsham, PA
© 2015
Janssen Pharmaceutical Companies
Under
license from Pharma Mar, S.A.
|
PATIENT INFORMATION
Yondelis® (yon-DEL-ess)
(trabectedin)
for injection
|
|
This Patient
Information has been approved by the U.S. Food and Drug Administration.
|
Revised May/2017
|
|
What is Yondelis?
Yondelis is a prescription medicine used to treat people with liposarcoma or
leiomyosarcoma that:
· cannot
be treated with surgery or has spread to other areas of the body, and
· who
have received treatment with certain other medicines.
It is not known
if Yondelis is safe and effective in children.
|
|
Who should not receive Yondelis?
You will not be given Yondelis if you have had
a severe allergic reaction to trabectedin, the active ingredient in
Yondelis. See the end of this leaflet for a complete list of ingredients
in Yondelis.
|
|
What should I tell my healthcare provider before receiving Yondelis?
Before receiving Yondelis, tell your healthcare provider about all of your
medical conditions, including if you:
· have
liver or kidney problems
· are
pregnant or plan to become pregnant. Yondelis can harm your unborn baby. You
should not become pregnant during treatment with Yondelis.
o Females who are able to become pregnant should use an
effective form of birth control during treatment with Yondelis and for 2
months after your last dose of Yondelis.
o Males should use an effective form of birth control
when having sex with female partners who are able to become pregnant, during
your treatment with Yondelis and for 5 months after your last dose of
Yondelis.
· are
breastfeeding or plan to breastfeed. It is not known if Yondelis passes into
your breast milk.
You should not
breastfeed during treatment with Yondelis.
Tell your healthcare provider about all the medicines you
take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
|
|
How will I receive Yondelis?
· Yondelis
is given by an intravenous (IV) infusion into a vein over 24 hours. To help
avoid irritation at the site where it is infused, Yondelis is given to you
into a large vein through a type of IV line called a central venous line.
· Yondelis
is usually given every 3 weeks.
· Your
healthcare provider may decrease your dose or delay doses if you have certain
side effects. If you have any side effects that are severe, your healthcare
provider may stop your treatment with Yondelis.
· Before
each treatment with Yondelis, you will receive a steroid medicine to help
reduce your risk of getting certain side effects.
· Your
healthcare provider will decide how long you will continue treatment with
Yondelis.
· Your
healthcare provider may do certain tests while you are receiving Yondelis to
check you for side effects, and to see how well you respond to the treatment.
|
|
What are the possible side effects of Yondelis?
Yondelis may cause serious side effects, including:
· Severe infections due to decreased white blood
cells. Decreased low white blood cell count is common with Yondelis, but it
can also lead to severe infections and death. Your healthcare provider may need to decrease
your dose of Yondelis, delay or stop your treatment, if your white blood cell
count is too low or you get a serious infection. Call your healthcare
provider right away if you develop fever or other signs of infection.
· Severe muscle problems (rhabdomyolysis). Yondelis can cause muscle problems
that can be severe and lead to death. Tell your healthcare provider right
away if you have severe muscle pain or weakness.
· Liver problems, including liver failure. Tell your healthcare provider right
away if you get:
|
|
|
· yellowing
of your skin and whites of your eyes
· pain
in your upper right stomach-area (abdomen)
· nausea
· vomiting
|
· generally
do not feel well
· problem
with concentration
· confusion
· sleepiness
|
|
· Heart muscle problems, including heart failure. Your healthcare provider will do a
test to check your heart function before you start Yondelis, and during
treatment. If you develop heart muscle problems or heart failure during
treatment with Yondelis, your healthcare provider may stop your treatment.
Tell your healthcare provider right away if you develop new chest pain,
shortness of breath, tiredness, swelling of your legs, ankles, or feet, or
heart palpitations.
· Leakage of Yondelis out of your vein during the
infusion. If
Yondelis leaks into the tissues around your infusion site, it can cause
damage and death of tissue cells around the infusion site. You may need to
have surgery to remove any dead tissue. Tell your healthcare provider right
away if you see any Yondelis leaking out of your vein or around the catheter
during your infusion, or if you notice any redness, swelling, itching or
discomfort at the infusion site at any time.
· Some
people have had allergic reactions to Yondelis. Some of these reactions were
severe. Your healthcare provider may need to stop your treatment with
Yondelis, and may give you medicines to treat the allergic reaction. Signs of an allergic reaction can include: difficulty
breathing, chest tightness, wheezing, swelling of the lips, or skin rash.
· Capillary leak syndrome. Yondelis can cause fluid to leak
from the blood vessels into the body's tissues. This condition is called
"Capillary Leak Syndrome" (CLS). CLS can cause you to have symptoms
that may lead to death. Tell your healthcare provider right away if you
develop swelling, dizziness or lightheadedness with or without a sudden drop
in blood pressure.
The most common side effects of Yondelis include:
|
|
· nausea
· tiredness
· vomiting
· constipation
· decreased
appetite
· diarrhea
· swelling
of your hands, ankles, or feet
|
· shortness
of breath
· headache
· decreased
red cell count (cells which carry oxygen in the blood). Tell your healthcare
provider if you feel more tired than usual or look pale.
· decreased
platelet cell counts (cells which help blood to clot). Tell your healthcare
provider if you bruise easily or have bleeding.
· changes
in liver and kidney function blood tests
|
|
Tell your
healthcare provider if you have any side effect that bothers you or that does
not go away.
These are not all the possible side effects of Yondelis. Call your doctor for
medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
|
|
General information about the safe and effective use of Yondelis
Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. You can ask your healthcare provider or
pharmacist for information about Yondelis that is written for health
professionals.
|
|
What are the ingredients in Yondelis?
Active ingredient: trabectedin
Inactive ingredients: potassium dihydrogen
phosphate, sucrose, phosphoric acid and potassium hydroxide.
Manufactured by: Baxter Oncology GmbH, Halle/Westfalen Germany
Manufactured for: Janssen Products, LP, Horsham, PA
For more information, call 1-800-526-7736 or go to www.Yondelis.com.
|
|
|
|
|
PRINCIPAL DISPLAY PANEL
- 1 Vial Carton
NDC 59676-610-01
Single
dose
Discard any unused portion
Yondelis®
(trabectedin)
for
Injection
1 mg per vial
Reconstitute
before further dilution
For Intravenous Infusion Only
Each
vial contains 1 mg of trabectedin as a
sterile lyophilized powder.
Store unopened vials in a refrigerator at
2–8 °C (36–46 °F).
Cytotoxic.
Keep out of reach of children.
Rx Only
Janssen
Under
license from Pharma Mar
Pharma
Mar
|
Yondelis trabectedin injection,
powder, lyophilized, for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:59676-610
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Trabectedin (Trabectedin)
|
Trabectedin
|
0.05 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
Sucrose
|
|
|
Potassium Phosphate, Monobasic
|
|
|
Phosphoric Acid
|
|
|
Potassium Hydroxide
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:59676-610-01
|
20 mL in 1
VIAL, SINGLE-USE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA207953
|
10/23/2015
|
|
|
|
Labeler - Janssen Products, LP (804684207)
|
|
Registrant - Janssen Pharmaceuticals, Inc. (063137772)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Pharma Mar S.A.
|
|
464884501
|
API
MANUFACTURE(59676-610)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Baxter Oncology
GmbH
|
|
344276063
|
API
MANUFACTURE(59676-610), MANUFACTURE(59676-610)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Janssen
Pharmaceutica NV
|
|
370005019
|
MANUFACTURE(59676-610)
|
Revised: 05/2017
Janssen Products, LP
Yondelis(曲贝替定[trabectedin])使用说明书2015年第一版
