SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONYONDELIS(R) (yon-DEL-ess)(trabectedin)for injectionThis Patient Information has been approved by the U.S. Food and Drug Administration.Revised 12/2017 What is YONDELISYONDELIS is 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 YONDELISYou will not be given YONDELIS if you have had severe allergic reaction to trabectedin, the active ingredient in YONDELIS. See the end of this leaflet for complete list of ingredients in YONDELIS.What should 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 problemsare pregnant or plan to become pregnant. YONDELIS can harm your unborn baby. You should not become pregnant during treatment with YONDELIS.Females who are able to become pregnant should use an effective form of birth control during treatment with YONDELIS and for months after your last dose of YONDELIS.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 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 receive YONDELISYONDELIS is given by an intravenous (IV) infusion into vein over 24 hours. To help avoid irritation at the site where it is infused, YONDELIS is given to you into large vein through type of IV line called central venous line.YONDELIS is usually given every 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 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 YONDELISYONDELIS 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 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 eyespain in your upper right stomach-area (abdomen)nauseavomitinggenerally do not feel wellproblem with concentrationconfusionsleepinessHeart muscle problems, including heart failure. Your healthcare provider will do 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 bodys 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 sudden drop in blood pressure.The most common side effects of YONDELIS include:nauseatirednessvomitingconstipationdecreased appetitediarrheaswelling of your hands, ankles, or feetshortness of breathheadachedecreased 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 testsTell 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 YONDELISMedicines are sometimes prescribed for purposes other than those listed in 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 YONDELISActive ingredient: trabectedinInactive ingredients: potassium dihydrogen phosphate, sucrose, phosphoric acid and potassium hydroxide.Product of SpainManufactured by: Baxter Oncology GmbH, Halle/Westfalen GermanyManufactured for: Janssen Products, LP, Horsham, PAFor more information, call 1-800-526-7736 or go to www.YONDELIS.com. cannot be treated with surgery or has spread to other areas of the body, and who have received treatment with certain other medicines.. You will not be given YONDELIS if you have had severe allergic reaction to trabectedin, the active ingredient in YONDELIS. See the end of this leaflet for complete list of ingredients in YONDELIS.. 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.Females who are able to become pregnant should use an effective form of birth control during treatment with YONDELIS and for months after your last dose of YONDELIS.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 months after your last dose of YONDELIS. Females who are able to become pregnant should use an effective form of birth control during treatment with YONDELIS and for months after your last dose of YONDELIS.. 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 months after your last dose of YONDELIS.. are breastfeeding or plan to breastfeed. It is not known if YONDELIS passes into your breast milk.. YONDELIS is given by an intravenous (IV) infusion into vein over 24 hours. To help avoid irritation at the site where it is infused, YONDELIS is given to you into large vein through type of IV line called central venous line.. YONDELIS is usually given every 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 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.. 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 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 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 bodys 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 sudden drop in blood pressure.. 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.

ADVERSE REACTIONS SECTION.

6 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)] 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)] The most common (>=20%) adverse reactions are nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common (>=5%) grades 3-4 laboratory abnormalities are: neutropenia, increased ALT, thrombocytopenia, anemia, increased AST, and increased creatine phosphokinase. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 months and 57 (8%) patients exposed to YONDELIS for greater than or equal to 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 ET743-SAR-3007). All patients received YONDELIS at the recommended dosing regimen of 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 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 and present selected adverse reactions and laboratory abnormalities, respectively, observed in Trial ET743-SAR-3007, 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 weeks (n=378) or dacarbazine 1000 mg/m2 intravenous infusion over 20 to 120 minutes once every 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 ET743-SAR-3007, 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 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 ET743-SAR-3007 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: to 127 weeks) with 30% of patients exposed to YONDELIS for greater than months and 7% of patients exposed to YONDELIS for greater than year.In Trial ET743-SAR-3007, 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 ReactionsLimited to adverse reactions at rate of >=10% in the trabectedin arm and at rate higher in the trabectedin arm compared with dacarbazine arm by >=5% in overall incidence or by >=2% for Grade 3-4 adverse reactions. Occurring in >=10% of Patients Receiving YONDELIS and at Higher Incidence than in the Control Arm Trial ET743-SAR-3007YONDELIS (N=378)Dacarbazine (N=172)System Organ Class Adverse ReactionAll GradesToxicity grade is based on NCI common toxicity criteria, version 4.0. (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Gastrointestinal disorders Nausea757501.7 Vomiting466221.2 Constipation370.8310.6 Diarrhea351.6230General disorders and administration site conditions FatigueFatigue is composite of the following adverse event terms: fatigue, asthenia, and malaise. 698521.7 Peripheral edema280.8130.6Metabolism and nutrition disorders Decreased appetite371.9210.6Respiratory, thoracic and mediastinal disorders Dyspnea254.2201.2Nervous system disorders Headache250.3190Musculoskeletal and connective tissue disorders Arthralgia15081.2 Myalgia12060Psychiatric disorders Insomnia150.390Other 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.General disorders and administration site conditions: mucosal inflammation.Table 4: Incidence of Selected Treatment-Emergent Laboratory AbnormalitiesTreatment-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. Trial ET743-SAR-3007Laboratory AbnormalitiesYONDELISDacarbazineAll Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients). Chemistry Increased ALT9031330.6 Increased AST8417321.2 Increased alkaline phosphatase701.6600.6 Hypoalbuminemia633.7513.0 Increased creatinine464.2291.2 Increased creatine phosphokinase336.490.6 Hyperbilirubinemia131.950.6 Hematology Anemia96197912 Neutropenia66434726 Thrombocytopenia59215720. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of YONDELIS. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Vascular disorders: capillary leak syndrome.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in bending of the DNA helix towards the major groove. Adduct formation triggers 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.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of trabectedin on the QT/QTc interval was evaluated in 75 patients who received placebo on day and trabectedin (1.3 mg/m2) as 3-hour intravenous infusion on day 2. No patients in the study showed 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.. 12.3 Pharmacokinetics. The pharmacokinetics of trabectedin is characterized by 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 weeks.. DistributionBinding 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.. EliminationThe estimated mean (% coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 175 hours.. MetabolismCYP3A 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.. ExcretionIn patients with solid tumors, following 3-hour or 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 PopulationsThe following population characteristics are not associated with 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 ImpairmentThe geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to times the upper limit of normal and AST and ALT less than times the upper limit of normal) following administration of single YONDELIS dose of 0.58 mg/m2 or 0.9 mg/m2 compared to patients with normal liver function following administration of 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 TrabectedinCoadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with single dose of YONDELIS (0.58 mg/m2) on day increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to single YONDELIS dose (1.3 mg/m2) given alone.. Effect of Strong CYP3A Inducers on TrabectedinCoadministration of multiple doses of rifampin (600 mg daily for days) with single YONDELIS dose (1.3 mg/m2) on day decreased trabectedin AUC by 31% and Cmax by 21% compared to single YONDELIS dose (1.3 mg/m2) given alone.. Effect of Trabectedin on CYP EnzymesIn vitro, trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The clinical efficacy and safety of YONDELIS in patients with metastatic or recurrent leiomyosarcoma or liposarcoma were demonstrated in Trial ET743-SAR-3007 (NCT01343277), randomized (2:1), open-label, active-controlled trial comparing treatment with YONDELIS 1.5 mg/m2 as 24-hour continuous intravenous infusion once every weeks to dacarbazine 1000 mg/m2 intravenous infusion (20 to 120 minutes) once every 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 ET743-SAR-3007 demonstrated statistically significant improvement in PFS. An exploratory analysis of independent radiology committee-determined PFS, in subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. Efficacy results from Trial ET743-SAR-3007 are presented in the table below.Table 5: Efficacy Results for Trial ET743-SAR-3007Efficacy EndpointYONDELISN=345DacarbazineN=173CR=Complete Response; PR=Partial Response; CI=Confidence Interval, HR=hazard ratio, NE=not estimable.Progression-free survival PFS Events, (%)217 (63%)112 (65%) Disease progression204109 Death133 Median (95% CI) (months)4.2 (3.0, 4.8)1.5 (1.5, 2.6) HR (95% CI)Cox proportional hazards model with treatment group as the only covariate. 0.55 (0.44, 0.70)p-valueUnstratified log rank test. <0.001Overall survivalBased on 384 patients randomized to YONDELIS arm and 193 patients randomized to dacarbazine. Events, (%)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 0.49Objective Response Rate (ORR: CR+PR) Number of patients (%)23 (7%)10 (6%) 95% CIFishers exact 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 ET743-SAR-3007. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer at 1.5 mg/m2 body surface area as 24-hour intravenous infusion, every weeks through central venous line (2.1, 2.5)Premedication: dexamethasone 20 mg intravenously, 30 min before each infusion (2.2)Hepatic Impairment: Administer at 0.9 mg/m2 body surface area as 24-hour intravenous infusion, every weeks through central venous line in patients with moderate hepatic impairment (2.1). Administer at 1.5 mg/m2 body surface area as 24-hour intravenous infusion, every weeks through central venous line (2.1, 2.5). Premedication: dexamethasone 20 mg intravenously, 30 min before each infusion (2.2). Hepatic Impairment: Administer at 0.9 mg/m2 body surface area as 24-hour intravenous infusion, every weeks through central venous line in patients with moderate hepatic impairment (2.1). 2.1Recommended Dosage. The recommended dose is 1.5 mg/m2 administered as an intravenous infusion over 24 hours through central venous line every 21 days (3 weeks), until disease progression or unacceptable toxicity.. Hepatic Impairment: The recommended dose is 0.9 mg/m2 in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to times the upper limit of normal, and AST and ALT less than times the upper limit of normal). Do not administer YONDELIS to patients with severe hepatic impairment (bilirubin levels above times the upper limit of normal, and any AST and ALT) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.2 Premedication. Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of YONDELIS.. 2.3Dose Modifications for Adverse Reactions. Permanently discontinue YONDELIS for:Persistent adverse reactions requiring delay in dosing of more than 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: bilirubin two times the upper limit of normal, and AST or ALT three times the upper limit of normal, and 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. Capillary leak syndrome. Rhabdomyolysis. Grade or cardiac adverse events (AEs) indicative of cardiomyopathy or for subjects with an LVEF that decreases below the lower limit of normal. 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 ModificationLaboratory Result or Adverse ReactionDELAY next dose of YONDELIS for up to 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 daysTotal bilirubinGreater 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 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 times the upper limit of normalOther non-hematologic adverse reactionsGrade or 4Grade or 4The recommended starting doses and dose reductions for YONDELIS are listed in Table 2:Table 2:Recommended Starting Doses and Dose ReductionsStarting Dose and Dose ReductionFor patients with normal hepatic function or mild hepatic impairmentIncluding patients with bilirubin greater than to 1.5 times the upper limit of normal, and any AST or ALT. prior to initiation of YONDELIS treatmentFor patients with moderate hepatic impairmentIncluding patients with bilirubin levels greater than 1.5 times to times the upper limit of normal, and AST and ALT less than times the upper limit of normal. prior to initiation of YONDELIS treatmentStarting Dose1.5 mg/m2 0.9 mg/m2 Dose ReductionFirst dose reduction1.2 mg/m2 0.6 mg/m2 Second dose reduction1.0 mg/m2 0.3 mg/m2 Persistent adverse reactions requiring delay in dosing of more than 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: bilirubin two times the upper limit of normal, and AST or ALT three times the upper limit of normal, and 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.. Capillary leak syndrome. Rhabdomyolysis. Grade or cardiac adverse events (AEs) indicative of cardiomyopathy or for subjects with an LVEF that decreases below the lower limit of normal. Less than 1,000 neutrophils/microliter with fever/infection. Less than 500 neutrophils/microliter lasting more than days. 2.4Preparation for Administration. YONDELIS is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Using 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 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.. YONDELIS is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Using 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 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.. 2.5Administration. Infuse the reconstituted, diluted solution over 24 hours through central venous line using an infusion set with 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.. Infuse the reconstituted, diluted solution over 24 hours through central venous line using an infusion set with 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of trabectedin is characterized by 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 weeks.. DistributionBinding 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.. EliminationThe estimated mean (% coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 175 hours.. MetabolismCYP3A 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.. ExcretionIn patients with solid tumors, following 3-hour or 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 PopulationsThe following population characteristics are not associated with 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 ImpairmentThe geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to times the upper limit of normal and AST and ALT less than times the upper limit of normal) following administration of single YONDELIS dose of 0.58 mg/m2 or 0.9 mg/m2 compared to patients with normal liver function following administration of 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 TrabectedinCoadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with single dose of YONDELIS (0.58 mg/m2) on day increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to single YONDELIS dose (1.3 mg/m2) given alone.. Effect of Strong CYP3A Inducers on TrabectedinCoadministration of multiple doses of rifampin (600 mg daily for days) with single YONDELIS dose (1.3 mg/m2) on day decreased trabectedin AUC by 31% and Cmax by 21% compared to single YONDELIS dose (1.3 mg/m2) given alone.. Effect of Trabectedin on CYP EnzymesIn vitro, trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2)Hepatic Impairment: Do not administer YONDELIS to patients with severe hepatic impairment (8.6, 12.3). Lactation: Advise not to breastfeed (8.2). Hepatic Impairment: Do not administer YONDELIS to patients with severe hepatic impairment (8.6, 12.3). 8.1 Pregnancy. Risk SummaryBased 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 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. 8.2 Lactation. Risk SummaryThere 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 nursing woman to discontinue nursing during treatment with YONDELIS.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating YONDELIS [see Use in Specific Populations (8.1)].. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during and for months after the last dose of YONDELIS [see Use in Specific Populations (8.1)].. MalesYONDELIS may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with female sexual partner of reproductive potential to use effective contraception during and for months after the last dose of YONDELIS [see Nonclinical Toxicology (13.1)].. InfertilityYONDELIS may result in decreased fertility in males and females [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.Safety (n=61) and efficacy (n=58) were assessed across five open-label studies (NCT00006463, NCT01453283, NCT00005625, NCT00070109, and ET-B-023-00) in pediatric patients (aged to <17 years) with pediatric histotypes of sarcoma (predominantly rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, and non-rhabdomyosarcoma soft tissue sarcoma). No new safety signals were observed in pediatric patients across these studies.Pharmacokinetic parameters in 17 pediatric patients (aged to 17 years) were within the range of values previously observed in adults given the same dose per body surface area.. 8.5 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.. 8.6Hepatic Impairment. The mean trabectedin exposure was (97%) higher in patients with moderate (bilirubin levels greater than 1.5 to times the upper limit of normal, and AST and ALT less than 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 times the upper limit of normal, and any AST and ALT) [see Warnings and Precautions (5.3)].. 8.7Renal 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Neutropenic sepsis: Severe, and fatal, neutropenic sepsis may occur. Monitor neutrophil count during treatment. Withhold YONDELIS for neutrophil count 1,500/mcL (2.3, 5.1)Rhabdomyolysis: Rhabdomyolysis may occur. Monitor creatine phosphokinase (CPK) levels prior to each administration. Withhold YONDELIS for CPK more than 2.5 times the upper limit of normal. (2.3, 5.2)Hepatotoxicity: Hepatotoxicity may occur. Monitor and delay and/or reduce dose if needed (5.3)Cardiomyopathy: Severe and fatal cardiomyopathy can occur. Patients with left ventricular ejection fraction (LVEF) lower limit of normal, prior cumulative anthracycline dose of >=300 mg/m2, age >=65 years, or history of cardiovascular disease may be at increased risk of developing new or worsening cardiac dysfunction. Discontinue YONDELIS in patients who develop decreased LVEF or cardiomyopathy (2.3, 5.4)Capillary leak syndrome: Monitor and discontinue YONDELIS for capillary leak syndrome (5.5)Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to fetus and use effective contraception (5.7, 8.1, 8.3). Neutropenic sepsis: Severe, and fatal, neutropenic sepsis may occur. Monitor neutrophil count during treatment. Withhold YONDELIS for neutrophil count 1,500/mcL (2.3, 5.1). Rhabdomyolysis: Rhabdomyolysis may occur. Monitor creatine phosphokinase (CPK) levels prior to each administration. Withhold YONDELIS for CPK more than 2.5 times the upper limit of normal. (2.3, 5.2). Hepatotoxicity: Hepatotoxicity may occur. Monitor and delay and/or reduce dose if needed (5.3). Cardiomyopathy: Severe and fatal cardiomyopathy can occur. Patients with left ventricular ejection fraction (LVEF) lower limit of normal, prior cumulative anthracycline dose of >=300 mg/m2, age >=65 years, or history of cardiovascular disease may be at increased risk of developing new or worsening cardiac dysfunction. Discontinue YONDELIS in patients who develop decreased LVEF or cardiomyopathy (2.3, 5.4). Capillary leak syndrome: Monitor and discontinue YONDELIS for capillary leak syndrome (5.5). Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to fetus and use effective contraception (5.7, 8.1, 8.3). 5.1Neutropenic Sepsis. Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial ET743-SAR-3007, the incidence of Grade or neutropenia, based on laboratory values, in patients receiving YONDELIS was 43% (161/378). The median time to the first occurrence of Grade or neutropenia was 16 days (range: days to 9.7 months); the median time to complete resolution of neutropenia was 13 days (range: days to 2.3 months). Febrile neutropenia (fever >=38.5C with Grade or neutropenia) occurred in 18 patients (5%) treated with YONDELIS. Ten patients (2.6%) experienced neutropenic sepsis, of whom had febrile neutropenia, which was fatal in patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS and periodically throughout the treatment cycle. Withhold or reduce dose of YONDELIS based on severity of adverse reaction [see Dosage and Administration (2.3)]. 5.2Rhabdomyolysis. YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial ET743-SAR-3007, rhabdomyolysis leading to death occurred in (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 or CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including patient (0.6%) with Grade CPK elevation. Among the 24 patients receiving YONDELIS with Grade or CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in of these 11 patients (1.1%). The median time to first occurrence of Grade or CPK elevations was months (range: to 11.5 months). The median time to complete resolution was 14 days (range: days to month). Assess CPK levels prior to each administration of YONDELIS. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3)]. 5.3Hepatotoxicity. 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 ET743-SAR-3007. In Trial ET743-SAR-3007, 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: 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: days to 4.4 months).In Trial ET743-SAR-3007, 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)]. 5.4Cardiomyopathy. Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with YONDELIS. In Trial ET743-SAR-3007, significant decrease in LVEF was defined as an absolute decrease of >=15% or below the lower limit of normal with an absolute decrease of >=5%. Patients with 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 ET743-SAR-3007, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS and in four patients (2.3%) receiving dacarbazine. Grade or cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS and patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in patient (0.3%) receiving YONDELIS and in none of the patients receiving dacarbazine. The median time to development of Grade or cardiomyopathy in patients receiving YONDELIS was 5.3 months (range: 26 days to 15.3 months). Patients with LVEF lower limit of normal, prior cumulative anthracycline dose of >=300 mg/m2, age >=65 years, or history of cardiovascular disease may be at increased risk of cardiac dysfunction. Assess LVEF by echocardiogram (ECHO) or multigated acquisition (MUGA) scan before initiation of YONDELIS and at 2- to 3-month intervals thereafter until YONDELIS is discontinued. Discontinue treatment with YONDELIS based on severity of adverse reaction [see Dosage and Administration (2.3)]. 5.5Capillary 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 need for intensive care [see Adverse Reactions (6.2)].. 5.6Extravasation Resulting in Tissue Necrosis. Extravasation of YONDELIS, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than week after the extravasation. There is no specific antidote for extravasation of YONDELIS. Administer YONDELIS through central venous line [see Dosage and Administration (2.5)].. 5.7Embryo-Fetal Toxicity. Based on its mechanism of action, YONDELIS can cause fetal harm when administered to pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 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 months after the last dose of YONDELIS [see Use in Specific Populations (8.1, 8.3)].