YONDELIS

1 INDICATIONS AND USAGE YONDELIS ® is indicated for the treatment of adult patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen [see Clinical Studies (14) ] . YONDELIS is an alkylating drug indicated for the treatment of adult patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen ( 1 )

2 DOSAGE AND ADMINISTRATION Administer at 1.5 mg/m 2 as a 24-hour intravenous infusion, every 3 weeks through a central venous line ( 2.1 , 2.6 ) Premedication: dexamethasone 20 mg intravenously, 30 min before each infusion ( 2.3 ) Hepatic Impairment: Administer at 0.9 mg/m 2 as a 24-hour intravenous infusion, every 3 weeks through a central venous line in patients with moderate hepatic impairment ( 2.2 ) 2.1 Recommended Dosage The recommended dose is 1.5 mg/m 2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks), until disease progression or unacceptable toxicity. 2.2 Recommended Dosage in Patients with Hepatic Impairment The recommended dosage of YONDELIS in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal) is 0.9 mg/m 2 every 21 days (3 weeks). Do not administer YONDELIS to patients with severe hepatic impairment (bilirubin levels above 3 times the upper limit of normal, and any AST and ALT) [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.3 Premedication Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of YONDELIS. 2.4 Dosage Modifications for Adverse Reactions 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/m 2 for patients with normal hepatic function or at 0.3 mg/m 2 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 3 or 4 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 Dosage 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 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 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 Including patients with bilirubin greater than 1 to 1.5 times the upper limit of normal, and any AST or ALT. prior to initiation of YONDELIS treatment For patients with moderate hepatic impairment Including patients with bilirubin levels greater than 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times …

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 ( 2.4 , 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. ( 2.4 , 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/m 2 , age ≥65 years, or a 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 ( 2.4 , 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 a fetus and use effective contraception ( 5.7 , 8.1 , 8.3 ) 5.1 Neutropenic Sepsis Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial ET743-SAR-3007, 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 or reduce dose of YONDELIS based on severity of adverse reaction [see Dosage and Administration (2.4) ] . 5.2 Rhabdomyolysis YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial ET743-SAR-3007, 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, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.4) ] . 5.3 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 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: 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 ET743-SAR-3007, the incidence of drug-induced liver injury (d…

4 CONTRAINDICATIONS YONDELIS is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin. Known hypersensitivity to trabectedin ( 4 )

7 DRUG INTERACTIONS CYP3A inhibitors: Avoid concomitant strong CYP3A inhibitors ( 7.1 ) CYP3A inducers: Avoid concomitant strong CYP3A inducers ( 7.2 ) 7.1 Effect 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) ] . 7.2 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) ] . 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/m 2 ) on day 1 increased trabectedin dose-normalized AUC by 66% and C max by 22% compared to a single YONDELIS dose (1.3 mg/m 2 ) 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/m 2 ) on day 6 decreased trabectedin AUC by 31% and C max by 21% compared to a single YONDELIS dose (1.3 mg/m 2 ) 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).

8.1 Pregnancy 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.

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) ] 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 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 ET743-SAR-3007). All patients received YONDELIS at the recommended dosing regimen of 1.5 mg/m 2 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 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/m 2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m 2 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 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 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 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: 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 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%), thrombocyt…