YONDELIS 0,25 mg

1 INDICATIONS AND USAGE EVDI 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) ] . EVDI 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 , 2.5 ) Premedication: dexamethasone 20 mg intravenously, 30 min before each infusion ( 2.2 ) 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 ( 2.1 ) 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 EVDI 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 EVDI 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 EVDI. 2.4 Dosage Modifications for Adverse Reactions Permanently discontinue EVDI for: Persistent adverse reactions requiring a delay in dosing of more than 3 weeks. Adverse reactions following the second dosage reduction of EVDI (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 dosage modifications for adverse reactions are listed in Table 1. Once reduced, the dose of EVDI should not be increased in subsequent treatment cycles. Table 1: Recommended Dosage Modification Laboratory Result or Adverse Reaction DELAY next dose of EVDI for up to 3 weeks REDUCE next dose of EVDI 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 EVDI 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 EVDI treatment For patients with moderate hepatic impairment** prior to initiation of EVDI treatment Starting Dose 1.5 mg/m 2 0.9 mg/m 2 Dose Reduction First dose reduction 1.2 mg/m 2 0.6 mg/m 2 Second dose reduction 1.0 mg/m 2 0.3 mg/m 2 * Including patients with bilirubin greater than 1 to 1.5 times the upper limit of normal, and any AST or ALT. ** 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 the upper limit of normal. 2.5 Preparation for Administration EVDI is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is clear colorless to pale brownish yellow. Discard the vial if particles are observed. Withdraw the calculated volume of trabectedin and dilute in 500 mL of 0.9% Sodium Chloride Injection, USP or in 500 mL of 5% Dextrose Injection, USP. Discard any unused portion left in the vial(s). EVDI 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. Do not mix EVDI with other drugs. The diluted EVDI infusion solution may be stored at room temperature 20°C to 25°C (68°F to 77°F) for up to 30 hours. 2.6 Administration Infuse the diluted solution over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter. Discard any unused portion of the infusion solution. Complete infusion within 30 hours of initial dilution. Discard any unused portion of the infusion solution after 30 hours.

5 WARNINGS AND PRECAUTIONS Neutropenic sepsis: Severe, and fatal, neutropenic sepsis may occur. Monitor neutrophil count during treatment. Withhold EVDI for neutrophil count < 1,500/mcL ( 2.3 , 5.1 ) Rhabdomyolysis: Rhabdomyolysis may occur. Monitor creatine phosphokinase (CPK) levels prior to each administration. Withhold EVDI 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/m 2 , age ≥65 years, or a history of cardiovascular disease may be at increased risk of developing new or worsening cardiac dysfunction. Discontinue EVDI in patients who develop decreased LVEF or cardiomyopathy ( 2.3 , 5.4 ) Capillary leak syndrome: Monitor and discontinue EVDI 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 EVDI. In Trial ET743-SAR-3007, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, in patients receiving trabectedin 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 trabectedin. 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 EVDI and periodically throughout the treatment cycle. Withhold or reduce dose of EVDI based on severity of adverse reaction [see Dosage and Administration (2.3) ] . 5.2 Rhabdomyolysis EVDI 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 trabectedin. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving trabectedin, 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 trabectedin 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 EVDI. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3) ] . 5.3 Hepatotoxicity Hepatotoxicity, including hepatic failure, can occur with EVDI. 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 to 4 elevated liver function tests (LFTs; defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving trabectedin. The median time to development of Grade 3 to 4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3 to 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 (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 trabectedin. ALT or AST elevation greater than eight times the upper limit of normal occurred in 18% (67/378) of patients receiving trabectedin. Assess LFTs prior to each administration of EVDI and as clinically indicated based on the 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) ] . 5.4 Cardiomyopathy Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with EVDI. In Trial ET743-SAR-3007, a 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 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 ET743-SAR-3007, cardiomyopathy occurred in 23 patients (6%) receiving trabectedin and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving trabectedin and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving EVDI and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving trabectedin 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/m 2 , age ≥65 years, or a 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 EVDI and at 2- to 3-month intervals thereafter until EVDI is discontinued. Discontinue treatment with EVDI based on severity of adverse reaction [see Dosage and Administration (2.3) ] . 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) characterized by hypotension, edema, and hypoalbuminemia has been reported with trabectedin, including serious CLS resulting in death. Monitor for signs and symptoms of CLS. Discontinue EVDI and promptly initiate standard management for patients with CLS, which may include a need for intensive care [see Adverse Reactions (6.2) ] . 5.6 Extravasation Resulting in Tissue Necrosis Extravasation of EVDI, 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 EVDI. Administer EVDI through a central venous line [see Dosage and Administration (2.5) ] . 5.7 Embryo-Fetal Toxicity Based on its mechanism of action, EVDI 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 8 months after the last dose of EVDI. 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 EVDI [see Use in Specific Populations (8.1 , 8.3) ] .

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 to 4 laboratory abnormalities are: neutropenia, increased ALT, thrombocytopenia, anemia, increased AST, and increased creatine phosphokinase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp at 1-800-706-5575 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 trabectedin in 755 patients with soft tissue sarcoma including 197 (26%) patients exposed to trabectedin for greater than or equal to 6 months and 57 (8%) patients exposed to trabectedin for greater than or equal to 1 year. The safety of trabectedin was evaluated in six open-label, single-arm trials, in which 377 patients received trabectedin and one open-label, randomized, active-controlled clinical trial in which 378 patients received trabectedin (Trial ET743-SAR-3007). All patients received trabectedin 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 trabectedin 1.5 mg/m 2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1,000 mg/m 2 intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172) [see Clinical Studies ( 14 )] . All patients treated with trabectedin were required to receive dexamethasone 20 mg intravenous injection 30 minutes prior to start of the trabectedin 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 trabectedin for greater than 6 months and 7% of patients exposed to trabectedin for greater than 1 year. In Trial ET743-SAR-3007, adverse reactions resulting in permanent discontinuation of trabectedin 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 trabectedin; 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 trabectedin; 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 a Occurring in ≥10% of Patients Receiving Trabectedin and at a Higher Incidence than in the Control Arm - Trial ET743-SAR-3007 System Organ Class Adverse Reaction Trabectedin (N=378) Dacarbazine (N=172) All Grades b (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) 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 c 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 a 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 to 4 adverse reactions. b Toxicity grade is based on NCI common toxicity criteria, version 4.0. c Fatigue is a composite of the following adverse event terms: fatigue, asthenia, and malaise. Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving trabectedin 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 Abnormalities a -Trial ET743-SAR-3007 Laboratory Abnormalities Trabectedin Dacarbazine All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) 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 a 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 to 4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement. Trabectedin group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of trabectedin. 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