Trabectedin

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 )

Injection: 1 mg/20 mL (0.05 mg/mL) sterile clear colorless to pale brownish yellow solution in a single-dose vial. Injection: 1 mg/20 mL (0.05 mg/mL) solution in a single dose vial ( 3 )

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

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) ] .

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

CYP3A inhibitors: Avoid concomitant strong CYP3A inhibitors ( 7.1 ) CYP3A inducers: Avoid concomitant strong CYP3A inducers ( 7.1 )

7.1 Effects of Other Drugs on EVDI Table 5 describes drug interactions where concomitant use of another drug affects EVDI. Table 5: Drug Interactions with EVDI Strong CYP3A Inhibitors Prevention or Management Avoid concomitant use of strong CYP3A inhibitors in patients taking EVDI. If concomitant use of a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) cannot be avoided, administer the strong CYP3A inhibitor 1 week after the EVDI infusion, and discontinue it the day prior to the next EVDI infusion Mechanism and Clinical Effect(s) Concomitant administration of trabectedin with ketoconazole, a strong CYP3A inhibitor, increased systemic exposure of trabectedin by 66% [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A Inducers Prevention or Management Avoid concomitant use of strong CYP3A inducers in patients taking EVDI. Mechanism and Clinical Effect(s) Concomitant administration of trabectedin with rifampin, a strong CYP3A4 inducer, decreased systemic exposure of trabectedin by 31% [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 EVDI (0.58 mg/m 2 ) on day 1 increased trabectedin dose-normalized AUC by 66% and C max by 22% compared to a single EVDI 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 EVDI dose (1.3 mg/m 2 ) on day 6 decreased trabectedin AUC by 31% and C max by 21% compared to a single EVDI 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).

Lactation: Advise not to breastfeed ( 8.2 ) Hepatic Impairment: Do not administer EVDI to patients with severe hepatic impairment ( 8.6 , 12.3 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, EVDI can cause fetal harm when administered during pregnancy [see Clinical Pharmacology ( 12.1 )]. There are no available data with the use of trabectedin 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.

8.2 Lactation Risk Summary There are no data on the presence of trabectedin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from EVDI in a breastfed child, advise a nursing woman to discontinue nursing during treatment with and for 3 months after the last dose of EVDI.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating EVDI [see Use in Specific Populations (8.1) ] . Contraception Females Advise female patients of reproductive potential to use effective contraception during and for 8 months after the last dose of EVDI [see Use in Specific Populations (8.1) ] . Males EVDI 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 EVDI [see Nonclinical Toxicology (13.1) ] . Infertility EVDI may result in decreased fertility in males and females [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use Safety and effectiveness of EVDI in pediatric patients have not been established. Safety (n=61) and efficacy (n=58) of trabectedin were assessed across five open-label studies (NCT00006463, NCT01453283, NCT00005625, NCT00070109, and ET-B-023-00) in pediatric patients (aged 2 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 3 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 trabectedin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment The mean trabectedin exposure was (97%) higher in patients with moderate (bilirubin levels greater than 1.5 to 3 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 EVDI dose in patients with moderate hepatic impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) ] . 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 Warnings and Precautions (5.3) ] .

8.7 Renal Impairment No dose adjustment of EVDI is recommended in patients with mild [creatinine clearance (CLcr) 60 to 89 mL/min] or moderate (CLcr of 30 to 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) ] .

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.