2.1 Recommended Dosage

The recommended dose is 1.5 mg/m 2administered 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 2every 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 2for patients with normal hepatic function or at 0.3 mg/m 2for 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.

The recommended starting doses and dose reductions for YONDELIS are listed in Table 2:

2.5 Preparation for Administration

• YONDELIS 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.
• 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 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.

2.6 Administration

• Infuse the reconstituted, diluted solution over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter.
• Complete infusion within 30 hours of initial reconstitution. Discard any unused portion of the reconstituted product or of the infusion solution.

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 (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 (2.4)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 YONDELIS. 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 YONDELIS and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS was 5.3 months (range: 26 days to 15.3 months).

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 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 (2.4)] .

5.5 Capillary Leak Syndrome

Capillary leak syndrome (CLS) characterized by hypotension, edema, and hypoalbuminemia has been reported with YONDELIS, including serious CLS resulting in death. Monitor for signs and symptoms of CLS. Discontinue YONDELIS and promptly initiate standard management for patients with CLS, which may include a need for intensive care [see Adverse Reactions (6.2)] .

5.6 Extravasation Resulting in Tissue Necrosis

Extravasation of YONDELIS, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS. Administer YONDELIS through a central venous line [see Dosage and Administration (2.6)] .

5.7 Embryo-Fetal Toxicity

Based on its mechanism of action, YONDELIS can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 8 months after the last dose of YONDELIS. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS [see Use in Specific Populations (8.1, 8.3)] .

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 2administered 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 2intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m 2intravenous 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%), 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.

Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving YONDELIS were:

Nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia.

Respiratory, thoracic, and mediastinal disorders: pulmonary embolism.

General disorders and administration site conditions: mucosal inflammation

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of YONDELIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular disorders: capillary leak syndrome

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)] .

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 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 YONDELIS 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 YONDELIS dose in patients with moderate hepatic impairment [see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)] .

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 Warnings and Precautions (5.3)] .

8.7 Renal Impairment

No dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60–89 mL/min] or moderate (CLcr of 30–59 mL/min) renal impairment.

The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease [see Clinical Pharmacology (12.3)] .

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 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of trabectedin is characterized by a rapid decline phase at the end of the infusion and slower exponential phases. Population pharmacokinetic analyses suggest that the pharmacokinetics of trabectedin is dose-proportional (over the dose range of 0.024 to 1.8 mg/m 2) and exposure is time-independent. No accumulation of trabectedin in plasma is observed upon repeated administrations every 3 weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Trabectedin is genotoxic in both in vitroand in vivostudies. Long-term carcinogenicity studies have not been performed.

Fertility studies with trabectedin were not performed. In male rats there were limited histopathological signs of hemorrhage and degeneration in the testes following repeated administration of trabectedin at doses approximately 0.2 times the 1.5 mg/m 2human dose based on body surface area.

Storage and Handling

Store YONDELIS vials in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F).

YONDELIS is a hazardous drug. Follow applicable special handling and disposal procedures. 1

Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness [see Warnings and Precautions (5.1)] .

Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness, or if they experience reddish-brown urine [see Warnings and Precautions (5.2)] .

Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion [see Warnings and Precautions (5.3)] .

Cardiomyopathy: Advise patients to contact their healthcare provider immediately for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations [see Warnings and Precautions (5.4)] .

Capillary leak syndrome: Advise patients to report symptoms such as edema with or without hypotension [see Warnings and Precautions (5.5)and Adverse Reactions (6.2)] .

Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site [see Warnings and Precautions (5.6)] .

Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash [see Contraindications (4)] .

Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with YONDELIS [see Warnings and Precautions (5.7)and Use in Specific Populations (8.1)] .

Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 8 months after last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 5 months after the last dose [see Warnings and Precautions (5.7)and Use in Specific Populations (8.3)] .

Lactation: Advise females not to breastfeed during treatment with and for 3 months after the last dose of YONDELIS [see Use in Specific Populations (8.2)] .