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)]

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.

Table 3: Selected Adverse Reactions *Occurring in ≥10% of Patients Receiving YONDELIS and at a Higher Incidence than in the Control Arm - Trial ET743-SAR-3007
	YONDELIS (N=378)		Dacarbazine (N=172)
System Organ Class Adverse Reaction	All Grades † (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
* 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 3–4 adverse reactions. † Toxicity grade is based on NCI common toxicity criteria, version 4.0. ‡ Fatigue is a composite of the following adverse event terms: fatigue, asthenia, and malaise.
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 ‡	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

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.

Table 4: Incidence of Selected Treatment-Emergent Laboratory Abnormalities *- Trial ET743-SAR-3007
Laboratory Abnormalities	YONDELIS		Dacarbazine
Laboratory Abnormalities	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients).
* Treatment-emergent laboratory abnormalities including those higher in the trabectedin arm compared with the dacarbazine arm by ≥5% (all Grades) or by ≥2% (Grade 3–4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement.
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

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