YONDELIS SIDE EFFECTS

  • Generic Name: trabectedin for injection
  • Brand Name: Yondelis
  • Drug Class: Antineoplastics, Alkylating
Last updated on MDtodate: 10/7/2022

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Anaphylaxis
  • Neutropenic Sepsis
  • Rhabdomyolysis
  • Hepatotoxicity
  • Cardiomyopathy
  • Capillary Leak Syndrome
  • Extravasation Resulting in Tissue Necrosis

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/m2 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/m2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2 intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172). 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 1: Selected Adverse Reactionsa Occurring in ≥10% of Patients Receiving YONDELIS and at a Higher Incidence than in the Control Arm -Trial ET743-SAR-3007

System Organ Class Adverse Reaction YONDELIS
(N=378)
Dacarbazine
(N=172)
All Gradesb
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
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
  Fatiguec 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 3-4 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 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 2: Incidence of Selected Treatment-Emergent Laboratory Abnormalitiesa -Trial ET743-SAR-3007

Laboratory Abnormalities YONDELIS Dacarbazine
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
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 3-4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement.
YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients).

 

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

 

SRC: NLM .