YONDELIS- trabectedin injection, powder, lyophilized, for solution
Janssen Products, LP
1 INDICATIONS AND USAGE
YONDELIS® is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose and Schedule
The recommended dose is 1.5 mg/m2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks), until disease progression or unacceptable toxicity, in patients with normal bilirubin and AST or ALT less than or equal to 2.5 times the upper limit of normal.
Hepatic Impairment: The recommended dose is 0.9 mg/m2 in patients with moderate hepatic impairment (bilirubin levels 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal). Do not administer YONDELIS to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT) [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of YONDELIS.
2.3 Dose Modifications
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/m2 for patients with normal hepatic function or at 0.3 mg/m2 for patients with pre-existing moderate hepatic impairment.
Severe liver dysfunction all of the following: bilirubin two times the upper limit of normal and AST or ALT three times the upper limit of normal with 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.
3 DOSAGE FORMS AND STRENGTHS
For injection: 1 mg, lyophilized powder in single-dose vial for reconstitution.
YONDELIS is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.
5 WARNINGS AND PRECAUTIONS
5.1 Neutropenic Sepsis
Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial 1, 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 YONDELIS for neutrophil counts of less than 1,500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS for life-threatening or prolonged, severe neutropenia in the preceding cycle [see Dosage and Administration (2.3)].
YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, 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 YONDELIS for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS for rhabdomyolysis [see Dosage and Administration (2.3)].
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 1. In Trial 1, 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).
Trabectedin is an alkylating agent with the chemical name (1′R ,6R ,6aR ,7R ,13S ,14S ,16R)-5-(acetyloxy)-3′,4′,6,6a,7,13,14,16-octahydro-6′,8,14-trihydroxy-7′,9-dimethoxy-4,10,23-trimethyl-spiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H -1,3-dioxolo[7,8]isoquino[3,2-b ]benzazocine-20,1′(2′H)-isoquinolin]-19-one. The molecular formula is C39 H43 N3 O11 S. The molecular weight is 761.84 daltons.
Trabectedin is hydrophobic and has a low solubility in water.
YONDELIS (trabectedin) for injection is supplied as a sterile lyophilized white to off-white powder/cake in a single-dose vial. Each single-dose vial contains 1 mg of trabectedin, 27.2 mg potassium dihydrogen phosphate, 400 mg sucrose, and phosphoric acid and potassium hydroxide (for pH adjustment to 3.6 – 4.2).
12 CLINICAL PHARMACOLOGY
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.