Yondelis

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.

There is no recommended dose of YONDELIS in patients with serum bilirubin levels above the institutional upper limit of normal [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

2.2 Premedication

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 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

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 dose reductions for YONDELIS are:

First dose reduction: YONDELIS 1.2 mg/m2 every 3 weeks Second dose reduction: YONDELIS 1.0 mg/m2 every 3 weeks Table 1: Recommended Dose Modification Laboratory Result or Adverse Reaction DELAY next dose of YONDELIS for up to 3 weeks REDUCE next dose of YONDELIS by one dose level for adverse reaction(s) during prior cycle Platelets Less than 100,000 platelets/microliter Less than 25,000 platelets/microliter Absolute neutrophil count Less than 1,500 neutrophils/microliter Less than 1,000 neutrophils/microliter with fever/infection Less than 500 neutrophils/microliter lasting more than 5 days Total bilirubin Greater than the upper limit of normal Greater than the upper limit of normal Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) More than 2.5 times the upper limit of normal More than 5 times the upper limit of normal Alkaline phosphatase (ALP) More than 2.5 times the upper limit of normal More than 2.5 times the upper limit of normal Creatine phosphokinase More than 2.5 times the upper limit of normal More than 5 times the upper limit of normal Decreased left ventricular ejection fraction Less than lower limit of normal; or Clinical evidence of cardiomyopathy Absolute decrease of 10% or more from baseline and less than lower limit of normal; or Clinical evidence of cardiomyopathy Other non-hematologic adverse reactions Grade 3 or 4 Grade 3 or 4 2.4 Preparation for Administration YONDELIS is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 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. 2.5 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 to reduce the risk of exposure to adventitious pathogens that may be introduced during solution preparation. Complete infusion within 30 hours of initial reconstitution. Discard any unused portion of the reconstituted product or of the infusion solution.