Yondelis (trabectedin)

Yondelis may cause serious side effects, including:

• Severe infections due to decreased white blood cells. Decreased low white blood cell count is common with Yondelis, but it can also lead to severe infections and death. Your healthcare provider may need to decrease your dose of Yondelis, delay or stop your treatment, if your white blood cell count is too low or you get a serious infection. Call your healthcare provider right away if you develop fever or other signs of infection.
• Severe muscle problems (rhabdomyolysis). Yondelis can cause muscle problems that can be severe and lead to death. Tell your healthcare provider right away if you have severe muscle pain or weakness.
• Liver problems, including liver failure. Tell your healthcare provider right away if you get:
  • yellowing of your skin and whites of your eyes
  • generally do not feel well
  • pain in your upper right stomach-area (abdomen)
  • problem with concentration
  • nausea
  • confusion
  • vomiting
  • sleepiness
• Heart muscle problems, including heart failure. Your healthcare provider will do a test to check your heart function before you start Yondelis, and during treatment. If you develop heart muscle problems or heart failure during treatment with Yondelis, your healthcare provider may stop your treatment. Tell your healthcare provider right away if you develop new chest pain, shortness of breath, tiredness, swelling of your legs, ankles, or feet, or heart palpitations.
• Leakage of Yondelis out of your vein during the infusion. If Yondelis leaks into the tissues around your infusion site, it can cause damage and death of tissue cells around the infusion site. You may need to have surgery to remove any dead tissue. Tell your healthcare provider right away if you see any Yondelis leaking out of your vein or around the catheter during your infusion, or if you notice any redness, swelling, itching or discomfort at the infusion site at any time.
• Some people have had allergic reactions to Yondelis. Some of these reactions were severe. Your healthcare provider may need to stop your treatment with Yondelis, and may give you medicines to treat the allergic reaction. Signs of an allergic reaction can include: difficulty breathing, chest tightness, wheezing, swelling of the lips, or skin rash.
• Capillary leak syndrome. Yondelis can cause fluid to leak from the blood vessels into the body’s tissues. This condition is called “Capillary Leak Syndrome” (CLS). CLS can cause you to have symptoms that may lead to death. Tell your healthcare provider right away if you develop swelling, dizziness or lightheadedness with or without a sudden drop in blood pressure.

The most common side effects of Yondelis include:

• nausea
• tiredness
• vomiting
• constipation
• decreased appetite
• diarrhea
• swelling of your hands, ankles, or feet
• shortness of breath
• headache
• decreased red cell count (cells which carry oxygen in the blood). Tell your healthcare provider if you feel more tired than usual or look pale.
• decreased platelet cell counts (cells which help blood to clot). Tell your healthcare provider if you bruise easily or have bleeding.
• changes in liver and kidney function blood tests

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Yondelis. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Recommended Dosage

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.

Hepatic Impairment

The recommended dose is 0.9 mg/m² 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). 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).

Premedication

Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of Yondelis.

Dose 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/m² for patients with normal hepatic function or at 0.3 mg/m² for 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.

Table 1: Recommended Dose Modification

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

Table 2: Recommended Starting Doses and Dose Reductions

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.

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.

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.

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.

• Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy.
• There are no available data with the use of Yondelis during pregnancy.
• There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production.
• Because of the potential for serious adverse reactions from Yondelis in breastfed infants, advise a nursing woman to discontinue nursing during treatment with Yondelis.