Yondelis

YONDELIS
^®is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen

• Administer at 1.5 mg/m
  
  ²body surface area as a 24-hour intravenous infusion, every 3 weeks through a central venous line (
  
  
  2.1 Recommended Dosage

  The recommended dose is 1.5 mg/m²administered 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/m²in 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)

  [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  .
  ,
  
  
  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.
  )
  
• Premedication: dexamethasone 20 mg intravenously, 30 min before each infusion (
  
  
  2.2 Premedication

  Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of YONDELIS.
  )
  
• Hepatic Impairment: Administer at 0.9 mg/m
  
  ²body surface area as a 24-hour intravenous infusion, every 3 weeks through a central venous line in patients with moderate hepatic impairment (
  
  
  2.1 Recommended Dosage

  The recommended dose is 1.5 mg/m²administered 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/m²in 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)

  [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]

  .
  )
  

For injection: 1 mg, lyophilized powder in single-dose vial for reconstitution.

• Lactation: Advise not to breastfeed (
  
  
  8.2 Lactation

  Risk Summary

  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.
  )
  
• Hepatic Impairment: Do not administer YONDELIS to patients with severe hepatic impairment (
  
  
  8.6 Hepatic Impairment

  The mean trabectedin exposure was (97%) higher in patients with moderate (bilirubin levels greater than 1.5 to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal) hepatic impairment compared to patients with normal (total bilirubin ≤ the upper limit of normal, and AST and ALT ≤ the upper limit of normal) liver function. Reduce YONDELIS dose in patients with moderate hepatic impairment

  [see Dosage and Administration (2.1)and Clinical Pharmacology (12.3)]

  .

  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)

  [see Warnings and Precautions (5.3)]

  .
  ,
  
  
  12.3 Pharmacokinetics

  The pharmacokinetics of trabectedin is characterized by a rapid decline phase at the end of the infusion and slower exponential phases. Population pharmacokinetic analyses suggest that the pharmacokinetics of trabectedin is dose-proportional (over the dose range of 0.024 to 1.8 mg/m²) and exposure is time-independent. No accumulation of trabectedin in plasma is observed upon repeated administrations every 3 weeks.

  Distribution

  Binding of trabectedin to human plasma proteins was approximately 97%, independent of trabectedin concentrations ranging from 10 ng/mL to 100 ng/mL. Steady state volume of distribution of trabectedin exceeds 5000 L.

  Elimination

  The estimated mean (% coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 175 hours.

  Metabolism

  CYP3A is the predominant CYP enzyme responsible for the hepatic metabolism of trabectedin.

  Trabectedin was extensively metabolized with negligible unchanged drug in urine and feces following administration of trabectedin to humans.

  Excretion

  In patients with solid tumors, following a 3-hour or a 24-hour intravenous infusion of¹⁴C-labeled trabectedin, 64% of the total administered radioactive dose was recovered in 24 days, with 58% in feces and 6% in urine.

  Specific Populations

  The following population characteristics are not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), body surface area (0.9 to 2.8 m²), mild hepatic impairment, or mild to moderate renal impairment. The effects of severe hepatic impairment, severe renal impairment or end stage renal disease on trabectedin exposure are unknown.

  Hepatic Impairment

  The geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) 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) following administration of a single YONDELIS dose of 0.58 mg/m²or 0.9 mg/m²compared to patients with normal liver function following administration of a single YONDELIS dose of 1.3 mg/m²

  [see Dosage and Administration (2.1)and Use in Specific Populations (8.6)]

  .

  Drug Interactions

  Effect of Strong CYP3A Inhibitors on Trabectedin

  Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of YONDELIS (0.58 mg/m²) on day 1 increased trabectedin dose-normalized AUC by 66% and C_maxby 22% compared to a single YONDELIS dose (1.3 mg/m²) given alone.

  Effect of Strong CYP3A Inducers on Trabectedin

  Coadministration of multiple doses of rifampin (600 mg daily for 6 days) with a single YONDELIS dose (1.3 mg/m²) on day 6 decreased trabectedin AUC by 31% and C_maxby 21% compared to a single YONDELIS dose (1.3 mg/m²) given alone.

  Effect of Trabectedin on CYP Enzymes

  In vitro

  , trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4).
  )
  

• Neutropenic sepsis: Severe, and fatal, neutropenic sepsis may occur. Monitor neutrophil count during treatment. Withhold YONDELIS for neutrophil count < 1,500/mcL (
  
  
  2.3 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/m²for patients with normal hepatic function or at 0.3 mg/m²for 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

  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
  Other non-hematologic adverse reactions	Grade 3 or 4	Grade 3 or 4

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

  Table 2: Recommended Starting Doses and Dose Reductions

  Starting Dose and Dose Reduction	For patients with normal hepatic function or mild hepatic impairmentIncluding patients with bilirubin greater than 1 to 1.5 times the upper limit of normal, and any AST or ALT.prior to initiation of YONDELIS treatment	For patients with moderate hepatic impairmentIncluding patients with 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.prior to initiation of YONDELIS treatment
  Starting Dose	1.5 mg/m2	0.9 mg/m2
  Dose Reduction
  First dose reduction	1.2 mg/m2	0.6 mg/m2
  Second dose reduction	1.0 mg/m2	0.3 mg/m2
  ,
  
  
  5.1 Neutropenic Sepsis

  Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial ET743-SAR-3007, 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 or reduce dose of YONDELIS based on severity of adverse reaction

  [see Dosage and Administration (2.3)]

  .
  )
  
• Rhabdomyolysis: Rhabdomyolysis may occur. Monitor creatine phosphokinase (CPK) levels prior to each administration. Withhold YONDELIS for CPK more than 2.5 times the upper limit of normal. (
  
  
  2.3 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/m²for patients with normal hepatic function or at 0.3 mg/m²for 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

  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
  Other non-hematologic adverse reactions	Grade 3 or 4	Grade 3 or 4

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

  Table 2: Recommended Starting Doses and Dose Reductions

  Starting Dose and Dose Reduction	For patients with normal hepatic function or mild hepatic impairmentIncluding patients with bilirubin greater than 1 to 1.5 times the upper limit of normal, and any AST or ALT.prior to initiation of YONDELIS treatment	For patients with moderate hepatic impairmentIncluding patients with 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.prior to initiation of YONDELIS treatment
  Starting Dose	1.5 mg/m2	0.9 mg/m2
  Dose Reduction
  First dose reduction	1.2 mg/m2	0.6 mg/m2
  Second dose reduction	1.0 mg/m2	0.3 mg/m2
  ,
  
  
  5.2 Rhabdomyolysis

  YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial ET743-SAR-3007, 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, reduce dose, or permanently discontinue based on severity of adverse reaction

  [see Dosage and Administration (2.3)]

  .
  )
  
• Hepatotoxicity: Hepatotoxicity may occur. Monitor and delay and/or reduce dose if needed (
  
  
  5.3 Hepatotoxicity

  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 ET743-SAR-3007. In Trial ET743-SAR-3007, 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).

  In Trial ET743-SAR-3007, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving YONDELIS. ALT or AST elevation greater than eight times the upper limit of normal occurred in 18% (67/378) of patients receiving YONDELIS.

  Assess LFTs prior to each administration of YONDELIS and as clinically indicated based on underlying severity of pre-existing hepatic impairment. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality

  [see Dosage and Administration (2.3)and Use in Specific Populations (8.6)].
  )
  
• Cardiomyopathy: Severe and fatal cardiomyopathy can occur. Patients with left ventricular ejection fraction (LVEF) < lower limit of normal, prior cumulative anthracycline dose of ≥300 mg/m
  
  ², age ≥65 years, or a history of cardiovascular disease may be at increased risk of developing new or worsening cardiac dysfunction. Discontinue YONDELIS in patients who develop decreased LVEF or cardiomyopathy (
  
  
  2.3 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/m²for patients with normal hepatic function or at 0.3 mg/m²for 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

  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
  Other non-hematologic adverse reactions	Grade 3 or 4	Grade 3 or 4

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

  Table 2: Recommended Starting Doses and Dose Reductions

  Starting Dose and Dose Reduction	For patients with normal hepatic function or mild hepatic impairmentIncluding patients with bilirubin greater than 1 to 1.5 times the upper limit of normal, and any AST or ALT.prior to initiation of YONDELIS treatment	For patients with moderate hepatic impairmentIncluding patients with 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.prior to initiation of YONDELIS treatment
  Starting Dose	1.5 mg/m2	0.9 mg/m2
  Dose Reduction
  First dose reduction	1.2 mg/m2	0.6 mg/m2
  Second dose reduction	1.0 mg/m2	0.3 mg/m2
  ,
  
  
  5.4 Cardiomyopathy

  Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with YONDELIS. In Trial ET743-SAR-3007, a significant decrease in LVEF was defined as an absolute decrease of ≥15% or below the lower limit of normal with an absolute decrease of ≥5%. Patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial ET743-SAR-3007, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS was 5.3 months (range: 26 days to 15.3 months).

  Patients with LVEF < lower limit of normal, prior cumulative anthracycline dose of ≥300 mg/m², age ≥65 years, or a history of cardiovascular disease may be at increased risk of cardiac dysfunction. Assess LVEF by echocardiogram (ECHO) or multigated acquisition (MUGA) scan before initiation of YONDELIS and at 2- to 3-month intervals thereafter until YONDELIS is discontinued. Discontinue treatment with YONDELIS based on severity of adverse reaction

  [see Dosage and Administration (2.3)]

  .
  )
  
• Capillary leak syndrome: Monitor and discontinue YONDELIS for capillary leak syndrome (
  
  
  5.5 Capillary Leak Syndrome

  Capillary leak syndrome (CLS) characterized by hypotension, edema, and hypoalbuminemia has been reported with YONDELIS, including serious CLS resulting in death. Monitor for signs and symptoms of CLS. Discontinue YONDELIS and promptly initiate standard management for patients with CLS, which may include a need for intensive care

  [see Adverse Reactions (6.2)]

  .
  )
  
• Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use effective contraception (
  
  
  5.7 Embryo-Fetal Toxicity

  Based on its mechanism of action, YONDELIS can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS

  [see Use in Specific Populations (8.1, 8.3)]

  .
  ,
  
  
  8.1 Pregnancy

  Risk Summary

  Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy

  [see Clinical Pharmacology (12.1)]

  . There are no available data with the use of YONDELIS during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
  ,
  
  
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating YONDELIS

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  Females

  Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of YONDELIS

  [see Use in Specific Populations (8.1)]

  .

  Males

  YONDELIS may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of YONDELIS

  [see Nonclinical Toxicology (13.1)]

  .

  Infertility

  YONDELIS may result in decreased fertility in males and females

  [see Nonclinical Toxicology (13.1)]

  .
  )