Yondelis

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Yondelis

Classes

Other Antineoplastic Agents

Administration

Hazardous Drugs Classification
NIOSH (Draft) 2020 List: Table 1
Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
Observe and exercise appropriate cautions for preparing, handling, and administering solutions of cytotoxic drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Moderate
Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
Vesicant
Administer drug through a central venous line.

Injectable Administration

For intravenous infusion use only.

Intravenous Administration

Reconstitution
Using aseptic technique, inject 20 mL of Sterile Water for Injection into the trabectedin vial; shake until complete dissolution.
The reconstituted solution should be clear and colorless to pale brownish yellow, containing 0.05 mg/mL of trabectedin.
Inspect for particulate matter and discoloration; discard vial if particles or discoloration are observed.
 
Infusion Preparation
Immediately after reconstitution, withdraw the calculated volume of trabectedin and dilute in 500 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
Do not mix trabectedin with other drugs.
The 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.
Discard any remaining solution within 30 hours of reconstituting the lyophilized powder.
 
Intravenous Infusion Administration
Premedication is required: Administer dexamethasone 20 mg IV 30 minutes prior to each trabectedin infusion dose.
Infuse over 24 hours through a central venous line, using an infusion set with a 0.2 micron PES in-line filter.
Complete the infusion within 30 hours of initial reconstitution. Discard any unused portion.

Adverse Reactions
Severe

neutropenia / Delayed / 43.0-43.0
elevated hepatic enzymes / Delayed / 1.6-31.0
thrombocytopenia / Delayed / 21.0-21.0
anemia / Delayed / 19.0-19.0
pulmonary embolism / Delayed / 0-10.0
fatigue / Early / 8.0-8.0
nausea / Early / 7.0-7.0
vomiting / Early / 6.0-6.0
renal failure (unspecified) / Delayed / 2.9-4.2
dyspnea / Early / 4.2-4.2
cardiomyopathy / Delayed / 4.0-4.0
hypoalbuminemia / Delayed / 3.7-3.7
hyperbilirubinemia / Delayed / 1.9-1.9
anorexia / Delayed / 1.9-1.9
diarrhea / Early / 1.6-1.6
rhabdomyolysis / Delayed / 0.8-1.1
constipation / Delayed / 0.8-0.8
peripheral edema / Delayed / 0.8-0.8
insomnia / Early / 0.3-0.3
headache / Early / 0.3-0.3
hepatic failure / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
capillary leak syndrome / Early / Incidence not known

Moderate

peripheral neuropathy / Delayed / 0-10.0

Mild

arthralgia / Delayed / 15.0-15.0
myalgia / Early / 12.0-12.0
hypoesthesia / Delayed / 0-10.0
paresthesias / Delayed / 0-10.0
asthenia / Delayed / Incidence not known
malaise / Early / Incidence not known

Common Brand Names

Yondelis

Dea Class

Rx

Description

Alkylating agent
Used for unresectable or metastatic liposarcoma and leiomyosarcoma following treatment with anthracycline-containing chemotherapy
Neutropenic sepsis, hepatotoxicity, rhabdomyolysis, and cardiomyopathy have been reported

Dosage And Indications
For the treatment of soft-tissue sarcoma.
NOTE: Trabectedin has been designated by the FDA as an orphan drug for the treatment of soft-tissue sarcoma.
For the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen. Intravenous dosage Adults

1.5 mg/m2 IV infusion via a central venous line over 24 hours on day 1 and repeated every 21 days until disease progression. Premedicate with dexamethasone 20 mg IV 30 minutes prior to each dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop severe toxicity.[60248] At a median follow-up time of 21.2 months, the primary endpoint of median overall survival (OS) time was not significantly improved with trabectedin compared with dacarbazine (13.7 months vs. 13.1 months; hazard ratio (HR) = 0.93; 95% CI, 0.75 to 1.15; p = 0.49) in patients with previously treated, unresectable locally advanced or metastatic liposarcoma or leiomyosarcoma in a multinational, randomized (2:1), open-label, phase 3 trial (n = 577). The median progression-free survival (PFS) time was significantly improved with trabectedin compared with dacarbazine (4.2 months vs. 1.5 months; HR = 0.55; 95% CI, 0.44 to 0.7; p less than 0.001). Patients in this study had previously received an anthracycline and ifosfamide or an anthracycline and 1 or more additional cytotoxic chemotherapy regimens. Cross-over treatment was not permitted in this study; 71% of patients in the trabectedin arm and 69% of patients in the dacarbazine arm had received subsequent anticancer therapy at the time of the final OS analysis. At a median follow-up time of 11 months, the primary endpoint of PFS time was significantly longer with trabectedin compared with best supportive care (BSC) (3.1 months vs. 1.5 months; HR = 0.39; 95% CI, 0.24 to 0.64; p less than 0.001) in patients with previously treated, unresectable or metastatic soft-tissue sarcoma in a randomized, open-label, phase 3 trial (n = 103). In a subgroup of patients with liposarcoma or leiomyosarcoma (n = 62; 60.2%), the median PFS times were 5.1 and 1.4 months in the trabectedin and BSC arms (HR = 0.29; 95% CI, 0.15 to 0.55; p less than 0.0001), respectively. Patients in this study had received a median of 1 (range, 0 to 3) prior therapy; 97.1% of patients had previously received an anthracycline. Cross-over treatment was permitted in this study and 91.8% of patients in the BCS arm subsequently received trabectedin. At a median follow-up time of 26 (range, 0.46 to 31.1) months, OS was not significantly different between study arms; however, this study was not powered to detect a difference in OS.

Dosing Considerations
Hepatic Impairment

Baseline Hepatic Impairment
Mild hepatic impairment (bilirubin level greater than 1- to 1.5-times the upper limit of normal (ULN) and any AST or ALT level): No initial dose reduction is necessary.Moderate hepatic impairment (bilirubin level greater than 1.5- to 3-times the ULN and AST and ALT level less than 8-times the ULN): Start at a reduced dose of 0.9 mg/m2 IV.Severe hepatic impairment (bilirubin level greater than 3-times the ULN and any AST and ALT level): Use not recommended.
Management of Treatment-Related Hepatotoxicity
Permanently discontinue trabectedin in patients:
with normal hepatic function at baseline who develop severe liver dysfunction (defined as a bilirubin level of 2-times the ULN and an AST or ALT level 3-times the ULN with an alkaline phosphatase (AP) level less than 2-times the ULN in the prior treatment cycle
with moderate hepatic impairment at baseline who have an exacerbation of liver dysfunction
who require a third dose reduction due to toxicity
who have persistent toxicity resulting in a dose delay of more than 3 weeks
Recommended Dose Reductions
NOTE: Dose reductions are based on baseline hepatic function. After a dose reduction, do not increase the dose in subsequent treatment cycles.
Baseline normal hepatic function or mild hepatic impairment:
First dose reduction: 1.2 mg/m2 IVSecond dose reduction: 1 mg/m2 IV
Baseline moderate hepatic impairment:
First dose reduction: 0.6 mg/m2 IVSecond dose reduction: 0.3 mg/m2 IV
Hyperbilirubinemia
Total bilirubin level greater than the ULN: Delay the next dose for up to 3 weeks; resume therapy at a reduced dose.
Elevated Hepatic Enzymes
AST or ALT level of 2.5- to 5-times the ULN: Delay the next dose for up to 3 weeks; resume therapy at the previous dose.AST or ALT level greater than 5-times the ULN: Delay the next dose for up to 3 weeks; resume therapy at a reduced dose.AP level greater than 2.5-times the ULN: Delay the next dose for up to 3 weeks; resume therapy at a reduced dose.[60248]

Renal Impairment

No dose adjustment necessary in patients with baseline mild (creatinine clearance (CrCl) 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. The pharmacokinetics of trabectedin have not been evaluated in patients with severe renal impairment (CrCl less than 30 mL/min) or end stage renal disease. Hemodialysis is not expected to enhance the elimination of trabectedin.

Drug Interactions

Adagrasib: (Major) Avoid the concomitant use of trabectedin with adagrasib due to the risk of increased trabectedin exposure. If short-term adagrasib (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Aldesleukin, IL-2: (Moderate) Use caution if coadministration of trabectedin and aldesleukin, IL-2 is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; aldesleukin increases IL-6 concentrations, and IL-6 is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to the risk of increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Apalutamide: (Major) Avoid the concomitant use of trabectedin with apalutamide due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Atazanavir: (Major) Avoid the concomitant use of trabectedin with atazanavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Atazanavir; Cobicistat: (Major) Avoid the concomitant use of trabectedin with atazanavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Carbamazepine: (Major) Avoid the concomitant use of trabectedin with carbamazepine due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Ceritinib: (Major) Avoid the concomitant use of trabectedin with ceritinib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Chloramphenicol: (Major) Avoid the concomitant use of trabectedin with chloramphenicol due to the risk of increased trabectedin exposure. If short-term chloramphenicol (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to the risk of increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Cobicistat: (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Darunavir: (Major) Avoid the concomitant use of trabectedin with darunavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Darunavir; Cobicistat: (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Major) Avoid the concomitant use of trabectedin with darunavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Major) Avoid the concomitant use of trabectedin with darunavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Delavirdine: (Major) Avoid the concomitant use of trabectedin with delavirdine due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Enzalutamide: (Major) Avoid the concomitant use of trabectedin with enzalutamide due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Flutamide: (Minor) Use caution if coadministration of trabectedin and flutamide is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, flutamide is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
Fosamprenavir: (Major) Avoid the concomitant use of trabectedin with fosamprenavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and fosamprenavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Fosphenytoin: (Major) Avoid the concomitant use of trabectedin with fosphenytoin due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Grapefruit juice: (Major) Avoid the concomitant use of trabectedin with grapefruit juice due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Idelalisib: (Major) Avoid the concomitant use of trabectedin with idelalisib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Indinavir: (Major) Avoid the concomitant use of trabectedin with indinavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of trabectedin with rifampin; coadministration resulted in decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with multiple doses of rifampin (600 mg PO daily for 6 days) decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of trabectedin with rifampin; coadministration resulted in decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with multiple doses of rifampin (600 mg PO daily for 6 days) decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Itraconazole: (Major) Avoid the concomitant use of trabectedin with itraconazole due to the risk of increased trabectedin exposure. Avoid trabectedin use during and for 2 weeks after discontinuation of itraconazole treatment. If short-term itraconazole (less than 14 days) cannot be avoided during trabectedin therapy, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Ketoconazole: (Major) Avoid the concomitant use of trabectedin with ketoconazole; coadministration resulted in increased trabectedin exposure. If short-term ketoconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg PO twice daily for 7.5 days) increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to the risk of increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Letermovir: (Moderate) An increase in the plasma concentration of trabectedin may occur if given with letermovir. Avoid coadministration in patients who are also receiving treatment with cyclosporine because the magnitude of this interaction may be amplified. Trabectedin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration of trabectedin and another strong CYP3A inhibitor increased systemic exposure of trabectedin by 66%.
Levoketoconazole: (Major) Avoid the concomitant use of trabectedin with ketoconazole; coadministration resulted in increased trabectedin exposure. If short-term ketoconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg PO twice daily for 7.5 days) increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Lonafarnib: (Major) Avoid the concomitant use of trabectedin with lonafarnib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Lopinavir; Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of trabectedin with lumacaftor; ivacaftor due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of trabectedin with lumacaftor; ivacaftor due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Mifepristone: (Major) Avoid the concomitant use of trabectedin with chronic use of mifepristone due to the risk of increased trabectedin exposure. If short-term mifepristone (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Mitotane: (Major) Avoid the concomitant use of trabectedin with mitotane due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Nefazodone: (Major) Avoid the concomitant use of trabectedin with nefazodone due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Nelfinavir: (Major) Avoid the concomitant use of trabectedin with nelfinavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Nirmatrelvir; Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Pentobarbital: (Major) Avoid the concomitant use of trabectedin with pentobarbital due to the potential for significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate. Barbiturates are known to induce hepatic CYP isoenzymes; most data describing barbiturate drug interactions have been documented with phenobarbital, a strong CYP3A inducer. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
Phenobarbital: (Major) Avoid the concomitant use of trabectedin with phenobarbital due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of trabectedin with phenobarbital due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Phenytoin: (Major) Avoid the concomitant use of trabectedin with phenytoin due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Posaconazole: (Major) Avoid the concomitant use of trabectedin with posaconazole due to the risk of increased trabectedin exposure. If short-term posaconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Primidone: (Major) Avoid the concomitant use of trabectedin with primidone due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Ribociclib: (Major) Avoid the concomitant use of trabectedin with ribociclib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Ribociclib; Letrozole: (Major) Avoid the concomitant use of trabectedin with ribociclib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Rifampin: (Major) Avoid the concomitant use of trabectedin with rifampin; coadministration resulted in decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with multiple doses of rifampin (600 mg PO daily for 6 days) decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Rifapentine: (Major) Avoid the concomitant use of trabectedin with rifapentine due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Saquinavir: (Major) Avoid the concomitant use of trabectedin with saquinavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of trabectedin with St. John's Wort due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Tipranavir: (Major) Avoid the concomitant use of trabectedin with tipranavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Tucatinib: (Major) Avoid the concomitant use of trabectedin with tucatinib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to the risk of increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Voriconazole: (Major) Avoid the concomitant use of trabectedin with voriconazole due to the risk of increased trabectedin exposure. If short-term voriconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.

How Supplied

Yondelis Intravenous Inj Pwd F/Sol: 1mg

Maximum Dosage
Adults

1.5 mg/m2 IV every 3 weeks.

Geriatric

1.5 mg/m2 IV every 3 weeks.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Trabectedin causes alkylation by binding guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.

Pharmacokinetics

Trabectedin is administered by intravenous infusion; it is highly bound to plasma proteins (97%), independent of concentrations ranging from 10 to 100 ng/mL. The steady-state volume of distribution (Vd) is greater than 5,000 liters. The mean clearance is 31.5 L/hour (CV%, 50%) and the terminal elimination half-life is approximately 175 hours. Trabectedin is extensively metabolized, with negligible unchanged drug in urine or feces. Trabectedin is not significantly renally excreted; in patients with solid tumors, 64% of a radiolabeled 3-hour or 24-hour dose was recovered in 24 days, with 6% in urine and 58% in feces.
Affected cytochrome P450 (CYP) isoenzymes: CYP3A
CYP3A is the predominant enzyme responsible for the hepatic metabolism of trabectedin. In vitro, trabectedin has limited inhibition or induction potential of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.[60248]

Intravenous Route

The pharmacokinetics of trabectedin are characterized by a rapid decline phase at the end of the infusion, and slower exponential phases. Based on population pharmacokinetic analyses, the pharmacokinetics are dose-proportional over a range of 0.024 to 1.8 mg/m2; exposure is time-dependent. Plasma accumulation of trabectedin is not observed when administered every 3 weeks.

Pregnancy And Lactation
Pregnancy

Although there are no adequate and well-controlled studies in pregnant women, trabectedin may cause fetal harm when administered during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted; however, placental transfer of trabectedin was demonstrated in pregnant rats.

It is not known whether trabectedin is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from trabectedin, advise women to discontinue breast-feeding during treatment.