Trabectedin, a synthetic alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata , is an alkylating antineoplastic agent.1, 14, 20, 21, 22, 25, 26, 28
Trabectedin is used for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received prior therapy with an anthracycline-containing regimen.1, 2, 15, 16, 17, 18 Trabectedin has been designated an orphan drug by FDA for the treatment of soft tissue sarcoma.19 In patients with unresectable or metastatic leiomyosarcoma or liposarcoma following therapy with either an anthracycline- and ifosfamide-containing chemotherapy regimen or an anthracycline-containing chemotherapy regimen and an additional chemotherapy regimen, trabectedin has been shown to prolong progression-free survival.1, 2
The efficacy and safety of trabectedin were demonstrated in a randomized, open-label, active-controlled, multicenter, phase 3 study (study 1) conducted in patients 15 years of age and older with unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma following therapy with at least either an anthracycline- and ifosfamide-containing chemotherapy regimen or an anthracycline-containing chemotherapy regimen and one or more additional cytotoxic chemotherapy regimen(s).1, 2 In this study, 518 patients were randomized (stratified by histologic subtype, ECOG performance status, and number of prior chemotherapy regimens) in a 2:1 ratio to receive trabectedin (initial dosage of 1.5 mg/m2 by IV infusion over 24 hours) or dacarbazine (initial dosage of 1 g/m2 by IV infusion over 20-120 minutes) on day 1 of each 21-day cycle.1, 2 Patients assigned to receive trabectedin also received dexamethasone phosphate 20 mg IV prior to each infusion of the drug.1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred.1 Patients randomized to receive dacarbazine were not permitted to cross over to trabectedin therapy upon disease progression.1
The efficacy end points of this study were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), objective response rate, overall survival, and duration of response.1, 2 The median age of enrolled patients was 56 years (range: 17-81 years); 76% of patients were white, 12% were black, and 4% were Asian; 30% were male; 73% had leiomyosarcomas and 27% had liposarcomas; and 49% had a baseline ECOG performance status of 0.1 The majority (89%) of patients had received at least 2 prior chemotherapy regimens; 90, 81, 74, and 59% of patients had previously received doxorubicin, gemcitabine, docetaxel, and ifosfamide, respectively, and approximately 10% of patients had previously received pazopanib.1
Final analysis of median progression-free survival in study 1 indicated that patients treated with trabectedin had a substantially longer median progression-free survival compared with patients treated with dacarbazine (4.2 versus 1.5 months).1, 2 The progression-free survival benefit for trabectedin was confirmed by independent blinded review.1, 2 The objective response rate was 7% in patients receiving trabectedin and 6% in those receiving dacarbazine;1 complete responses were not achieved in either treatment group.2 At the time of analysis, the median duration of response for all responders was 6.9 months in patients receiving trabectedin and 4.2 months in those receiving dacarbazine.1 No substantial difference in overall survival was observed between the 2 treatment groups in this study.1 Results of a subgroup analysis (based on age, gender, ethnicity, histologic subtype, ECOG performance status, number of prior chemotherapy regimens, and body mass index [BMI]) suggested that trabectedin's effect on progression-free survival was consistent across all subgroups.2
To help prevent nausea and vomiting and reduce the risk of hepatotoxicity associated with trabectedin therapy, premedication with dexamethasone phosphate 20 mg should be administered IV 30 minutes prior to each infusion of trabectedin.1, 3, 9, 28 Additional antiemetics may be administered as needed.9, 28
Because trabectedin may cause neutropenia and associated sepsis, the manufacturer states that the neutrophil count should be assessed prior to administration of each dose of the drug and periodically throughout the treatment cycle.1 (See Neutropenic Sepsis under Cautions: Warnings/Precautions.)
Because trabectedin may cause rhabdomyolysis, the manufacturer states that serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations should be assessed prior to administration of each dose of the drug.1 (See Rhabdomyolysis under Cautions: Warnings/Precautions.)
Because hepatotoxicity may occur with trabectedin, liver function tests should be assessed prior to each infusion of the drug.1 (See Hepatic Toxicity under Cautions: Warnings/Precautions.)
Because cardiomyopathy may occur with trabectedin, the manufacturer states that left ventricular ejection fraction (LVEF) should be assessed by echocardiogram or multiple gated acquisition (MUGA) scan prior to initiation of trabectedin and at 2- to 3-month intervals thereafter.1 (See Cardiomyopathy under Cautions: Warnings/Precautions.)
Restricted Distribution Program
Trabectedin can only be obtained through specialty distributors.5 Clinicians may consult the Yondelis® website for specific availability information ([Web]).5
Procedures for proper handling and disposal of antineoplastic agents should be followed.1
Trabectedin is administered by continuous IV infusion over 24 hours via a central venous line using an infusion set with a 0.2-µm polyethersulfone inline filter.1
Unreconstituted vials of trabectedin powder for injection should be stored at 2-8°C.1
Prior to administration, commercially available trabectedin powder for injection must be reconstituted and diluted using proper aseptic technique.1 The lyophilized powder is reconstituted by adding 20 mL of sterile water for injection to a vial labeled as containing 1 mg of trabectedin to provide a solution containing 0.05 mg/mL of the drug.1 The vial should then be shaken until complete dissolution of the powder occurs and inspected visually for particulate matter and discoloration prior to dilution.1 The solution should be clear and colorless to pale brownish-yellow; the vial should be discarded if particulate matter or discoloration is present.1 The reconstituted trabectedin solution should be diluted immediately.1 Any partially used vials should be discarded.1
For preparation of the final diluted trabectedin solution for infusion, the appropriate volume of reconstituted solution should be withdrawn from the vial and further diluted in 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 Final diluted solutions of trabectedin are stable for 30 hours following reconstitution when stored at 2-8°C or room temperature in ambient light.1, 4 Administration of the drug must be completed within 30 hours following reconstitution.1 Any unused portion of reconstituted solution or diluted infusion solution should be discarded.1 Trabectedin should not be admixed with any other drug.1
Trabectedin may adsorb to certain infusion materials;26 however, the manufacturer states that diluted solutions of trabectedin are compatible with type I colorless glass vials; polyvinylchloride (PVC) and polyethylene bags and tubing; polyethylene and polypropylene mixture bags; polyethersulfone inline filters; titanium, platinum, or plastic ports; silicone and polyurethane catheters; and infusion pumps having contact surfaces made of PVC, polyethylene, or polyethylene/polypropylene.1
For the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received prior therapy with an anthracycline-containing regimen, the recommended adult dosage of trabectedin is 1.5 mg/m2 administered as a continuous IV infusion over 24 hours every 3 weeks.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of trabectedin should be considered.1 When dosage reduction is necessary, an initial dosage reduction to 1.2 mg/m2 every 3 weeks is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 1 mg/m2 every 3 weeks.1 If a dosage of 1 mg/m2 every 3 weeks is not tolerated, trabectedin should be permanently discontinued.1
Dosage of trabectedin should not be re-escalated following a dosage reduction.1
Trabectedin should be permanently discontinued in patients experiencing persistent adverse reactions requiring a treatment delay of more than 3 weeks.1
For an absolute neutrophil count (ANC) less than 1500/mm3 or a platelet count less than 100,000/mm3, trabectedin therapy should be withheld for up to 3 weeks.1 Therapy may then be resumed at the same dosage.1
If an ANC less than 1000/mm3 and signs or symptoms of infection (e.g., fever) occurred during the preceding cycle, the trabectedin dosage should be reduced.1
If an ANC less than 500/mm3 occurred for more than 5 days during the preceding cycle, the trabectedin dosage should be reduced.1
If platelet counts less than 25,000/mm3 occurred during the preceding cycle, the trabectedin dosage should be reduced.1
If life-threatening or prolonged and severe neutropenia occurred during the preceding cycle, the trabectedin dosage should be permanently reduced.1 (See Neutropenic Sepsis under Cautions: Warnings/Precautions.)
For elevations in total bilirubin concentrations exceeding the upper limit of normal (ULN) or serum aminotransferase (ALT or AST) or alkaline phosphatase concentrations exceeding 2.5 times the ULN, trabectedin therapy should be withheld for up to 3 weeks.1 Therapy may then be resumed at the same dosage.1
If total bilirubin concentrations exceeded the ULN, AST or ALT concentrations exceeded 5 times the ULN, or alkaline phosphatase concentrations exceeded 2.5 times the ULN during the preceding cycle, the trabectedin dosage should be reduced.1
If severe hepatic dysfunction (total bilirubin concentrations at least 2 times the ULN and AST or ALT concentrations at least 3 times the ULN with alkaline phosphatase concentrations less than 2 times the ULN) occurred during the preceding cycle, trabectedin therapy should be permanently discontinued.1 (See Hepatic Toxicity under Cautions: Warnings/Precautions.)
For serum CK concentrations exceeding 2.5 times the ULN, trabectedin therapy should be withheld for up to 3 weeks.1 Therapy may then be resumed at the same dosage.1
If serum CK concentrations exceeded 5 times the ULN during the preceding cycle, the trabectedin dosage should be reduced.1
If rhabdomyolysis occurs, trabectedin should be permanently discontinued.1 (See Rhabdomyolysis under Cautions: Warnings/Precautions.)
For left ventricular ejection fraction (LVEF) values less than the lower limit of normal (LLN) or evidence of cardiomyopathy, trabectedin therapy should be withheld for up to 3 weeks.1 Therapy may then be resumed at the same dosage.1
If LVEF less than the LLN with an absolute decrease from baseline of 10% or more or clinical evidence of cardiomyopathy occurred during the preceding cycle, the trabectedin dosage should be reduced.1
If symptomatic cardiomyopathy or prolonged left ventricular dysfunction (LVEF does not recover to LLN within 3 weeks) occurs, trabectedin therapy should be permanently discontinued.1 (See Cardiomyopathy under Cautions: Warnings/Precautions.)
For any other grade 3 or 4 nonhematologic adverse effects, trabectedin therapy should be withheld for up to 3 weeks.1 Therapy may then be resumed at the same dosage.1
If any other grade 3 or 4 nonhematologic adverse effects occurred during the preceding cycle, the trabectedin dosage should be reduced.1
Pending further study of the effect of hepatic impairment on trabectedin pharmacokinetics, the manufacturer states that dosage adjustment is not necessary in patients with normal serum bilirubin concentrations and serum ALT or AST concentrations up to 2.5 times the ULN1 or in those with liver metastases.3 Trabectedin should not be used in patients with serum bilirubin concentrations exceeding the ULN or serum aminotransferase (ALT or AST) concentrations exceeding 2.5 times the ULN.1 The manufacturer states that there is no recommended dosage of the drug in patients with serum bilirubin concentrations that are above the institutional ULN.1, 3 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 Trabectedin has not been studied in patients with severe renal impairment or in those with end-stage renal disease and the manufacturer does not provide specific dosage recommendations for such patients.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Trabectedin is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to the drug.1
In the European Medicines Agency (EMEA) labeling, the manufacturer states that concurrent use of trabectedin with yellow fever vaccine is contraindicated.9 (See Live Vaccines under Drug Interactions.)
Neutropenic sepsis, sometimes fatal, has been reported in patients receiving trabectedin.1, 2 In the principal efficacy study evaluating trabectedin in patients with liposarcoma or leiomyosarcoma, grade 3 or 4 neutropenia occurred in 43% of patients receiving the drug.1 The median time to first occurrence of grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months) and the median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months).1 Febrile neutropenia (defined as grade 3 or 4 neutropenia with fever of 38.5°C or higher) occurred in 5% of trabectedin-treated patients.1 Neutropenic sepsis occurred in 10 of 378 patients (2.6%) receiving trabectedin; 5 of these patients had febrile neutropenia, which was fatal in 4 patients (1.1%).1
Absolute neutrophil count (ANC) should be monitored prior to each dose of trabectedin and periodically throughout the treatment cycle.1 Temporary interruption, dosage reduction, or discontinuance of trabectedin may be necessary if neutropenia occurs during therapy with the drug.1 (See Hematologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration and see also Advice to Patients.)
Trabectedin can cause rhabdomyolysis and musculoskeletal toxicity.1, 2, 13 In the principal efficacy study, rhabdomyolysis resulting in death occurred in 3 of 378 patients (0.8%) receiving trabectedin.1 Elevations of serum creatine kinase (CK, creatine phosphokinase, CPK) were reported in 32% (grade 3 or 4 in 6%) of patients receiving trabectedin and in 9% (grade 3 in 0.6%) of patients receiving dacarbazine.1 Renal failure occurred in 11 of 24 patients experiencing grade 3 or 4 serum CK elevations during trabectedin therapy; rhabdomyolysis resulting in renal failure occurred in 4 of these patients.1 The median time to first occurrence of grade 3 or 4 CK elevations was 2 months (range: 1-11.5 months) and the median time to complete resolution was 14 days (range: 5 days to 1 month).1
Serum CK concentrations should be evaluated prior to each dose of trabectedin.1 Temporary interruption, dosage reduction, or discontinuance of trabectedin may be necessary if elevated CK concentrations occur during therapy with the drug.1 (See Creatine Kinase Elevation under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Trabectedin should be permanently discontinued if rhabdomyolysis occurs.1
Hepatotoxicity, including hepatic failure, may occur with trabectedin.1, 2 In the principal efficacy study, grade 3 or 4 elevations in liver function tests (i.e., ALT, AST, total bilirubin, or alkaline phosphatase) occurred in 35% of patients receiving trabectedin.1 Patients with serum bilirubin concentrations exceeding the upper limit of normal (ULN), serum aminotransferase concentrations exceeding 2.5 times the ULN, or significant chronic liver disease (e.g., cirrhosis, hepatitis) were excluded from this study.1 The median time to development of grade 3 or 4 elevations in serum aminotransferase (ALT or AST) concentrations was 29 days (range: 3 days to 11.5 months).1 The majority (85%) of patients experiencing grade 3 or 4 elevations in liver function tests had complete resolution; the median time to complete resolution was 13 days (range: 4 days to 4.4 months).1 Drug-induced hepatic injury (defined as concurrent elevations in ALT or AST concentrations exceeding 3 times the ULN, alkaline phosphatase concentrations less than 2 times the ULN, and total bilirubin concentrations at least 2 times the ULN) occurred in 1.3% of patients receiving trabectedin.1 Elevations in aminotransferase concentrations exceeding 8 times the ULN occurred in 18% of patients receiving the drug.1
Liver function tests should be performed prior to administration of each dose of trabectedin.1 Temporary interruption, dosage reduction, or discontinuance of trabectedin based on the severity and duration of the elevation in the liver function test result may be necessary.1 (See Hepatic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Cardiomyopathy (including heart failure, congestive heart failure, decreased left ventricular ejection fraction [LVEF], diastolic dysfunction, or right ventricular dysfunction) may occur with trabectedin therapy.1 In the principal efficacy study, cardiomyopathy occurred in 6% (grade 3 or 4 in 4%) of patients receiving trabectedin and in 2.3% (grade 3 or 4 in 1.2%) of those receiving dacarbazine; cardiomyopathy resulting in death occurred in one patient receiving trabectedin and in none of those receiving dacarbazine.1 Patients with New York Heart Association (NYHA) class II to IV heart failure, left ventricular dysfunction at baseline, or history of myocardial infarction within 6 months prior to therapy initiation were excluded from the principal efficacy study evaluating trabectedin in patients with liposarcoma or leiomyosarcoma.1, 2 The median time to development of grade 3 or 4 cardiomyopathy in trabectedin-treated patients was 5.3 months (range: 26 days to 15.3 months).1
LVEF should be assessed using echocardiogram or multiple gated acquisition (MUGA) scan prior to initiation of trabectedin and then every 2 to 3 months during treatment.1 Temporary interruption, dosage reduction, or discontinuance of trabectedin may be necessary if decreased LVEF occurs during therapy with the drug.1 (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Extravasation Resulting in Tissue Necrosis
Extravasation of trabectedin may cause tissue necrosis requiring debridement.1, 9, 27 Tissue necrosis may develop more than 1 week following the extravasation.1, 27 Severe local tissue inflammation and necrosis associated with extravasation of trabectedin from central venous access devices have been reported in 2 patients; both patients had full-thickness injuries that required surgical debridement, suggesting that trabectedin is a vesicant.27
Specific treatment for extravasation of trabectedin has not been established.1 Because of the risk of extravasation and resulting tissue necrosis, the manufacturer states that a central venous line should be used to administer the drug.1, 9 (See Dosage and Administration: Administration.)
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, trabectedin may cause fetal harm if administered to pregnant women.1 There are no available data concerning the use of trabectedin during pregnancy.1 Animal reproductive and developmental studies at relevant dosages have not been conducted with trabectedin; however, the drug has been shown to cross the placenta in pregnant animals.1, 26 Pregnancy should be avoided during therapy.1 Women of childbearing potential should use effective methods of contraception while receiving the drug and for at least 2 months after the last dose of the drug.1
Trabectedin may damage spermatozoa, possibly resulting in genetic and fetal abnormalities.1 Men with female partners of childbearing potential should use effective methods of contraception during trabectedin therapy and for at least 5 months after the last dose of the drug.1
Trabectedin may result in decreased fertility in males and females.1 Fertility studies were not performed with trabectedin.1 In male animals, limited evidence of hemorrhage and degeneration in testes was observed with repeated administration of trabectedin at dosages approximately 0.2 times the recommended human dosage.1
Trabectedin may cause fetal harm if administered to pregnant women based on its mechanism of action.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
It is not known whether trabectedin is distributed into milk.1 The effects of the drug on nursing infants and on milk production also are unknown.1 Because of the potential for serious adverse reactions to trabectedin in nursing infants, women should be advised to discontinue nursing while receiving the drug.1, 9 In the European Union, the manufacturer also recommends discontinuing nursing for 3 months after discontinuance of the drug.9
Safety and efficacy of trabectedin have not been established in pediatric patients with liposarcoma or leiomyosarcoma.1, 2
In a phase 2 study evaluating the pharmacokinetics of trabectedin 1.5 mg/m2 by IV infusion over 24 hours in pediatric patients (12-21 years of age) weighing 15 kg or more with rhabdomyosarcoma, Ewing sarcoma, or non-rhabdomyosarcoma soft tissue sarcoma, pharmacokinetic parameters were generally similar to those observed in adults.14
Clinical studies of trabectedin did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1 (See Dosage and Administration: Special Populations.)
Population pharmacokinetic analyses in adults indicate that age (19-83 years) does not have clinically important effects on the pharmacokinetics of trabectedin.1, 3, 23
Because trabectedin is extensively metabolized in the liver, hepatic impairment is likely to affect the pharmacokinetics of the drug.3 A population pharmacokinetic analysis showed no relationship between serum aminotransferase or bilirubin concentrations and the clearance of trabectedin.3, 9 In a phase 1 trial, the pharmacokinetics of trabectedin were not substantially affected in cancer patients with liver metastases (stratified by serum alkaline phosphatase concentrations) within a dosage range of 0.75-1.3 mg/m2.3 However, the manufacturer states that the effect of any degree of hepatic impairment on trabectedin exposure is not known.1
Pending further study of the drug in patients with hepatic impairment, the manufacturer states that trabectedin dosage adjustment is not necessary in patients with normal serum bilirubin concentrations and serum ALT or AST concentrations up to 2.5 times the ULN1 or in those with liver metastases.3
Pharmacokinetic data for trabectedin in patients with moderate to severe hepatic impairment and those with total bilirubin concentrations exceeding the ULN are not yet available.1, 3 In addition, trabectedin may cause hepatotoxicity.1 (See Hepatic Toxicity under Cautions: Warnings/Precautions.) The prescribing information indicates that trabectedin should not be used in patients with moderate to severe hepatic impairment and states that there is no recommended dosage of the drug in patients with serum bilirubin concentrations above the ULN.1, 3
In a population pharmacokinetic analysis, mild to moderate renal impairment did not have clinically important effects on the pharmacokinetics of trabectedin.1, 3, 23 The pharmacokinetics of trabectedin have not been systematically studied in patients with severe renal impairment or end-stage renal disease.1 However, hemodialysis is not expected to enhance elimination of trabectedin because the drug is highly bound to plasma proteins and is not substantially excreted renally.1
Trabectedin dosage adjustment is not necessary in patients with mild (creatinine clearance 60-89 mL/minute) or moderate (creatinine clearance 30-59 mL/minute) renal impairment.1 The manufacturer does not provide specific dosage recommendations for patients with severe renal impairment or end-stage renal disease.1
Adverse effects reported in 10% or more of patients receiving trabectedin for the treatment of advanced leiomyosarcoma or liposarcoma and at an incidence that is at least 2% higher than that reported with dacarbazine include nausea,1, 2 vomiting,1, 2 constipation,1, 2 decreased appetite,1, 2 diarrhea,1, 2 fatigue (includes asthenia and malaise),1, 2 peripheral edema,1, 2 dyspnea,1, 2 headache,1, 2 arthralgia,1 myalgia,1 and insomnia.1
Laboratory abnormalities reported in more than 10% of patients receiving trabectedin for the treatment of advanced leiomyosarcoma or liposarcoma and at an incidence that is at least 2% higher than that reported with dacarbazine include anemia,1, 2 increased concentrations of alkaline phosphatase,1, 2 neutropenia,1, 2 hypoalbuminemia,1 thrombocytopenia,1 increased concentrations of serum creatinine,1 increased concentrations of CK,1 increased concentrations of aminotransferases (i.e., ALT, AST),1, 2 and hyperbilirubinemia.1
Trabectedin is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4;1, 3, 7, 9 other CYP isoenzymes (e.g., 2C9, 2C19, 2D6, and 2E1) may contribute to the drug's metabolism to a minor extent.7, 9 In vitro studies indicate that trabectedin has limited inhibition or induction potential of CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 at clinically relevant concentrations.1, 3
In vitro studies indicate that trabectedin undergoes glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 2B15.7
Trabectedin is a substrate of P-glycoprotein (P-gp).3, 8, 9
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of trabectedin with potent inhibitors of CYP3A may result in increased peak plasma concentrations and systemic exposure of trabectedin.1, 10 When the potent CYP3A inhibitor ketoconazole (200 mg twice daily for 7.5 days) was administered concomitantly with trabectedin (single 0.58 mg/m2 dose on day 1), peak plasma concentrations and area under the plasma concentration-time curve (AUC) of trabectedin were increased by 22 and 66%, respectively, compared with a single 1.3 mg/m2 dose of trabectedin.1, 10
Concomitant use of trabectedin with potent inhibitors of CYP3A (e.g., aprepitant, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, ritonavir-boosted lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) should be avoided.1, 8 If concomitant short-term (less than 14 days) therapy with a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends administering the potent CYP3A inhibitor 1 week following completion of the trabectedin infusion and discontinuing the potent CYP3A inhibitor 1 day prior to the next trabectedin infusion.1
Concomitant use of trabectedin with potent inducers of CYP3A may result in decreased peak plasma concentrations and systemic exposure of trabectedin.1, 9, 10 When the potent CYP3A inducer rifampin (600 mg daily for 6 days) was administered concomitantly with trabectedin (single dose of 1.3 mg/m2 IV on day 6), peak plasma concentrations and AUC of trabectedin were decreased by 21 and 31%, respectively.1, 10
Concomitant use of trabectedin with potent CYP3A inducers (e.g., phenobarbital, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided.1, 9
Grapefruit products are potent CYP3A inhibitors and should be avoided in patients receiving trabectedin because of the potential for increased plasma concentrations of the drug during concurrent use.1
Drugs Affecting Efflux Transport Systems
Trabectedin is a substrate of the efflux transporter P-gp.3, 8, 9 Concomitant use of trabectedin with drugs that inhibit P-gp (e.g., cyclosporine, verapamil) may affect the pharmacokinetics (i.e., distribution and elimination) of trabectedin.8, 9 The clinical relevance of this interaction is not known; therefore, P-gp inhibitors and trabectedin should be used concomitantly with caution.8, 9
Pharmacokinetic analyses indicate no clinically important pharmacokinetic interactions between trabectedin and doxorubicin or docetaxel.6, 8, 11
Pharmacokinetics of trabectedin were not affected when gemcitabine, carboplatin, or paclitaxel was administered prior to trabectedin.8
Concurrent administration of trabectedin and carboplatin, cisplatin, or paclitaxel did not alter the pharmacokinetics of carboplatin, cisplatin, or paclitaxel.8
Alcohol and Other Hepatotoxic Drugs
The prescribing information for trabectedin in the US does not provide information concerning the concurrent use of potentially hepatotoxic drugs and alcohol during therapy.1 However, the manufacturer in the European Union recommends caution during concomitant use of trabectedin and other drugs with hepatotoxic potential and states that alcohol should be avoided during trabectedin therapy.9 (See Hepatic Toxicity under Cautions: Warnings/Precautions.)
Drugs Associated with Rhabdomyolysis
Drugs associated with rhabdomyolysis such as HMG CoA reductase inhibitors (statins; e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) should be used with caution in patients receiving trabectedin because the risk of rhabdomyolysis may be increased in such patients.9 (See Rhabdomyolysis under Cautions: Warnings/Precautions.)
The prescribing information for trabectedin in the US does not provide information concerning the use of live vaccines during therapy.1 In the European Union, the manufacturer states that concomitant use of live attenuated vaccines is not recommended during trabectedin therapy and that use of yellow fever vaccine with trabectedin is specifically contraindicated.9
Trabectedin, a synthetic tetrahydroisoquinoline alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata , is an alkylating antineoplastic agent.1, 3, 14, 20, 21, 22, 26 Unlike conventional alkylating agents that bind to DNA in the major groove,20, 22 trabectedin forms covalent adducts with guanine residues in the minor groove of DNA, which induces bending of the DNA helix toward the major groove.1, 16, 20, 21, 22, 26 This adduct formation triggers a cascade of events that can alter the subsequent actions of DNA binding proteins, including transcription factors and DNA repair pathways, resulting in G2/M phase arrest, inhibition of progression of cells from the S phase, and, subsequently, cell growth arrest and apoptosis.1, 2, 21, 22, 26 Trabectedin has demonstrated antiproliferative activity in vitro and in vivo against a range of human tumor cell lines and experimental tumors, including malignancies such as sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer, and melanoma.9
The pharmacokinetics of trabectedin appear to be biphasic with an initial rapid decline in plasma concentrations of the drug followed by a slower rate of disappearance.1, 3 Pharmacokinetics of trabectedin are dose proportional over a dosage range of 0.024-1.8 mg/m2.1, 21, 23 The drug exhibits time-independent exposure.1 Following repeated doses of trabectedin administered every 3 weeks, systemic accumulation of the drug was not observed.1 Trabectedin is extensively metabolized in the liver, principally by cytochrome P-450 (CYP) isoenzyme 3A4.1, 3, 7, 9 The drug is approximately 97% bound to plasma proteins, and protein binding is independent of plasma drug concentration over the range of 0.01-0.1 mcg/mL.1 Trabectedin is principally excreted via biliary elimination.3 Following IV infusion of trabectedin over 3 or 24 hours, 58% of the administered dose is recovered in feces and 6% is recovered in urine within 24 days; a negligible amount of unchanged drug is excreted in feces and urine.1 The terminal half-life of trabectedin is approximately 7.3 days.1, 3
Importance of instructing patients to read the manufacturer's patient information.1
Risk of myelosuppression.1 Importance of monitoring absolute neutrophil counts (ANC) prior to each dose of trabectedin and periodically throughout the treatment cycle.1 Importance of promptly informing clinician if fever, unusual bruising, bleeding, fatigue, or pallor occurs.1
Risk of rhabdomyolysis.1 Importance of creatine kinase (CK, creatine phosphokinase, CPK) monitoring.1 Importance of advising patients to promptly inform clinician if they experience severe muscle pain or weakness.1
Risk of hepatotoxicity.1 Importance of monitoring liver function tests prior to each dose of trabectedin.1 Importance of immediately contacting clinician if possible manifestations of hepatotoxicity (e.g., jaundice, abdominal pain [particularly in the right upper quadrant], severe nausea or vomiting, difficulty concentrating, disorientation, confusion) occur.1
Risk of cardiomyopathy.1 Importance of cardiac monitoring before initiating trabectedin and periodically during therapy.1 Importance of immediately contacting clinician if new chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations occur.1
Risk of hypersensitivity reactions.1 Importance of advising patients to seek immediate medical attention if symptoms of an allergic reaction, including difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips, or rash, occur.1
Risk of extravasation.1 Importance of contacting a clinician if redness, swelling, pruritus, or discomfort or leakage at the injection site occurs.1
Risk of fetal harm.1 Necessity of advising women of childbearing potential to use effective contraception during trabectedin therapy and for at least 2 months after the last dose of the drug.1 Necessity of advising men who are partners of such women that they should use effective contraception during trabectedin therapy and for at least 5 months after the last dose of the drug.1 If pregnancy occurs, advise patient of potential risk to the fetus.1
Importance of advising women to avoid breast-feeding while receiving trabectedin.1 (See Lactation under Warnings/Precautions: Specific Populations, in Cautions.)
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.1
Importance of advising patients to avoid grapefruit during trabectedin therapy.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of trabectedin is restricted.5 (See Restricted Distribution Program under Dosage and Administration: General.)
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions October 24, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Janssen Products LP. Yondelis® (trabectedin) for injection prescribing information. Horsham, PA; 2015 Oct.
2. Demetri GD, von Mehren M, Jones RL et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol . 2016; 34:786-93. [PubMed 26371143]
3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207953Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. Accessed 2016 May. [Web]
4. Janssen Products. Titusville, NJ: Personal communication.
5. Janssen Products. Ordering information. 2016 May. From Janssen Products for US Healthcare Professionals website. [Web]
6. Sessa C, Perotti A, Noberasco C et al. Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer. Eur J Cancer . 2009; 45:1153-61. [PubMed 19114300]
7. Brandon EF, Meijerman I, Klijn JS et al. In-vitro cytotoxicity of ET-743 (Trabectedin, Yondelis), a marine anti-cancer drug, in the Hep G2 cell line: influence of cytochrome P450 and phase II inhibition, and cytochrome P450 induction. Anticancer Drugs . 2005; 16:935-43. [PubMed 16162970]
8. Leporini C, Patanè M, Saullo F et al. A comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations. BioDrugs . 2014; 28:499-511. [PubMed 25209722]
9. Pharma Mar, S.A. Yondelis® (trabectedin) for injection. Annex I: Summary of product characteristics. Madrid, Spain. (undated) [Web]
10. Machiels JP, Staddon A, Herremans C et al. Impact of cytochrome P450 3A4 inducer and inhibitor on the pharmacokinetics of trabectedin in patients with advanced malignancies: open-label, multicenter studies. Cancer Chemother Pharmacol . 2014; 74:729-37. [PubMed 25100135]
11. von Mehren M, Bookman M, Meropol NJ et al. Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies. Cancer Chemother Pharmacol . 2015; 75:1047-55. [PubMedCentral][PubMed 25791363]
12. Thertulien R, Manikhas GM, Dirix LY et al. Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol . 2012; 69:341-50. [PubMed 21739119]
13. Grosso F, D'Incalci M, Cartoafa M et al. A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with trabectedin. Cancer Chemother Pharmacol . 2012; 69:1557-65. [PubMedCentral][PubMed 22484722]
14. Baruchel S, Pappo A, Krailo M et al. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group. Eur J Cancer . 2012; 48:579-85. [PubMed 22088484]
15. Le Cesne A, Blay JY, Judson I et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol . 2005; 23:576-84. [PubMed 15659504]
16. Garcia-Carbonero R, Supko JG, Manola J et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol . 2004; 22:1480-90. [PubMed 15084621]
17. Demetri GD, Chawla SP, von Mehren M et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol . 2009; 27:4188-96. [PubMed 19652065]
18. Le Cesne A, Blay JY, Domont J et al. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Lancet Oncol . 2015; 16:312-9. [PubMed 25680558]
19. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 May 4. [Web]
20. Saponara M, Stacchiotti S, Gronchi A. The safety and efficacy of trabectedin for the treatment of liposarcoma or leiomyosarcoma. Expert Rev Anticancer Ther . 2016; 16:473-84. [PubMed 27043847]
21. van Kesteren C, Cvitkovic E, Taamma A et al. Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res . 2000; 6:4725-32. [PubMed 11156226]
22. Cioffi A, Italiano A. Clinical and pharmacokinetic evaluation of trabectedin for the treatment of soft-tissue sarcoma. Expert Opin Drug Metab Toxicol . 2012; 8:113-22. [PubMed 22176591]
23. Perez-Ruixo JJ, Zannikos P, Hirankarn S et al. Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients. Clin Pharmacokinet . 2007; 46:867-84. [PubMed 17854236]
24. Grosso F, Sanfilippo R, Virdis E et al. Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series. Ann Oncol . 2009; 20:1439-44. [PubMed 19465423]
25. Forni C, Minuzzo M, Virdis E et al. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther . 2009; 8:449-57. [PubMed 19190116]
26. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207953Orig1s000: Pharmacology review(s). From FDA website. Accessed 2016 May. [Web]
27. Theman TA, Hartzell TL, Sinha I et al. Recognition of a new chemotherapeutic vesicant: trabectedin (ecteinascidin-743) extravasation with skin and soft tissue damage. J Clin Oncol . 2009; 27:198-200.
28. Thornton KA. Trabectedin: the evidence for its place in therapy in the treatment of soft tissue sarcoma. Core Evid . 2009; 4:191-8.