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Trabectedin

Class: Antineoplastic Agents
ATC Class: L01CX01
VA Class: AN900
Chemical Name: (1′R,6R,6aR,7R,13S,14S,16R) - 5 - (acetyloxy) - 3′,4′,6,6a,7,13,14,16 - octahydro - 6′,8,14 - trihydroxy - 7′,9 - dimethoxy - 4,10,23 - trimethyl - spiro[6,16 - (epithiopropanoxymethano) - 7,13 - imino - 12H - 1,3 - dioxolo[7,8]isoquino[3,2 - b][3]benzazocine - 20,1′(2′H) - isoquinolin] - 19 - one
Molecular Formula: C39H43N3O11S
CAS Number: 114899-77-3
Brands: Yondelis

Introduction

Alkylating antineoplastic agent; a synthetic alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata.1 14 20 21 22 26 28

Uses for Trabectedin

Soft Tissue Sarcomas

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

Designated an orphan drug by FDA for the treatment of soft tissue sarcoma.19

Efficacy determined based on investigator-assessed progression-free survival.1 2

Trabectedin Dosage and Administration

General

  • To help prevent nausea and vomiting and reduce the risk of hepatotoxicity, premedicate with dexamethasone phosphate 20 mg IV 30 minutes before each trabectedin infusion.1 3 9 28 May administer additional antiemetics as needed.9 28

  • Monitor neutrophil count prior to administration of each dose of trabectedin and periodically thereafter.1 (See Neutropenic Sepsis under Cautions.)

  • Monitor serum CK concentrations and liver function tests prior to administration of each dose of trabectedin.1 (See Rhabdomyolysis and also see Hepatic Toxicity under Cautions.)

  • Assess left ventricular ejection fraction (LVEF) 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.)

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Restricted Distribution Program

  • Available only through specialty distributors.5 Consult the Yondelis website for specific availability information (http://www.yondelis.com/ordering).5

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by continuous IV infusion over 24 hours through central venous line; use an infusion set with a 0.2-mcm polyethersulfone inline filter.1

Do not admix with other drugs.1

Trabectedin powder for injection must be reconstituted and diluted prior to administration.1 Complete infusion within 30 hours following initial reconstitution.1 (See Storage under Stability.)

Diluted solutions are compatible with type I colorless glass vials; 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

Reconstitution

Reconstitute vial containing 1 mg of trabectedin with 20 mL of sterile water for injection to provide a solution containing 0.05 mg/mL.1 Shake vial to ensure complete dissolution.1 Discard any partially used vials.1

Dilution

Dilute appropriate dose in 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 Discard any unused solution.1

Rate of Administration

Administer over 24 hours.1

Dosage

Adults

Soft Tissue Sarcomas
IV

1.5 mg/m2 every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity
IV

When dosage modification is required, initially reduce dosage to 1.2 mg/m2 every 3 weeks.1 If further dosage reduction is necessary, reduce dosage to 1 mg/m2 every 3 weeks.1

If a dosage of 1 mg/m2 every 3 weeks requires further reduction, permanently discontinue the drug.1

Do not re-escalate dosage following dosage reduction.1

Permanently discontinue therapy if persistent adverse reactions requiring a treatment delay of >3 weeks occur.1

Hematologic Toxicity
IV

For ANC <1500/mm3 or platelet count <100,000/mm3, interrupt therapy for up to 3 weeks, and then resume at the same dosage.1

If ANC <1000/mm3 and signs or symptoms of infection (e.g., fever) occurred during preceding cycle, reduce dosage.1

If ANC <500/mm3 for >5 days occurred during preceding cycle, reduce dosage.1

If platelet counts <25,000/mm3 occurred during preceding cycle, reduce dosage.1

If life-threatening or prolonged and severe neutropenia occurred during preceding cycle, permanently reduce dosage.1

Hepatic Toxicity
IV

If total bilirubin concentrations exceeding the ULN or serum hepatic aminotransferase (ALT or AST) or alkaline phosphatase concentrations >2.5 times ULN occur, interrupt therapy for up to 3 weeks, and then resume at the same dosage.1

If total bilirubin concentrations exceeding the ULN, AST or ALT concentrations >5 times ULN, or alkaline phosphatase concentrations >2.5 times ULN occurred during preceding cycle, reduce dosage.1

If severe hepatic dysfunction (total bilirubin concentrations ≥2 times ULN and AST or ALT concentrations ≥3 times ULN with alkaline phosphatase concentrations <2 times ULN) occurred during preceding cycle, permanently discontinue therapy.1

CK Elevation
IV

For CK concentrations >2.5 times ULN, interrupt therapy for up to 3 weeks and then resume at the same dosage.1

If CK concentrations >5 times ULN occurred during preceding cycle, reduce dosage.1

If rhabdomyolysis occurs, permanently discontinue therapy.1

Cardiovascular Toxicity
IV

If LVEF decreases to less than the lower limit of normal (LLN) or clinical evidence of cardiomyopathy occurs, interrupt therapy for up to 3 weeks and then resume at the same dosage.1

If LVEF decreased below the LLN with absolute decrease from baseline of ≥10% or clinical evidence of cardiomyopathy occurred during preceding cycle, reduce dosage.1

If symptomatic cardiomyopathy or prolonged left ventricular dysfunction (LVEF does not recover to LLN within 3 weeks) occurs, permanently discontinue therapy.1

Other Nonhematologic Toxicity
IV

For any other grade 3 or 4 nonhematologic adverse effects, interrupt therapy for up to 3 weeks, and then resume at the same dosage.1

If any other grade 3 or 4 nonhematologic adverse effects occurred during preceding cycle, reduce dosage.1

Special Populations

Hepatic Impairment

Dosage adjustment 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

Serum bilirubin concentrations exceeding the ULN or aminotransferase (ALT or AST) concentrations >2.5 times the ULN: Use not recommended.1 Manufacturer does not provide specific dosage recommendations for patients with serum bilirubin concentrations above the ULN.1 3 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild (Clcr 60–89 mL/minute) or moderate (Clcr of 30–59 mL/minute) renal impairment: No dosage adjustment required.1

Severe renal impairment or end-stage renal disease: Pharmacokinetics not studied; manufacturer does not provide specific dosage recommendations.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Trabectedin

Contraindications

  • Known severe hypersensitivity, including anaphylaxis, to trabectedin.1

  • In the European Medicines Agency (EMEA) labeling, concurrent use with yellow fever vaccine contraindicated.9 (See Live Vaccines under Interactions.)

Warnings/Precautions

Neutropenic Sepsis

Neutropenic sepsis, sometimes fatal, reported.1 2 In the principal efficacy study, grade 3 or 4 neutropenia occurred in 43% of trabectedin-treated patients.1 Median time to first occurrence of grade 3 or 4 neutropenia was 16 days and median time to complete resolution was 13 days.1 Neutropenic sepsis reported in 10 of 378 patients (2.6%) receiving trabectedin; fatal in 4 patients (1.1%).1

Monitor ANC prior to each dose and periodically throughout the treatment cycle.1 If neutropenia occurs, interrupt therapy, reduce dosage, or discontinue drug.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Rhabdomyolysis

Elevated CK concentrations and rhabdomyolysis, sometimes fatal, reported.1 2 13 Renal failure following rhabdomyolysis or grade 3 or 4 elevations of CK concentrations reported.1 Median time to first occurrence of grade 3 or 4 CK elevations was 2 months and median time to complete resolution was 14 days.1

Evaluate serum CK concentrations prior to each dose of trabectedin.1 If elevated CK concentrations occur, interrupt therapy, reduce dosage, or discontinue drug.1 If rhabdomyolysis occurs, permanently discontinue therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hepatic Toxicity

Hepatotoxicity, including hepatic failure, may occur.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; the median time to development of grade 3 or 4 elevations in serum ALT or AST concentrations was 29 days (range: 3 days to 11.5 months).1 Grade 3 or 4 elevations in liver function tests completely resolved in most patients; median time to complete resolution was 13 days.1

Perform liver function tests prior to each dose of trabectedin.1 If elevated liver function tests occur, interrupt therapy, reduce dosage, or discontinue drug.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Cardiomyopathy

Cardiomyopathy (including heart failure, congestive heart failure, decreased LVEF, diastolic dysfunction, or right ventricular dysfunction) may occur.1 In the principal efficacy study, cardiomyopathy occurred in 6% (grade 3 or 4 in 4%) of trabectedin-treated patients, including one fatal case.1 Median time to development of grade 3 or 4 cardiomyopathy was 5.3 months (range: 26 days to 15.3 months).1

Assess LVEF using echocardiogram or MUGA prior to initiation of trabectedin and then every 2–3 months during treatment.1 If decreased LVEF occurs, interrupt therapy, reduce dosage, or discontinue drug.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Extravasation Resulting in Tissue Necrosis

Extravasation of trabectedin may cause tissue necrosis requiring debridement.1 9 27 Tissue necrosis may develop >1 week following extravasation.1 27 Severe local tissue inflammation and necrosis associated with extravasation of trabectedin from central venous access devices reported in 2 patients.27

Because of the risk of extravasation and resulting tissue necrosis, use a central venous line to administer the drug.1 9 (See Administration under Dosage and Administration.) Specific treatment for extravasation not established.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on its mechanism of action.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective methods of contraception while receiving the drug and for ≥2 months after last dose of drug.1

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 ≥5 months after last dose of drug.1

Impairment of Fertility

May decrease fertility in males and females based on animal findings.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing during therapy.1 9

In the European Union, the manufacturer recommends discontinuing nursing during therapy and for 3 months after discontinuance of drug.9

Effects of trabectedin on nursing infants or milk production not known.1

Pediatric Use

Safety and efficacy not established.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Because trabectedin is extensively metabolized in the liver, hepatic impairment is likely to affect pharmacokinetics.3 (See Pharmacokinetics.)

Dosage adjustment not necessary in patients with normal serum bilirubin concentrations and serum ALT or AST concentrations ≤2.5 times the ULN1 or in those with liver metastases.3

Pharmacokinetic data in patients with moderate to severe hepatic impairment and those with total bilirubin concentrations exceeding the ULN not yet available.1 3 In addition, trabectedin may cause hepatotoxicity.1 (See Hepatic Toxicity under Cautions.) 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 exceeding the ULN.1 3

Renal Impairment

Pharmacokinetics not substantially affected by mild or moderate renal impairment.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Not formally studied in patients with severe renal impairment or end-stage renal disease.1 However, hemodialysis unlikely to enhance elimination because trabectedin is highly protein bound and not substantially excreted renally.1 (See Pharmacokinetics.)

Common Adverse Effects

Nausea,1 2 vomiting,1 2 constipation,1 2 decreased appetite,1 2 diarrhea,1 2 fatigue (includes asthenia and malaise),1 2 neutropenia,1 2 increased ALT/AST concentrations,1 2 anemia,1 2 thrombocytopenia,1 dyspnea,1 2 peripheral edema,1 2 headache,1 2 increased alkaline phosphatase concentrations,1 2 arthralgia,1 myalgia,1 insomnia,1 hypoalbuminemia,1 increased Scr,1 increased CK concentrations,1 hyperbilirubinemia.1

Interactions for Trabectedin

Principally metabolized by CYP3A4 and,1 3 7 9 to a minor extent, by other CYP isoenzymes (e.g., 2C9, 2C19, 2D6, 2E1).7 9 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, undergoes glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 2B15.7

Substrate of P-glycoprotein (P-gp).3 8 9

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased concentrations and systemic exposure of trabectedin).1 10 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.) If concomitant short-term therapy (≤14 days) with a potent CYP3A inhibitor cannot be avoided, administer potent CYP3A inhibitor 1 week following completion of trabectedin infusion and discontinue potent CYP3A inhibitor 1 day prior to next trabectedin infusion.1

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased concentrations and systemic exposure of trabectedin).1 9 10 Avoid concomitant use.1 9 (See Specific Drugs and Foods under Interactions.)

Drugs Affecting Efflux Transport Systems

P-gp inhibitors: Possible altered distribution and/or elimination of trabectedin.8 9 Clinical relevance not known; use with caution.8 9

Other Hepatotoxic Drugs

Possible increased risk of hepatotoxicity; use with caution.9 (See Hepatic Toxicity under Cautions.)

Drugs Associated with Rhabdomyolysis

Possible increased risk of rhabdomyolysis; use with caution.9 (See Rhabdomyolysis under Cautions.)

Live Vaccines

US prescribing information does not provide information concerning use of vaccines during therapy.1 In the European Union, manufacturer states that concomitant use of live attenuated vaccines is not recommended and that use of yellow fever vaccine is specifically contraindicated.9

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Alcohol

Possible increased risk of hepatotoxicity9

Manufacturer in US does not provide specific recommendations about alcohol use;1 manufacturer in the European Union recommends avoiding alcohol during therapy9

Anticonvulsants (e.g., phenobarbital)

Potent CYP3A inducers: Possible decreased trabectedin exposure1 9

Potent CYP3A inducers (e.g., phenobarbital): Avoid concomitant use1 9

Antifungals, azoles (e.g., itraconazole, ketoconazole, posaconazole, voriconazole)

Itraconazole, posaconazole, voriconazole: Possible increased trabectedin exposure1

Ketoconazole: Increased trabectedin AUC and peak concentrations by 66 and 22%, respectively1

Itraconazole, ketoconazole, posaconazole, voriconazole: Avoid concomitant use1

If concomitant short-term therapy (≤14 days) with the potent CYP3A inhibitor cannot be avoided, administer the antifungal 1 week following completion of trabectedin infusion and discontinue the antifungal 1 day prior to next trabectedin infusion1

Antiretroviral agents, HIV protease inhibitors (e.g., indinavir, lopinavir, nelfinavir, ritonavir, saquinavir)

Indinavir, lopinavir, nelfinavir, ritonavir, saquinavir: Possible increased trabectedin exposure1

Indinavir, lopinavir, nelfinavir, ritonavir, saquinavir: Avoid concomitant use1

Aprepitant

Possible increased trabectedin exposure1

Avoid concomitant use1

If concomitant short-term therapy (≤14 days) cannot be avoided, administer aprepitant 1 week following completion of trabectedin infusion and discontinue aprepitant 1 day prior to next trabectedin infusion1

Carboplatin

No substantial effect on pharmacokinetics of either drug8

Cisplatin

No substantial effect on pharmacokinetics of cisplatin8

Conivaptan

Possible increased trabectedin exposure1

Avoid concomitant use1

If concomitant short-term therapy (≤14 days) cannot be avoided, administer conivaptan 1 week following completion of trabectedin infusion and discontinue conivaptan 1 day prior to next trabectedin infusion1

Cyclosporine

May alter trabectedin (P-gp substrate) pharmacokinetics8 9

Use with caution8 9

Doxorubicin

No substantial effect on pharmacokinetics of either drug6 8 11

Gemcitabine

No substantial effect on pharmacokinetics of trabectedin8

Grapefruit or grapefruit juice

Possible increased trabectedin exposure1

Avoid concomitant use1

HMG CoA reductase inhibitors (statins; e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)

Possible increased risk of rhabdomyolysis9

Use with caution9 (see Rhabdomyolysis under Cautions)9

Macrolides (clarithromycin, telithromycin)

Clarithromycin, telithromycin: Possible increased trabectedin exposure1

Clarithromycin, telithromycin: Avoid concomitant use1

If concomitant short-term therapy (≤14 days) with clarithromycin or telithromycin cannot be avoided, administer the macrolide 1 week following completion of trabectedin infusion and discontinue the macrolide 1 day prior to next trabectedin infusion1

Nefazodone

Possible increased trabectedin exposure1

Avoid concomitant use1

Paclitaxel

No substantial effect on pharmacokinetics of either drug8

Rifampin

Decreased trabectedin AUC and peak concentrations by 31 and 21%, respectively1

Avoid concomitant use1 9

St. John’s wort (Hypericum perforatum)

Possible decreased trabectedin exposure1 9

Avoid concomitant use1 9

Verapamil

May alter trabectedin (P-gp substrate) pharmacokinetics8 9

Use with caution8 9

Trabectedin Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are dose proportional (dosage range of 0.024–1.8 mg/m2).1 21 23 Exposure is independent of time.1

Systemic accumulation not observed when administered IV every 3 weeks.1

Special Populations

Hepatic impairment: Effect of any degree of hepatic impairment on exposure not known.1

Distribution

Extent

Widely distributed.1 9

Not known whether trabectedin is distributed into milk.1 (See Lactation under Cautions.)

Crosses placenta in animals.1 26

Plasma Protein Binding

Approximately 97%; independent of plasma drug concentration.1

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A1 3 7 9 and, to a minor extent, by other CYP isoenzymes (e.g., 2C9, 2C19, 2D6, 2E1).7 9

Elimination Route

Excreted mainly via biliary elimination.3 Approximately 64% of a single dose recovered in urine and feces within 24 days following an IV infusion, with 58% eliminated in feces and 6% in urine.1

Half-life

Biphasic; terminal half-life is approximately 7.3 days.1 3

Special Populations

Hepatic impairment: A population pharmacokinetic analysis showed no relationship between serum aminotransferase or bilirubin concentrations and clearance.3 9 Pharmacokinetics not studied in patients with moderate to severe hepatic impairment or those with total bilirubin concentrations exceeding the ULN.1 Liver metastases do not appear to substantially affect pharmacokinetics.3

Renal impairment: In a population pharmacokinetic analysis, no clinically important effect of mild or moderate renal impairment on clearance.1 Pharmacokinetics not formally studied in patients with severe renal impairment or end-stage renal disease.1 However, hemodialysis unlikely to enhance elimination because trabectedin is highly bound to plasma proteins and not substantially excreted renally.1

Age (19–83 years), gender, body weight, and body surface area do not appear to substantially affect pharmacokinetics.1 3 23

In a phase 2 study, pharmacokinetics in pediatric patients (12–21 years of age) weighing ≥15 kg generally were similar to those observed in adults.14

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 2–8°C.1

Reconstituted and diluted infusion solution: 2–8°C or room temperature in ambient light for ≤30 hours.1 4 Complete IV infusion within 30 hours of initial reconstitution; discard any unused portion of reconstituted solution or infusion solution.1 4

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1 4

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • Synthetic tetrahydroisoquinoline alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata.1 3 14 20 21 22 26

  • Alkylating antineoplastic agent; forms covalent adducts with guanine residues in the minor groove of DNA, bending the helix towards the major groove.1 16 20 21 22 26

  • Appears to affect function of DNA binding proteins, including transcription factors and DNA repair pathways, thereby inducing G2/M phase arrest, blocking progression of cells from the S phase, and subsequently inducing cell growth arrest and apoptosis.1 2 21 22 26

  • Demonstrated antiproliferative activity in vitro and in vivo against a range of human tumor cell lines and experimental tumors, including sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer, and melanoma.9

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • Risk of myelosuppression.1 Importance of monitoring ANC prior to each dose of trabectedin and periodically throughout treatment cycle.1 Importance of promptly informing clinician if fever, unusual bruising, bleeding, fatigue, or pallor occurs.1

  • Risk of rhabdomyolysis.1 Importance of monitoring CK concentrations.1 Advise 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 a clinician if new-onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations occur.1

  • Risk of hypersensitivity reactions.1 Advise patients to seek immediate medical attention if symptoms of an allergic reaction (e.g., difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips, 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 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.)

Preparations

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.)

Trabectedin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

1 mg

Yondelis

Janssen

AHFS DI Essentials. © Copyright 2016, Selected Revisions October 25, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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.

4. Janssen Products. Titusville, NJ: Personal communication.

5. Janssen Products. Ordering information. 2016 May. From Janssen Products for US Healthcare Professionals website.

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)

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. [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. [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.

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.

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. [PubMed 19805684]

28. Thornton KA. Trabectedin: the evidence for its place in therapy in the treatment of soft tissue sarcoma. Core Evid. 2009; 4:191-8. [PubMed 20694075]

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