Trabectedin (Monograph)

Brand name: Yondelis
Drug 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

Introduction

Alkylating antineoplastic agent; a synthetic alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata.

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.

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

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

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. May administer additional antiemetics as needed.

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

• Monitor serum CK concentrations and liver function tests prior to administration of each dose of trabectedin. (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. (See Cardiomyopathy under Cautions.)

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

Restricted Distribution Program

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

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-µm polyethersulfone inline filter.

Do not admix with other drugs.

Trabectedin powder for injection must be reconstituted and diluted prior to administration. Complete infusion within 30 hours following initial reconstitution. (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.

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. Shake vial to ensure complete dissolution. Discard any partially used vials.

Dilution

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

Rate of Administration

Administer over 24 hours.

Dosage

Adults

Soft Tissue Sarcomas

IV

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

Dosage Modification for Toxicity

IV

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

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

Do not re-escalate dosage following dosage reduction.

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

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.

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

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

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

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

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.

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.

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.

CK Elevation

IV

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

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

If rhabdomyolysis occurs, permanently discontinue therapy.

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.

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

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

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.

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

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 ULN or in those with liver metastases.

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

Renal Impairment

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

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

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Trabectedin

Contraindications

• Known severe hypersensitivity, including anaphylaxis, to trabectedin.

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

Warnings/Precautions

Neutropenic Sepsis

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

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

Rhabdomyolysis

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

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

Hepatic Toxicity

Hepatotoxicity, including hepatic failure, may occur. 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). Grade 3 or 4 elevations in liver function tests completely resolved in most patients; median time to complete resolution was 13 days.

Perform liver function tests prior to each dose of trabectedin. If elevated liver function tests occur, interrupt therapy, reduce dosage, or discontinue drug. (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. In the principal efficacy study, cardiomyopathy occurred in 6% (grade 3 or 4 in 4%) of trabectedin-treated patients, including one fatal case. Median time to development of grade 3 or 4 cardiomyopathy was 5.3 months (range: 26 days to 15.3 months).

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

Extravasation Resulting in Tissue Necrosis

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

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on its mechanism of action.

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

May damage spermatozoa, possibly resulting in genetic and fetal abnormalities. 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.

Impairment of Fertility

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

Specific Populations

Pregnancy

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

Lactation

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

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

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

Pediatric Use

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

Hepatic Impairment

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

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

Pharmacokinetic data in patients with moderate to severe hepatic impairment and those with total bilirubin concentrations exceeding the ULN not yet available. In addition, trabectedin may cause hepatotoxicity. (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.

Renal Impairment

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

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

Common Adverse Effects

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

Drug Interactions

Principally metabolized by CYP3A4 and, to a minor extent, by other CYP isoenzymes (e.g., 2C9, 2C19, 2D6, 2E1). Limited inhibition or induction potential of CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 at clinically relevant concentrations.

In vitro, undergoes glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 2B15.

Substrate of P-glycoprotein (P-gp).

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased concentrations and systemic exposure of trabectedin). Avoid concomitant use. (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.

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

Drugs Affecting Efflux Transport Systems

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

Other Hepatotoxic Drugs

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

Drugs Associated with Rhabdomyolysis

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

Live Vaccines

US prescribing information does not provide information concerning use of vaccines during therapy. 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.

Specific Drugs and Foods

Trabectedin Pharmacokinetics

Absorption

Bioavailability

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

Systemic accumulation not observed when administered IV every 3 weeks.

Special Populations

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

Distribution

Extent

Widely distributed.

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

Crosses placenta in animals.

Plasma Protein Binding

Approximately 97%; independent of plasma drug concentration.

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A and, to a minor extent, by other CYP isoenzymes (e.g., 2C9, 2C19, 2D6, 2E1).

Elimination Route

Excreted mainly via biliary elimination. 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.

Half-life

Biphasic; terminal half-life is approximately 7.3 days.

Special Populations

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

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

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

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.

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 2–8°C.

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

Compatibility

Parenteral

Solution Compatibility

Actions

• Synthetic tetrahydroisoquinoline alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata.

• Alkylating antineoplastic agent; forms covalent adducts with guanine residues in the minor groove of DNA, bending the helix towards the major groove.

• 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.

• 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.

Advice to Patients

• Importance of reading the manufacturer's patient information.

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

• Risk of rhabdomyolysis. Importance of monitoring CK concentrations. Advise patients to promptly inform clinician if they experience severe muscle pain or weakness.

• Risk of hepatotoxicity. Importance of monitoring liver function tests prior to each dose of trabectedin. 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.

• Risk of cardiomyopathy. Importance of cardiac monitoring before initiating trabectedin and periodically during therapy. Importance of immediately contacting a clinician if new-onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations occur.

• Risk of hypersensitivity reactions. 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.

• Risk of extravasation. Importance of contacting a clinician if redness, swelling, pruritus, or discomfort or leakage at the injection site occurs.

• Risk of fetal harm. 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. 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. If pregnancy occurs, advise patient of potential risk to the fetus.

• Importance of advising women to avoid breast-feeding while receiving trabectedin. (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.

• Importance of advising patients to avoid grapefruit during trabectedin therapy.

• Importance of informing patients of other important precautionary information. (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. (See Restricted Distribution Program under Dosage and Administration.)

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