trabectedin (Rx)

>10%

Nausea, all grades (75%)

Fatigue, all grades (69%)

Vomiting, all grades (46%)

Constipation, all grades (37%)

Decreased appetite, all grades (37%)

Diarrhea, all grades (35%)

Peripheral edema, all grades (28%)

Dyspnea, all grades (25%)

Headache, all grades (25%)

Arthralgia, all grades (15%)

Insomnia, all grades (15%)

Myalgia, all grades (12%)

Laboratory abnormalities

• Anemia, all grades (96%)
• Increased ALT, all grades (90%)
• Increased AST, all grades (84%)
• Increased alkaline phosphatase, all grades (70%)
• Neutropenia, all grades (66%)
• Hypoalbuminemia, all grades (63%)
• Thrombocytopenia, all grades (59%)
• Increased creatinine, all grades (46%)
• Neutropenia, grades 3-4 (43%)
• Increased CPK, all grades (33%)
• Increased ALT, grades 3-4 (31%)
• Thrombocytopenia, grades 3-4 (21%)
• Anemia, grades 3-4 (19%)
• Increased AST, grades 3-4 (17%)
• Hyperbilirubinemia, all grades (13%)

1-10%

Fatigue, grades 3-4 (8%)

Nausea, grades 3-4 (7%)

Increased CPK, grades 3-4 (6.4%)

Vomiting, grades 3-4 (6%)

Dyspnea, grades 3-4 (4.2%)

Increased creatinine, grades 3-4 (4.2%)

Hypoalbuminemia, grades 3-4 (3.7%)

Decreased appetite, grades 3-4 (1.9%)

Hyperbilirubinemia, grades 3-4 (1.9%)

Diarrhea, grades 3-4 (1.6%)

Increased alkaline phosphatase, grades 3-4 (1.6%)

<1%

Constipation, grades 3-4

Peripheral edema, grades 3-4

Headache, grades 3-4

Insomnia, grades 3-4

Postmarketing Reports

Capillary leak syndrome

Mucosal inflammation at administration site

Contraindications

Known hypersensitivity, including anaphylaxis, to trabectedin

Cautions

Neutropenic sepsis, including fatal cases, were reported during clinical trials; assess neutrophil count prior to administration of each dose and periodically throughout the treatment cycle (see Dosage Modifications)

May cause rhabdomyolysis and musculoskeletal toxicity; assess CPK levels prior to each administration; reduce dose, or permanently discontinue based on severity of adverse reaction (see Dosage Modifications)

Hepatotoxicity, including hepatic failure, reported during clinical trials (see Dosage Modifications)

Assess LFTs prior to each administration and as clinically indicated based on underlying severity of pre-existing hepatic impairment; manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality; not for administration to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT); reduce dose in patients with moderate hepatic impairment

Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction, can occur; discontinue treatment based on severity of adverse reaction (also see Dosage Modifications)

Extravasation, resulting in tissue necrosis, requiring debridement, can occur; evidence of tissue necrosis can occur >1 week after the extravasation; there is no specific antidote for extravasation of trabectedin; administer through a central venous line (see Administration)

Capillary leak syndrome (CLS) characterized by hypotension, edema, and hypoalbuminemia reported, including serious CLS resulting in death; monitor for signs and symptoms of CLS; discontinue therapy and promptly initiate standard management for patients with CLS, which may include a need for intensive care

Based on its mechanism of action, can cause fetal harm when administered to a pregnant woman (see Pregnancy)

Coadministration with strong CYP3A inhibitors and inducers

• Trabectedin is a CYP3A substrate
• Avoid coadministration with strong CYP3A inhibitors or inducers
• Clinical trials showed systemic exposure of trabectedin by increased by 66% with ketoconazole, a strong CYP3A inhibitor
• Coadministration with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%

Pregnancy

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

There are no available data on trabectedin use during pregnancy

Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats

Contraception

• Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose
• Males: May damage spermatozoa, resulting in possible genetic and fetal abnormalities; advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose

Infertility

• May result in decreased fertility in males and females

Lactation

Unknown if distributed in human breast milk

Because of the potential for serious adverse reactions from trabectedin in breastfed infants, advise a nursing woman to discontinue nursing during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix toward the major groove

Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA-binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death

Distribution

Protein bound: ~97%

Vd: >5,000 L

Metabolism

Extensively metabolized in liver, predominantly by CYP3A

Elimination

Half-life: 175 hr

Clearance: 31.5 L/hr

Excretion

• Extensively metabolized, with negligible unchanged drug in urine and feces following administration
• Collection over 24 days: 58% in feces; 6% in urine

IV Compatibilities

Dextrose 5% water

0.9% NaCl

IV Preparation

Cytotoxic drug; follow applicable special handling and disposal

Using aseptic technique, inject 20 mL of sterile water for injection into the vial

Shake the vial until complete dissolution

The reconstituted solution is clear, colorless to pale brownish-yellow

Resulting concentration following reconstitution is 0.05 mg/mL

Immediately following reconstitution, withdraw the calculated volume of trabectedin and further dilute in 500 mL of 0.9% NaCl or D5W

Do not mix with other drugs

Discard any remaining solution within 30 hr of reconstituting the lyophilized powder

Diluted solution compatibility with containers, filters, and infusion lines

• Type I colorless glass vials
• Polyvinylchloride (PVC) bags
• Polyethylene (PE) bags, mixture bags, and tubing
• Polypropylene (PP) mixture bags
• Polyethersulfone (PES) in-line filters
• Titanium, platinum, or plastic ports
• Silicone and polyurethane catheters
• Pumps with contact surfaces made of PVC, PE, or PE/PP

IV Administration

Administer dexamethasone 20 mg IV 30 minutes prior to each dose

Administer trabectedin by IV infusion over 24 hr

Use an infusion set with a 0.2-micron polyethersulfone (PES) in-line filter to reduce the risk of exposure to adventitious pathogens that may be introduced during solution preparation

Complete infusion within 30 hr of initial reconstitution

Discard any unused portion of the reconstituted product or of the infusion solution

Storage

Cytoxic agent; follow applicable special handling and disposal procedures

Refrigerate unopened vials at 2-8ºC (36-46ºF)