Dosing and uses of Yondelis (trabectedin)
Adult dosage forms and strengths
lyophilized powder for reconstitution
- 1mg/vial
Soft Tissue Sarcoma
Indicated for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen
Premedicate with dexamethasone prior to each dose
1.5 mg/m² IV q3wk until disease progression or unacceptable toxicity
Infuse over 24 hr via a central venous line
Note: Patients must have normal bilirubin and AST or ALT ≤2.5 x ULN; there is no recommended dose in patients with serum bilirubin levels above the institutional ULn
Dosage modifications
Bilirubin >ULN: Not studied
Hepatic impairment
- Moderate hepatic impairment (bilirubin levels 1.5 times to 3 times upper limit of normal, and AST and ALT < 8 times upper limit of normal): 0.9 mg/ m²
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dose adjustment required
- Severe (CrCl <30 mL/min) or ESRD: Not studied
Permanently discontinue
- Persistent adverse reactions requiring a delay in dosing of >3 weeks
- Adverse reactions requiring dose reduction following dose of 1 mg/m²
- Severe liver dysfunction including all of the following in the prior treatment cycle
- Severe hepatic impairment (bilirubin levels >3 times to 10 times upper limit of normal, AND
- AST or ALT 3 x ULN, WITH
- Alkaline phosphatase <2 x ULN
Dose reductions
- First dose reduction: 1.2 mg/m² q3wk
- Second dose reduction: 1 mg/m² q3wk
Delay next dose for up to 3 weeks
- Platelets: <100,000 platelets/mc
- Absolute neutrophil count (ANC): <1500 neutrophils/mcL
- Total bilirubin: >ULN AST or ALT: >2.5 x ULN
- Alkaline phosphatase: >2.5 x ULN
- Creatinine phosphate (CPK): >2.5 x ULN
- Decreased LVEF: Less than lower limit of normal or clinical evidence of cardiomyopathy
- Other nonhematologic adverse reactions: Grade 3 or 4
Reduce next dose by one dose level for adverse reaction(s) during prior cycle
- Platelets: <25,000 platelets/mcL
- ANC: <1000 neutrophils/mcL with fever/infection
- ANC: <500 neutrophils/mcL lasting >5 days
- AST or ALT: >5 x ULN Total bilirubin: >ULN
- Alkaline phosphatase: >5 x ULN
- CPK: >5 x ULN
- Decreased LVEF: Absolute decrease of ≥10% from baseline and less than lower limit of normal, or clinical evidence of cardiomyopathy
- Other nonhematologic adverse reactions: Grade 3 or 4
Pediatric dosage forms and strengths
Safety and efficacy not established
Yondelis (trabectedin) adverse (side) effects
>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
Warnings
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 (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 (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)
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
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.
Pharmacology of Yondelis (trabectedin)
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
Administration
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)
