Trabectedin

>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

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.

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

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You will need to have heart function tests while taking trabectedin. Talk with the doctor.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• Low white blood cell counts have happened with drugs like this one. This may lead to a higher chance of getting an infection. Deadly infections have rarely happened. Tell your doctor if you have ever had a low white blood cell count. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• Avoid grapefruit and grapefruit juice.
• This medicine may cause a very bad and sometimes deadly problem called capillary leak syndrome (CLS). CLS may lead to low blood pressure and harm to the body. It may also lead to a heartbeat that is not normal, chest pain or pressure, heart attack, lung or breathing problems, bleeding or lower blood flow in the stomach or bowel, kidney problems, swelling, or feeling confused. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 5 months after care ends. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant within 5 months after your care has ended, call your doctor right away.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking trabectedin and for at least 2 months after your last dose.
• If you get pregnant while taking this medicine or within 2 months after your last dose, call your doctor right away.

Soft tissue sarcoma: Treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) in patients who have received a prior anthracycline-containing regimen.

Known, severe hypersensitivity (including anaphylaxis) to trabectedin or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Active serious or uncontrolled infection; breastfeeding

CrCl ≥30 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute or ESRD: There is no dosage adjustment provided in the manufacturer's labeling (has not been studied).

Hemodialysis: Hemodialysis is not expected to enhance elimination of trabectedin.

Soft tissue sarcoma:

Recommended dose reduction levels (once a dose is reduced it should not be increased in subsequent cycles):

First dose reduction: 1.2 mg/m2 once every 3 weeks

Second dose reduction: 1 mg/m2 once every 3 weeks

Hematologic toxicity:

ANC <1,500/mm3: Delay dose for up to 3 weeks

ANC <1,000/mm3 with fever or infection or <500/mm3 lasting >5 days during prior cycle: Delay dose for up to 3 weeks and reduce the next dose by one dose level

Platelets <100,000/mm3: Delay dose for up to 3 weeks

Platelets <25,000/mm3 during prior cycle: Delay dose for up to 3 weeks and reduce the next dose by one dose level

Nonhematologic toxicity:

Creatine phosphokinase >2.5 times ULN: Delay dose for up to 3 weeks

Creatine phosphokinase >5 times ULN during prior cycle: Delay dose for up to 3 weeks and reduce the next dose by one dose level

Decreased left ventricular ejection fraction (LVEF): Less than the lower limit of normal (LLN) or clinical evidence of cardiomyopathy: Delay dose for up to 3 weeks

Decreased LVEF: Absolute decrease of 10% or more from baseline and less than the LLN or clinical evidence of cardiomyopathy during prior cycle: Delay dose for up to 3 weeks and reduce the next dose by one dose level

Other nonhematologic toxicity: Grade 3 or 4: Delay dose for up to 3 weeks and reduce the next dose by one dose level

Adverse reactions with trabectedin administered at 1 mg/m2 (in patients with normal hepatic function) or 0.3 mg/m2 (in patients with preexisting moderate hepatic impairment; refer do dosing in hepatic impairment) and requiring further dose reduction: Permanently discontinue.

Capillary leak syndrome: Discontinue treatment.

Persistent adverse events requiring a delay of more than 3 weeks: Permanently discontinue.

Trabectedin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Roila 2016).

Infuse through a central line with a 0.2 micron polyethersulfone filter. Infusion must be completed within 30 hours of reconstitution. Premedicate with a corticosteroid (eg, dexamethasone 20 mg IV) 30 minutes prior to treatment; additional antiemetics may be needed.

Soft tissue sarcoma: Single-agent therapy: Infuse as a continuous infusion over 24 hours

Ovarian cancer (off-label use): Combination therapy with doxorubicin liposomal: Administer doxorubicin liposomal first (flush line with D5W) then follow with trabectedin infusion over 3 hours (Monk 2010).

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.

Avoid grapefruit and grapefruit juice.

-Normal Bilirubin and AST or ALT 2.5 Times the Upper Limit of Normal (ULN) or Less:
1.5 mg/m2 via IV infusion every 21 days (3 weeks)

-Serum Bilirubin Levels Above Institutional ULN:
No recommended dose.

Duration of Therapy: Until disease progression or unacceptable toxicity

Comments:
-Administer this drug over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter.
-Complete infusion within 30 hours of drug reconstitution.
-Administer dexamethasone 20 mg IV 30 minutes prior to each dose.

Use: Treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

SEVERE LIVER DYSFUNCTION (Bilirubin 2 x ULN and AST or ALT 3 x ULN with Alkaline Phosphatase Less than 2 x ULN) in the prior treatment cycle: Permanently discontinue treatment.

FOR ELEVATED ALT, AST, ALKALINE PHOSPHATASE, or TOTAL BILIRUBIN:
-First Dose Reduction: 1.2 mg/m2 every 3 weeks
-Second Dose Reduction: 1.0 mg/m2 every 3 weeks
-Once reduced, the dose should not be increased in subsequent treatment cycles.

ALT or AST:
-More than 2.5 x ULN: Delay next dose for up to 3 weeks.
-More than 5 x ULN: Reduce next dose by one dose level.

Alkaline Phosphatase:
-More than 2.5 x ULN: Delay next dose for up to 3 weeks and reduce next dose by one dose level.

Total Bilirubin:
-Greater than the ULN: Delay next dose for up to 3 weeks and reduce next dose by one dose level.

PERMANENTLY DISCONTINUE TREATMENT FOR:
-Persistent adverse reactions requiring a dosing delay of more than 3 weeks.
-Adverse reactions requiring dose reduction following administration of this drug at 1.0 mg/m2.