trabectedin

Absorption: IV administration results in complete bioavailability.

Distribution: Extensively distributed.

Protein Binding: 97%.

Metabolism/Excretion: Primarily metabolized via CYP3A in liver to inactive metabolites. 58% excreted in feces and 6% in urine (primarily as metabolites).

Half-Life: 175 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
IV	unknown	unknown	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Severe hypersensitivity;
Severe hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Moderate hepatic impairment (↓ dose);
Severe renal impairment;
Left ventricular ejection fraction (LVEF) <40%, prior cumulative doxorubicin dose ≥300 mg/m², or cardiovascular disease (↑ risk of cardiomyopathy);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: edema, CAPILLARY LEAK SYNDROME, HF

GI: constipation, diarrhea, hepatotoxicity, nausea, vomiting

GU: ↑serum creatinine, ↓fertility, renal failure

Hemat: anemia, neutropenia, thrombocytopenia

Local: extravasation

Metab: ↓appetite

MS: ↑creatine kinase, arthralgia, myalgia, RHABDOMYOLYSIS

Neuro: fatigue, headache, insomnia

Resp: dyspnea

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inhibitors, including clarithromycin, conivaptan, itraconazole, ketoconazole (oral), lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, or voriconazole, may ↑ levels and risk of toxicity; avoid concurrent use.
Strong CYP3A4 inducers, including phenobarbital or rifampin, may ↓ levels and effectiveness; avoid concurrent use.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Route/Dosage ⬆ ⬇

IV (Adults ): 1.5 mg/m² every 21 days; continue until disease progression or unacceptable toxicity.

Hepatic Impairment

IV (Adults ): Moderate hepatic impairment (bilirubin 1.5–3 times upper limit of normal [ULN] and AST/ALT <8 times ULN): 0.9 mg/m² every 21 days; continue until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Lyophilized powder for injection: 1 mg/vial

Assessment ⬆ ⬇

Monitor for signs and symptoms of hypersensitivity (difficulty breathing, chest tightness, wheezing, swelling of the lips, skin rash) during therapy.
Monitor for adverse reactions. Discontinue therapy if adverse reactions delay infusion for >3 wk; adverse reactions require dose ↓ following trabectedin infusion of 1.0 mg/m² (in patients with normal hepatic function) or 0.3 mg/m² (in patients with pre-existing moderate hepatic impairment); severe hepatic impairment; exacerbation of hepatic impairment in patients with pre-existing moderate hepatic impairment; capillary leak syndrome; rhabdomyolysis; or Grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for patients with an LVEF that ↓ below lower limit of normal.
Monitor LVEF via echocardiogram or multigated acquisition (MUGA) scan before starting trabectedin and every 2–3 mo until during therapy. Withhold dose if LVEF is below lower limit of normal. Permanently discontinue trabectedin if symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 wk occurs.
Monitor for signs and symptoms of capillary leak syndrome (hypotension, edema, hypoalbuminemia); may be fatal. Discontinue trabectedin and begin symptomatic treatment promptly.
Monitor infusion site for extravasation during therapy. May result in tissue necrosis resulting in debridement; evidence of tissue necrosis may occur >1 wk after extravasation.

Lab Test Considerations:

Verify negative pregnancy test prior to starting therapy.
Assess CBC prior to each infusion and periodically as indicated. If ANC <1,500 mm³ or platelet count <100,000 /mm³ on day of infusion, delay dose for up to 3 wk. If ANC <1000/mm³ with fever or infection, <500 /mm³ lasting >5 days or platelet count <25,000 /mm³,↓ next dose by one level.
Assess CK levels prior to each infusion. If CK>2.5 times ULN, delay dose for up to 3 wk. If CK >5 times ULN,↓ next dose by one level. If rhabdomyolysis occurs, permanently discontinue trabectedin.
Assess liver function tests prior to each infusion and as clinically indicated. If total bilirubin > upper limit of normal or AST, ALT, or alkaline phosphatase >2.5 times ULN, delay dose for up to 3 wk. If total bilirubin > ULN, AST or ALT >5 times ULN, or alkaline phosphatase >2.5 times ULN,↓ next dose by one level. If total bilirubin 2 times ULN and AST/ALT 3 times ULN, and alkaline phosphatase <2 times ULN in prior treatment cycle for patients with normal liver function at baseline, permanently discontinue trabectedin.
May cause anemia, hypoalbuminemia, and ↑ serum creatinine.

Implementation ⬆ ⬇

Administer dexamethasone 20 mg IV 30 min before each infusion.
Dose reduction for patients with normal hepatic function or mild hepatic impairment: 1st dose reduction: 1.2 mg/m². 2nd dose reduction: 1 mg/m².
Dose reduction for patients with moderate hepatic impairment: 1st dose reduction: 0.6 mg/m². 2nd dose reduction: 0.3 mg/m².
High Alert: Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order and dose calculations.
Medication is a vesicant. 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.

IV Administration:

Wear gloves, gown, and mask while handling medication. Discard equipment in specially designated containers.
Intermittent Infusion: Reconstitution: Reconstitute vial with 20 mL sterile water for injection; shake vial to completely dissolve. Solution is clear, colorless to pale brownish-yellow. Discard if solution is discolored or contains particulate matter. Refrigerate vials during storage. Concentration: 0.05 mg/mL. Diluent: Withdraw appropriate volume of solution from vial and inject into a 500 mL bag of D5W or 0.9% NaCl. Diluted solution is compatible with Type I colorless glass vials; polyvinylchloride (PVC) and polyethylene (PE) bags and tubing; PE and polypropylene (PP) mixture bags; polyethersulfone (PES) in-line filters; titanium, platinum, or plastic ports; silicone and polyurethane catheters; and pumps having contact surfaces made of PVC, PE, or PE/PP.
Rate: Infuse over 24 hr via central line through a 0.2 micron PES in-line filter to ↓ risk of pathogens introduced during reconstitution. Complete infusion within 30 hr; discard unused solution 30 hr after reconstitution.
Y-Site Compatibility:
- doxorubicin liposomal.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Emphasize the need for periodic lab tests to monitor for side effects.
Advise parents to notify health care professional of all Rx or OTC medications, vitamins, or herbal products, especially St. John's wort, being taken and to consult with health care professional before taking other medications.
Advise patient to notify health care professional immediately if signs and symptoms of myelosuppression (fever, unusual bruising, bleeding, tiredness, paleness), rhabdomyolysis (severe muscle pain or weakness), hepatotoxicity (yellowing of skin and eyes, pain in upper right quadrant, severe nausea or vomiting, difficulty concentrating, disorientation, confusion), cardiomyopathy (new onset chest pain, shortness of breath, fatigue, lower extremity edema, heart palpitations), hypersensitivity (difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips, skin rash), extravasation (redness, swelling, itchiness and discomfort or leakage at infusion site), or capillary leak syndrome (edema with or without hypotension) occur.
Rep: May cause fetal harm. Advise female patients of reproductive potential of the need for effective contraception and to avoid breastfeeding during therapy and for 2 mo following final dose. Advise male patients with female partners of reproductive potential to use effective contraception during and for ≥5 mo after last dose. May damage spermatozoa, leading to potential genetic and fetal abnormalities. May ↓ fertility in males and females. Advise patient to notify health care professional if pregnancy is planned or suspected.

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇