tra-BEK-te-din

Therapeutic Classification: antineoplastics

Pharmacologic Classification: alkylating agents

• Unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have previously received an anthracycline-containing regimen.

• Interferes with DNA transcription, ultimately disrupting protein synthesis and causing cell death.

• Death of rapidly replicating cells, particularly malignant ones. Significantly improves progression-free survival rates.

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.

(blood levels)

Contraindicated in:

• Severe hypersensitivity
• Severe hepatic impairment
• Concurrent use of strong CYP3A4 inhibitors or inducers
• OB: Pregnancy (may cause fetal harm)
• Lactation: Lactation.

Use Cautiously in:

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

CV: peripheral edema, HF, CAPILLARY LEAK SYNDROME.

GI: ↓appetite, constipation, diarrhea, hepatotoxicity, nausea, vomiting.

GU: ↑serum creatinine, ↓ fertility, renal failure.

Hemat: anemia, neutropenia, thrombocytopenia.

Local: extravasation.

MS: ↑creatine kinase, arthralgia, myalgia, RHABDOMYOLYSIS.

Neuro: fatigue, headache, insomnia.

Resp: dyspnea.

Drug-Drug:

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

Drug-Natural Products:

• St. John's wortmay ↓ levels and effectiveness; avoid concurrent use.

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

• Lyophilized powder for injection: 1 mg/vial;

• 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 wks, adverse reactions require dose reduction following trabectedin infusion of 1.0 mg/m²or 0.3 mg/m² in patients with moderate hepatic dysfunction, severe liver dysfunction or exacerbation of liver impairment in patients with pre-existing moderate hepatic impairment occur, capillary leak syndrome, rhabdomyolysis, Grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for patients with an LVEF that ↓ below lower limit of normal.
• Monitor left ventricular ejection fraction (LVEF) 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 therapy if symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks occurs.
• Monitor for signs and symptoms of capillary leak syndrome (CLS) (hypotension, edema, hypoalbuminemia); may be fatal. Discontinue therapy 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.

• Verify negative pregnancy test prior to starting therapy.
• Assess CBC and platelet count prior to each infusion and periodically as indicated. If absolute neutrophil count <1.5 cells/mm³ or platelet count <100,000 platelets/mm³ on day of infusion: delay dose for up to 3 wks. If absolute neutrophil count <1000 cells/mm³ with fever or infection, <500 cells/mm³ lasting >5 days or platelet count <25,000 platelets/mm³: reduce next dose by 1 level.
• Assess creatinine kinase (CK) levels prior to each infusion. If CK levels >2.5 times upper limit of normal: withhold dose for up to 3 wks. If CK >5 times upper limit of normal: reduce next dose by one level. Permanently discontinue trabectedin if rhabdomyolysis occurs.
• Assess liver function tests prior to each infusion and as clinically indicated. If total bilirubin is >upper limit of normal or AST, ALT, or alkaline phosphatase >2.5 times upper limit of normal: delay dose for up to 3 wks. If total bilirubin is >upper limit of normal or AST or ALT >5 times upper limit of normal, or alkaline phosphatase >2.5 times upper limit of normal: reduce next dose by one level. Permanently discontinue trabectedin if severe liver dysfunction: (bilirubin 2 times upper limit of normal, and AST or ALT 3 times upper limit of normal, and alkaline phosphatase <2 times upper limit of normal in prior treatment cycle for patients with normal liver function at baseline.
• May cause anemia, hypoalbuminemia, and ↑ creatinine.

• Dose reduction recommendations: First dose reduction: For patients with normal hepatic function or mild hepatic impairment before starting therapy, 1.5 mg/mm². For patients with moderate hepatic impairment before starting therapy, 0.6 mg/mm². Second dose reduction: For patients with normal hepatic function or mild hepatic impairment before starting therapy,1.0 mg/mm²For patients with moderate hepatic impairment before starting therapy,0.3 mg/mm².
• 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.
• Premedicate with dexamethasone 20 mg IV 30 min prior to each infusion.

IV Administration:

• Solution should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling medication. Discard equipment in specially designated containers.
• Intermittent Infusion: Reconstitute vial with 20 mL Sterile Water for Injection; shake vial to completely dissolve. Solution is clear, colorless to pale brownish-yellow with a concentration of 0.05 mg/mL. Discard if solution discolored or contains particulate matter. Refrigerate vials during storage. Immediately withdraw volume and dilute with 500 mL 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 hrs via central line through a 0.2 micron polyethersulfone (PES) in-line filter to decrease risk of pathogens introduced during reconstitution. Complete infusion within 30 hrs; discard unused solution 30 hrs after reconstitution.
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• Explain purpose of trabectedin to patient. Advise patient to read Patient Information before starting therapy.
• 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, or 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.
• 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.
• May be teratogenic. Advise female patients of reproductive potential of the need for effective contraception and to avoid breast feeding during and for 2 mo following final dose. Advise male patients with female partners of reproductive potential to use effective contraception during and for at least 5 mo after last dose. May damage spermatozoa, leading to potential genetic and fetal abnormalities. May decrease fertility in males and females. Advise patient to notify health care professional if pregnancy is planned or suspected.
• Emphasize the need for periodic lab tests to monitor for side effects.

• Death of rapidly replicating cells, particularly malignant ones. Significant improvement in progression-free survival rates.

Yondelis