Trabectedin

Anemia, neutropenia, and thrombocytopenia commonly occur; neutropenic fever and neutropenic sepsis (with fatalities) have been reported. The median onset for first occurrence of grade 3/4 neutropenia was 16 days (range: 8 days to ~10 months) and median time to recovery was 13 days (range: 3 days to ~2 months). Monitor blood counts prior to each dose and periodically throughout treatment cycle. Withhold treatment for neutrophil count 3. Reduce dose (permanently) for life-threatening or prolonged severe neutropenia in the preceding cycle.

Capillary leak syndrome (CLS) has been reported, including serious cases resulting in death. Symptoms include hypotension, edema, and hypoalbuminemia; monitor for signs/symptoms of CLS. Discontinue if CLS develops and manage as appropriate.

Cardiomyopathy, including HF, decreased ejection fraction, diastolic dysfunction, or right ventricular dysfunction, has been observed; some events were grades 3 and 4. The median time to development of grades 3 and 4 cardiomyopathy was ~5 months (range: 1 to 15 months). Monitor left ventricular ejection fraction (LVEF) by echocardiogram or MUGA scan prior to treatment initiation and every 2 to 3 months until trabectedin is discontinued. Withhold treatment if LVEF is below the lower limit of normal (LLN); permanently discontinue for symptomatic cardiomyopathy or persistent ventricular dysfunction that does not recover to LLN within 3 weeks. Patients with a history of New York Heart Association class II, III, or IV heart failure or abnormal LVEF were excluded from the sarcoma study.

Vesicant; ensure proper needle or catheter placement prior to and during infusion. Infuse through a central line. Avoid extravasation. Extravasation of trabectedin with subsequent tissue necrosis requiring debridement has been reported; evidence of necrosis may be delayed up to 1 week after extravasation. There are no specific antidotes for trabectedin extravasation.

Trabectedin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016). Nausea and vomiting are common; corticosteroid premedication (eg, dexamethasone) is recommended; other antiemetics may also be needed. Constipation and diarrhea (generally mild) also commonly occur.

Hepatotoxicity (including hepatic failure) may occur with trabectedin. Grade 3 and 4 LFT elevations (AST, ALT, total bilirubin, or alkaline phosphatase) occurred in over one-third of patients. The median onset for grade 3/4 ALT or AST elevations was 29 days (range: 3 days to 11.5 months) and the median time to resolution was 13 days (range: 4 days to ~4 months); some patients experienced complete resolution. Drug-induced liver injury (ALT or AST elevation >3 times ULN, alkaline phosphatase 8 times ULN have been reported. Monitor LFTs prior to each dose (more frequently if clinically indicated); elevated LFTs may require treatment interruption, dose reduction, and/or discontinuation (based on severity and duration). Premedication with dexamethasone (4 mg twice daily the day prior to administration) has been reported to reduce the incidence of hepatotoxicity (Grosso 2006). Patients with bilirubin above the ULN or AST or ALT >2.5 times the ULN were excluded from the sarcoma clinical trial.

Symptoms of hypersensitivity reactions have been reported.

Trabectedin may cause rhabdomyolysis and musculoskeletal toxicity (some fatal). Creatine phosphokinase (CPK) elevations occurred in nearly one-third of patients receiving trabectedin; grade 3 and 4 CPK elevations, some complicated by renal failure, occurred. The median time to first occurrence of grade 3 or 4 CPK elevation was 2 months (range: 1 to 11.5 months) and the median time to complete resolution was 14 days (range: 5 to 30 days). Monitor CPK levels prior to each dose; withhold treatment for CPK levels >2.5 times ULN; discontinue permanently if rhabdomyolysis occurs.

Pulmonary embolism has been reported. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.