TRABECTEDIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRABECTEDIN (TRABECTEDIN).
Trabectedin binds to the minor groove of DNA, forming adducts that lead to DNA strand breaks and inhibition of transcription. It also affects the tumor microenvironment by modulating cytokine production and inhibiting activated macrophages.
| Metabolism | Primarily hepatic via CYP3A4; also a substrate of P-glycoprotein. |
| Excretion | Primarily fecal (approximately 58% of administered dose) with minor renal excretion (about 21% as unchanged drug and metabolites). Biliary excretion accounts for a significant portion of elimination via feces. |
| Half-life | Terminal elimination half-life ranges from 26 to 40 hours (mean ~33 hours) in patients with normal hepatic function, allowing for a 3-weekly dosing interval. |
| Protein binding | Approximately 97-98% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution at steady state is approximately 1000 L (>10 L/kg), indicating extensive tissue distribution and binding. |
| Bioavailability | Not applicable; administered intravenously. Oral bioavailability is negligible due to extensive first-pass metabolism. |
| Onset of Action | Not applicable; clinical effects (antitumor activity) require multiple cycles. For infusion-related effects, onset within minutes to hours. |
| Duration of Action | Duration of therapeutic effect varies with disease and regimen; typically monitored over multiple 3-week cycles. Infusion-related adverse effects may persist hours to days. |
1.5 mg/m² intravenously over 24 hours every 3 weeks.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh C). For moderate hepatic impairment (Child-Pugh B), reduce starting dose to 0.9 mg/m². For mild hepatic impairment (Child-Pugh A), no dose adjustment but monitor closely. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment recommended based on age alone; monitor renal and hepatic function due to potential age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRABECTEDIN (TRABECTEDIN).
| Breastfeeding | Unknown if trabectedin is excreted in human milk; however, due to potential serious adverse reactions in breastfeeding infants, women should discontinue breastfeeding during treatment and for at least 3 weeks after the last dose. M/P ratio is not available. |
| Teratogenic Risk | Trabectedin is teratogenic based on animal studies. It is contraindicated in pregnancy. First trimester exposure carries high risk of major malformations and pregnancy loss. Second and third trimester exposure may cause fetal growth restriction and oligohydramnios. Effective contraception is required during treatment and for at least 3 months after the last dose. |
■ FDA Black Box Warning
Trabectedin is associated with severe and fatal neutropenic sepsis, rhabdomyolysis with renal failure, cardiotoxicity (cardiomyopathy, heart failure), hepatotoxicity, and extravasation leading to tissue necrosis. It should only be administered under the supervision of a qualified healthcare provider experienced in the use of antineoplastic agents.
| Common Effects | Headache Fatigue Vomiting Weakness Nausea Increased liver enzymes Low blood platelets Increased creatine phosphokinase C P K level in blood Decreased white blood cell count neutrophils Decreased appetite Constipation |
| Serious Effects |
Hypersensitivity to trabectedin or any of its excipients, concomitant use with yellow fever vaccine, severe hepatic impairment.
| Precautions | Myelosuppression (neutropenia, thrombocytopenia, anemia), hepatotoxicity (elevated liver enzymes, bilirubin, hepatic failure), cardiotoxicity (LVEF decline, heart failure), rhabdomyolysis, extravasation injury, hypersensitivity reactions, and embryo-fetal toxicity. |
Loading safety data…
| Fetal Monitoring | Pregnancy status should be confirmed before starting therapy. Monitor complete blood counts (neutropenia, thrombocytopenia), liver function tests, creatine phosphokinase, and cardiac function (ejection fraction) regularly. Fetal monitoring includes ultrasound for growth and amniotic fluid volume if exposure occurs. |
| Fertility Effects | Trabectedin may impair male and female fertility. In males, oligospermia, azoospermia, and testicular atrophy have been observed. In females, amenorrhea, ovarian failure, and reduced ovarian reserve can occur. Effects may be irreversible. |