Trabectedin
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Alkylating Drug
Dosing in kidney impairment
Renal Impairment No dose adjustment of EVDI is recommended in patients with mild [creatinine clearance (CLcr) 60 to 89 mL/min] or moderate (CLcr of 30 to 59 mL/min) renal impairment. The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease [see Clinical Pharmacology ] .
Dosing in liver impairment
Recommended Dosage in Patients with Hepatic Impairment The recommended dosage of EVDI in patients with moderate hepatic impairment (bilirubin levels greater than 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal) is 0.9 mg/m 2 every 21 days (3 weeks). Do not administer EVDI to patients with severe hepatic impairment (bilirubin levels above 3 times the upper limit of normal, and any AST and ALT) [see Use in Specific Populations and Clinical Pharmacology].
| Table 2: Recommended Starting Doses and Dose Reductions | ||
| Starting Dose and Dose Reduction | For patients with normal hepatic function or mild hepatic impairment* prior to initiation of EVDI treatment | For patients with moderate hepatic impairment** prior to initiation of EVDI treatment |
| Starting Dose | 1.5 mg/m2 | 0.9 mg/m2 |
| Dose Reduction | ||
| First dose reduction | 1.2 mg/m2 | 0.6 mg/m2 |
| Second dose reduction | 1.0 mg/m2 | 0.3 mg/m2 |
Preparation and administration
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Recommended Dosage The recommended dose is 1.5 mg/m 2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks), until disease progression or unacceptable toxicity.
Preparation for Administration EVDI is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is clear colorless to pale brownish yellow.
Discard the vial if particles are observed. Withdraw the calculated volume of trabectedin and dilute in 500 mL of 0.9% Sodium Chloride Injection, USP or in 500 mL of 5% Dextrose Injection, USP. Discard any unused portion left in the vial(s). EVDI 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.
Do not mix EVDI with other drugs. The diluted EVDI infusion solution may be stored at room temperature 20°C to 25°C (68°F to 77°F) for up to 30 hours.
Administration Infuse the diluted solution over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter. Discard any unused portion of the infusion solution. Complete infusion within 30 hours of initial dilution. Discard any unused portion of the infusion solution after 30 hours.
Drug interactions
Check trabectedin against a medication listLabel text (5 paragraphs)
7 DRUG INTERACTIONS CYP3A inhibitors: Avoid concomitant strong CYP3A inhibitors ( 7.1 ) CYP3A inducers: Avoid concomitant strong CYP3A inducers ( 7.1 )
7.1 Effects of Other Drugs on EVDI Table 5 describes drug interactions where concomitant use of another drug affects EVDI. Table 5: Drug Interactions with EVDI Strong CYP3A Inhibitors Prevention or Management Avoid concomitant use of strong CYP3A inhibitors in patients taking EVDI.
If concomitant use of a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) cannot be avoided, administer the strong CYP3A inhibitor 1 week after the EVDI infusion, and discontinue it the day prior to the next EVDI infusion Mechanism and Clinical Effect(s) Concomitant administration of trabectedin with ketoconazole, a strong CYP3A inhibitor, increased systemic exposure of trabectedin by 66% [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A Inducers Prevention or Management Avoid concomitant use of strong CYP3A inducers in patients taking EVDI.
Mechanism and Clinical Effect(s) Concomitant administration of trabectedin with rifampin, a strong CYP3A4 inducer, decreased systemic exposure of trabectedin by 31% [see Clinical Pharmacology ( 12.3 )]. Drug Interactions Effect of Strong CYP3A Inhibitors on Trabectedin Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of EVDI (0.58 mg/m 2 ) on day 1 increased trabectedin dose-normalized AUC by 66% and C max by 22% compared to a single EVDI dose (1.3 mg/m 2 ) given alone.
Effect of Strong CYP3A Inducers on Trabectedin Coadministration of multiple doses of rifampin (600 mg daily for 6 days) with a single EVDI dose (1.3 mg/m 2 ) on day 6 decreased trabectedin AUC by 31% and C max by 21% compared to a single EVDI dose (1.3 mg/m 2 ) given alone. Effect of Trabectedin on CYP Enzymes In vitro , trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4).
Contraindications
4 CONTRAINDICATIONS EVDI is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin. Known hypersensitivity to trabectedin ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on its mechanism of action, EVDI can cause fetal harm when administered during pregnancy [see Clinical Pharmacology ( 12.1 )]. There are no available data with the use of trabectedin 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. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S.
general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
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