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  • CLASSES

    Other Antineoplastic Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Novel chemotherapy agent that works as an alkylating drug, binding guanine residues in the minor groove of DNA
    Indicated for unresectable or metastatic specific soft tissue sarcomas (liposarcoma and leiomyosarcoma) following treatment with anthracycline-containing chemotherapy
    Warnings regarding potential for fatal neutropenic sepsis, rhabdomyolysis, hepatotoxicity, and cardiomyopathy

    COMMON BRAND NAMES

    Yondelis

    HOW SUPPLIED

    Yondelis Intravenous Inj Pwd F/Sol: 1mg

    DOSAGE & INDICATIONS

    For the treatment of soft-tissue sarcoma.
    NOTE: Trabectedin has been designated by the FDA as an orphan drug for the treatment of soft-tissue sarcoma.
    For the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen.
    Intravenous dosage
    Adults

    1.5 mg/m2 IV infusion via a central venous line over 24 hours on day 1 and repeated every 21 days until disease progression. Premedicate with dexamethasone 20 mg IV 30 minutes prior to each dose. Avoid concomitant use with strong CYP3A inhibitors or inducers. If short-term use (i.e., less than 14 days) of a strong CYP3A inhibitor is unavoidable, administer the strong CYP3A inhibitor 1 week after the trabectedin infusion and discontinue use the day prior to the next trabectedin infusion. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop severe toxicity. In a preplanned interim analysis of a multinational, randomized (2:1), open-label, phase III trial (n = 518), the median progression-free survival time was significantly improved with trabectedin compared with dacarbazine (4.2 months vs. 1.5 months; hazard ratio (HR) = 0.55; 95% CI, 0.44 to 0.7; p < 0.001) in patients with unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma who had previously received an anthracycline and ifosfamide or an anthracycline and 1 or more additional cytotoxic chemotherapy regimens. However, the median overall survival (OS) time (primary endpoint) was not significantly different with trabectedin compared with dacarbazine (12.4 months vs. 12.9 months; p = 0.37) in this analysis. This trial is ongoing and cross-over treatment was not permitted; 47% of patients in the trabectedin arm and 56% of patients in the dacarbazine arm had received subsequent anticancer therapy at the time of this analysis.

    MAXIMUM DOSAGE

    Adults

    1.5 mg/m2 IV every 3 weeks.

    Geriatric

    1.5 mg/m2 IV every 3 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Normal hepatic function or mild hepatic impairment (bilirubin level within normal limits and AST or ALT level of 2.5 times the upper limit of normal (ULN) or less): no initial dose reduction is necessary.
    Moderate hepatic impairment (bilirubin level of 1.5- to 3-times the ULN and AST and ALT level less than 8-times the ULN): start at a reduced dose of 0.9 mg/m2 IV.
    Severe hepatic impairment (bilirubin level greater than 3-times to 10-times the ULN and any AST and ALT level): use not recommended.
    Management of Treatment-Related Hepatotoxicity
    Recommended Dose Reductions
    Baseline normal hepatic function or mild hepatic impairment (including a bilirubin level of 1- to 1.5-times the upper limit of normal (ULN) and any AST or ALT level): first dose reduction, 1.2 mg/m2 IV; second dose reduction, 1 mg/m2 IV. In patients with normal hepatic function at baseline, permanently discontinue trabectedin for a bilirubin level of 2-times the ULN and an AST or ALT level 3-times the ULN with an alkaline phosphatase level less than 2-times the ULN in the prior treatment cycle or if a third dose reduction is necessary.
    Baseline moderate hepatic impairment: first dose reduction, 0.6 mg/m2 IV; second dose reduction, 0.3 mg/m2 IV. Permanently discontinue trabectedin in patients who develop an exacerbation of liver dysfunction or if a third dose reduction is necessary.
     
    Hyperbilirubinemia
    Total bilirubin level greater than the ULN: Delay the next dose for up to 3 weeks. Resume therapy at a reduced dose; do not increase the dose in subsequent treatment cycles. If elevated total bilirubin levels last longer than 3 weeks, permanently discontinue trabectedin.
    Elevated hepatic enzymes
    AST or ALT level of 2.5 to 5 times the ULN: Delay the next dose for up to 3 weeks. Resume therapy at the previous dose.  If elevated AST or ALT levels last longer than 3 weeks, permanently discontinue trabectedin.
    AST or ALT greater than 5-times the ULN: Delay the next dose for up to 3 weeks. Resume therapy at a reduced dose; do not increase the dose in subsequent treatment cycles. If elevated AST or ALT levels last longer than 3 weeks, permanently discontinue trabectedin.
    Alkaline phosphatase (AP) level greater than 2.5 times the ULN: Delay the next dose for up to 3 weeks. Resume therapy at a reduced dose; do not increase the dose in subsequent treatment cycles. If elevated AP levels last longer than 3 weeks, permanently discontinue trabectedin.

    Renal Impairment

    No dose adjustment necessary in patients with baseline mild (creatinine clearance (CrCl) 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. The pharmacokinetics of trabectedin have not been evaluated in patients with severe renal impairment (CrCl less than 30 mL/min) or end stage renal disease. Hemodialysis is not expected to enhance the elimination of trabectedin.

    ADMINISTRATION

    Injectable Administration

    Observe and exercise appropriate cautions for preparing, handling, and administering solutions of cytotoxic drugs.
    For intravenous infusion use only.

    Intravenous Administration

    Reconstitution
    Using aseptic technique, inject 20 mL of Sterile Water for Injection into the trabectedin vial; shake until complete dissolution.
    The reconstituted solution should be clear and colorless to pale brownish yellow, containing 0.05 mg/mL of trabectedin.
    Inspect for particulate matter and discoloration; discard vial if particles or discoloration are observed.
     
    Infusion Preparation
    Immediately after reconstitution, withdraw the calculated volume of trabectedin and dilute in 500 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
    Do not mix trabectedin with other drugs.
    The 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.
    Discard any remaining solution within 30 hours of reconstituting the lyophilized powder.
     
    Intravenous Infusion Administration
    Premedication is required: Administer dexamethasone 20 mg IV 30 minutes prior to each trabectedin infusion dose.
    Infuse over 24 hours through a central venous line, using an infusion set with a 0.2 micron PES in-line filter.
    Complete the infusion within 30 hours of initial reconstitution. Discard any unused portion.

    STORAGE

    Yondelis:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container
    - Store reconstituted product in accordance with package insert instructions

    CONTRAINDICATIONS / PRECAUTIONS

    Bone marrow suppression, chemotherapy, fungal infection, herpes infection, infection, neutropenia, radiation therapy, viral infection

    Severe neutropenia and neutropenic sepsis, including some fatalities, has occurred with trabectedin therapy. Monitor the neutrophil count prior to administration of each dose of trabectedin and periodically throughout the treatment cycle; do not administer trabectedin if the ANC on the day of dosing is less than 1,500/mm3. A dose reduction or discontinuation of therapy may be necessary. In a randomized, open-label clinical trial of patients with previously treated leiomyosarcoma or liposarcoma, the median time to first occurrence of grade 3 or 4 neutropenia in patients treated with trabectedin (n = 345) was 16 days (range, 8 days to 9.7 months), and the median time to complete resolution was 13 days (range, 3 days to 2.3 months). Patients who have had previous myelosuppressive therapy such as chemotherapy or pelvic radiation therapy may be at risk of increased bone marrow suppression; therefore, this drug should be used only by clinicians experienced in chemotherapy. Patients with an active infection should be treated prior to receiving trabectedin. Opportunistic infections, including fungal infection, may occur in some patients due to severe myelosuppression. Patients with a history of varicella zoster, herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.

    Rhabdomyolysis

    Musculoskeletal adverse reactions, elevated serum creatine phosphokinase (CPK) levels, and rhabdomyolysis, in some cases leading to renal failure, have been reported with trabectedin therapy in patients with leiomyosarcoma and liposarcoma in a randomized, open-label clinical trial (n = 518). Obtain baseline CPK levels prior to each dose of trabectedin and periodically monitor serum creatinine (SCr); an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Permanently discontinue trabectedin therapy for rhabdomyolysis. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. The median time to onset of grade 3 or higher CPK elevations was 2 months (range, 1 to 11.5 months) and the median time to complete resolution was 14 days (range, 5 days to 1 month).

    Hepatic disease, hepatotoxicity

    Hepatotoxicity, including hepatic failure, has been reported with trabectedin therapy. An initial dose reduction is necessary in patients with moderate hepatic impairment (bilirubin level of 1.5- to 3-times the ULN and AST and ALT level less than 8-times the ULN); use in patients with severe hepatic disease/impairment (bilirubin level greater than 3-times to 10-times the ULN and any AST and ALT level) is not recommended. Obtain liver function tests before each dose of trabectedin and as clinically indicated based on the severity of pre-existing hepatic impairment. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary in patients who develop hepatic impairment. The median time to onset of grade 3 or 4 elevations of AST/ALT in patients treated with trabectedin was 29 days (range, 3 days to 11.5 months); 85% of these patients experienced complete resolution in a median of 13 days (range, 4 days to 4.4 months).

    Cardiac disease, cardiomyopathy, heart failure, ventricular dysfunction

    Cardiomyopathy, including cardiac failure, congestive heart failure, decreased ejection fraction, diastolic dysfunction, or right ventricular dysfunction, leading to death may occur with trabectedin therapy. Monitor the left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before starting therapy with trabectedin and every 2 to 3 months thereafter until discontinuation of therapy. Do not administer trabectedin if the LVEF is below the lower limit of normal, and permanently discontinue trabectedin for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to the lower limit of normal within 3 weeks. The median time to onset of grade 3 or 4 cardiomyopathy in patients who received trabectedin was 5.3 months (range, 26 days to 15.3 months). Patients with class II or higher congestive heart failure or left ventricular dysfunction (LVD) manifested by an abnormal left ventricular ejection fraction (LVEF) were excluded from the randomized clinical trial; patients with a history of cardiac disease may be at increased risk for developing cardiac adverse events.

    Extravasation

    Extravasation, resulting in tissue necrosis requiring debridement, may occur with trabectedin therapy; evidence of tissue necrosis may occur more than 1 week after an extravasation. Administer trabectedin through a central venous line. There is no specific antidote for trabectedin extravasation.

    Capillary leak syndrome

    Capillary leak syndrome (CLS) has been reported with trabectedin use; some cases have been fatal. Monitor patients for signs and symptoms of CLS (e.g., hypotension, edema, and hypoalbuminemia). Discontinue trabectedin if CLS occurs; promptly treat using standard management.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, trabectedin may cause fetal harm when administered during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted; however, placental transfer of trabectedin was demonstrated in pregnant rats.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during trabectedin treatment. Trabectedin can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 2 months after treatment with trabectedin. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during trabectedin therapy and for at least 5 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of trabectedin. Women who become pregnant while receiving trabectedin should be apprised of the potential hazard to the fetus. Trabectedin may also result in impaired fertility or infertility.

    Breast-feeding

    It is not known whether trabectedin is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from trabectedin, advise women to discontinue breast-feeding during treatment.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 43.0-43.0
    elevated hepatic enzymes / Delayed / 1.6-31.0
    thrombocytopenia / Delayed / 21.0-21.0
    anemia / Delayed / 19.0-19.0
    pulmonary embolism / Delayed / 0-10.0
    fatigue / Early / 8.0-8.0
    nausea / Early / 7.0-7.0
    vomiting / Early / 6.0-6.0
    renal failure (unspecified) / Delayed / 2.9-4.2
    dyspnea / Early / 4.2-4.2
    cardiomyopathy / Delayed / 4.0-4.0
    hypoalbuminemia / Delayed / 3.7-3.7
    hyperbilirubinemia / Delayed / 1.9-1.9
    anorexia / Delayed / 1.9-1.9
    diarrhea / Early / 1.6-1.6
    rhabdomyolysis / Delayed / 0.8-1.1
    constipation / Delayed / 0.8-0.8
    peripheral edema / Delayed / 0.8-0.8
    insomnia / Early / 0.3-0.3
    headache / Early / 0.3-0.3
    hepatic failure / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    capillary leak syndrome / Early / Incidence not known

    Moderate

    peripheral neuropathy / Delayed / 0-10.0

    Mild

    arthralgia / Delayed / 15.0-15.0
    myalgia / Early / 12.0-12.0
    hypoesthesia / Delayed / 0-10.0
    paresthesias / Delayed / 0-10.0
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) Use caution if coadministration of trabectedin and aldesleukin, IL-2 is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; aldesleukin increases IL-6 concentrations, and IL-6 is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Amiodarone: (Moderate) Use caution if coadministration of trabectedin and amiodarone is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and amiodarone is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to significantly increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to significantly increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Aprepitant, Fosaprepitant: (Moderate) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and may be used in combination with trabectedin. However, use caution and monitor for a possible increase in non-emetogenic trabectedin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Trabectedin is a CYP3A substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of trabectedin. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The AUC of a single dose of midazolam, another CYP3A4 substrate, increased by 2.3-fold on day 1 and by 3.3-fold on day 5 when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Atazanavir: (Major) Avoid the concomitant use of trabectedin with atazanavir due to significantly increased trabectedin exposure. If short-term atazanavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Atazanavir; Cobicistat: (Major) Avoid the concomitant use of trabectedin with atazanavir due to significantly increased trabectedin exposure. If short-term atazanavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Moderate) Use caution if coadministration of trabectedin and cobicistat is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the concomitant use of trabectedin with phenobarbital due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Basiliximab: (Moderate) Use caution if coadministration of trabectedin and basiliximab is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; basiliximab may cause a down-regulation of CYP3A4 activity by increasing IL-2 binding to the IL-2 receptors on hepatic and intestinal cells. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of trabectedin with phenobarbital due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Bexarotene: (Moderate) Use caution if coadministration of trabectedin and bexarotene is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Boceprevir: (Major) Avoid the concomitant use of trabectedin with boceprevir due to significantly increased trabectedin exposure. If short-term boceprevir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and boceprevir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Bosentan: (Moderate) Use caution if coadministration of trabectedin and bosentan is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Brigatinib: (Moderate) Monitor for decreased efficacy of trabectedin if coadministration with brigatinib is necessary. Trabectedin is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration of trabectedin with a strong CYP3A inducer decreased trabectedin exposure by 31%; brigatinib may also decrease trabectedin exposure.
    Cabozantinib: (Minor) Use caution if coadministration of trabectedin and cabozantinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, cabozantinib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Ceritinib: (Moderate) Monitor for trabectedin-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and trabectedin is metabolized by CYP3A4. Coadministration with a strong CYP3A inhibitor increased systemic exposure of trabectedin by 66%; the degree of CYP3A4 inhibition by ceritinib is unknown.
    Chloramphenicol: (Major) Avoid the concomitant use of trabectedin with chloramphenicol due to significantly increased trabectedin exposure. If short-term chloramphenicol (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Cimetidine: (Moderate) Use caution if coadministration of trabectedin and cimetidine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cimetidine is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Clarithromycin: (Major) Avoid the concomitant use of trabectedin with clarithromycin due to significantly increased trabectedin exposure. If short-term clarithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Cobicistat: (Moderate) Use caution if coadministration of trabectedin and cobicistat is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use caution if coadministration of trabectedin and cobicistat is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution if coadministration of trabectedin and cobicistat is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Conivaptan: (Major) Avoid the concomitant use of trabectedin with conivaptan due to significantly increased trabectedin exposure. If short-term conivaptan (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and conivaptan is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Cyclosporine: (Moderate) Use caution if coadministration of trabectedin and cyclosporine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cyclosporine is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Dabrafenib: (Moderate) Use caution if coadministration of trabectedin and dabrafenib is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducer.
    Dalfopristin; Quinupristin: (Major) Avoid the concomitant use of trabectedin with dalfopristin; quinupristin due to significantly increased trabectedin exposure. If short-term dalfopristin; quinupristin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and quinupristin is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Danazol: (Moderate) Use caution if coadministration of trabectedin and danazol is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Darunavir: (Major) Avoid the concomitant use of trabectedin with darunavir due to significantly increased trabectedin exposure. If short-term darunavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Darunavir; Cobicistat: (Major) Avoid the concomitant use of trabectedin with darunavir due to significantly increased trabectedin exposure. If short-term darunavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Moderate) Use caution if coadministration of trabectedin and cobicistat is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to significantly increased trabectedin exposure. If short-term ritonavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Dasatinib: (Moderate) Use caution if coadministration of trabectedin and dasatinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and dasatinib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Deferasirox: (Moderate) Use caution if coadministration of trabectedin and deferasirox is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and deferasirox is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Delavirdine: (Major) Avoid the concomitant use of trabectedin with delavirdine due to significantly increased trabectedin exposure. If short-term delavirdine (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Dexamethasone: (Moderate) Use caution if coadministration of trabectedin and dexamethasone is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and dexamethasone is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Diltiazem: (Moderate) Use caution if coadministration of trabectedin and diltiazem is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Dronedarone: (Moderate) Use caution if coadministration of trabectedin and dronedarone is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and dronedarone is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Efavirenz: (Moderate) Use caution if coadministration of trabectedin and efavirenz is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution if coadministration of trabectedin and efavirenz is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Elbasvir; Grazoprevir: (Moderate) Administering trabectedin with elbasvir; grazoprevir may result in elevated trabectedin plasma concentrations. Trabectedin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eluxadoline: (Minor) Use caution if coadministration of trabectedin and eluxadoline is necessary, due to the potential risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; although the CYP3A4 inhibitory effects of eluxadoline have not been definitively established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Enzalutamide: (Major) Avoid the concomitant use of trabectedin with enzalutamide due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Erythromycin: (Moderate) Use caution if coadministration of trabectedin and erythromycin is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Erythromycin; Sulfisoxazole: (Moderate) Use caution if coadministration of trabectedin and erythromycin is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Eslicarbazepine: (Moderate) Use caution if coadministration of trabectedin and eslicarbazepine is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducer.
    Ethanol: (Moderate) Avoid the concomitant use of trabectedin with alcohol (ethanol) due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and alcohol is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Etravirine: (Moderate) Use caution if coadministration of trabectedin and etravirine is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and etravirine is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Fluconazole: (Moderate) Use caution if coadministration of trabectedin and fluconazole is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Fluoxetine: (Moderate) Use caution if coadministration of trabectedin and fluoxetine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and fluoxetine is a weak CYP3A inhibitor. According to the manufacturer, the inhibition of CYP3A4 by fluoxetine is not clinically significant; reported in vivo studies have been single dose. However, norfluoxetine (its active metabolite) is a moderate inhibitor of CYP3A4, and the possibility of clinically relevant drug interactions cannot be excluded. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Fluoxetine; Olanzapine: (Moderate) Use caution if coadministration of trabectedin and fluoxetine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and fluoxetine is a weak CYP3A inhibitor. According to the manufacturer, the inhibition of CYP3A4 by fluoxetine is not clinically significant; reported in vivo studies have been single dose. However, norfluoxetine (its active metabolite) is a moderate inhibitor of CYP3A4, and the possibility of clinically relevant drug interactions cannot be excluded. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Flutamide: (Minor) Use caution if coadministration of trabectedin and flutamide is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, flutamide is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Fluvoxamine: (Major) Avoid the concomitant use of trabectedin with fluvoxamine due to significantly increased trabectedin exposure. If short-term fluvoxamine (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and fluvoxamine is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Fosamprenavir: (Major) Avoid the concomitant use of trabectedin with fosamprenavir due to significantly increased trabectedin exposure. If short-term fosamprenavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and fosamprenavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. Fosamprenavir is also a moderate CYP3A inducer; coadministration with rifampin, a strong CYP3A inducer, decreased trabectedin exposure by 31%.
    Fosphenytoin: (Major) Avoid the concomitant use of trabectedin with fosphenytoin due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Grapefruit juice: (Major) Avoid the concomitant use of trabectedin with grapefruit juice due to significantly increased trabectedin exposure. Trabectedin is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Griseofulvin: (Moderate) Use caution if coadministration of trabectedin and griseofulvin is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, griseofulvin is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Idelalisib: (Major) Avoid the concomitant use of trabectedin with idelalisib due to significantly increased trabectedin exposure. If short-term idelalisib (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Imatinib: (Moderate) Use caution if coadministration of trabectedin and imatinib, STI-571 is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Indinavir: (Major) Avoid the concomitant use of trabectedin with indinavir due to significantly increased trabectedin exposure. If short-term indinavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Isavuconazonium: (Moderate) Use caution if coadministration of trabectedin and isavuconazonium is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Isoniazid, INH: (Moderate) Use caution if coadministration of trabectedin and isoniazid, INH is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and isoniazid is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of trabectedin with rifampin due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days) decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. (Moderate) Use caution if coadministration of trabectedin and isoniazid, INH is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and isoniazid is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of trabectedin with rifampin due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days) decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. (Moderate) Use caution if coadministration of trabectedin and isoniazid, INH is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and isoniazid is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Itraconazole: (Major) Avoid trabectedin use during and for 2 weeks after discontinuation of itraconazole treatment. If short-term itraconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of trabectedin by 66%.
    Ivacaftor: (Moderate) Use caution if coadministration of trabectedin and ivacaftor is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ivacaftor is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Ketoconazole: (Major) Avoid the concomitant use of trabectedin with ketoconazole due to significantly increased trabectedin exposure. If short-term ketoconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days) increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Lapatinib: (Moderate) Use caution if coadministration of trabectedin and lapatinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and lapatinib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of trabectedin; monitor for potential reduction in efficacy. Trabectedin is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of trabectedin; monitor for potential reduction in efficacy. Trabectedin is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to significantly increased trabectedin exposure. If short-term ritonavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of trabectedin with lumacaftor; ivacaftor due to significantly increased trabectedin exposure. If short-term lumacaftor; ivacaftor (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and lumacaftor is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Moderate) Use caution if coadministration of trabectedin and ivacaftor is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ivacaftor is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of trabectedin with lumacaftor; ivacaftor due to significantly increased trabectedin exposure. If short-term lumacaftor; ivacaftor (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and lumacaftor is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Mephobarbital: (Major) Avoid the concomitant use of trabectedin with mephobarbital due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and mephobarbital is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Metyrapone: (Moderate) Use caution if coadministration of trabectedin and metyrapone is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and metyrapone is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Mifepristone, RU-486: (Moderate) Use caution if coadministration of trabectedin and mifepristone, RU-486 is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, mifepristone is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Mirabegron: (Moderate) Use caution if coadministration of trabectedin and mirabegron is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and mirabegron is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Mitotane: (Major) Avoid the concomitant use of mitotane with trabectedin; if coadministration cannot be avoided, monitor for decreased efficacy of trabectedin. Mitotane is a strong CYP3A4 inducer and trabectedin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of trabectedin. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Modafinil: (Moderate) Use caution if coadministration of trabectedin and modafinil is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and modafinil is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Nafcillin: (Minor) Use caution if coadministration of trabectedin and nafcillin is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, nafcillin is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Nefazodone: (Major) Avoid the concomitant use of trabectedin with nefazodone due to significantly increased trabectedin exposure. If short-term nefazodone (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Nelfinavir: (Major) Avoid the concomitant use of trabectedin with nelfinavir due to significantly increased trabectedin exposure. If short-term nelfinavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Netupitant; Palonosetron: (Moderate) Netupitant; palonosetron is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and may be used in combination with trabectedin. However, use caution and monitor for a possible increase in non-emetogenic trabectedin-related adverse effects. Trabectedin is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Nevirapine: (Moderate) Use caution if coadministration of trabectedin and nevirapine is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and nevirapine is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Nicardipine: (Minor) Use caution if coadministration of trabectedin and nicardipine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, nicardipine is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/metered squared) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Nilotinib: (Moderate) Use caution if coadministration of trabectedin and nilotinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Octreotide: (Moderate) Use caution if coadministration of trabectedin and octreotide is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; octreotide suppresses growth hormone secretion, which may cause a decrease in the metabolic clearance of drugs metabolized by CYP3A4. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to significantly increased trabectedin exposure. If short-term ritonavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Oxcarbazepine: (Moderate) Use caution if coadministration of trabectedin and oxcarbazepine is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and oxcarbazepine is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducer.
    Palbociclib: (Moderate) Use caution if coadministration of trabectedin and palbociclib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and palbociclib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Pantoprazole: (Minor) Use caution if coadministration of trabectedin and pantoprazole is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, pantoprazole is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Pazopanib: (Moderate) Use caution if coadministration of trabectedin and pazopanib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and pazopanib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Pentobarbital: (Major) Avoid the concomitant use of trabectedin with pentobarbital due to the potential for significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate. Barbiturates are known to induce hepatic CYP isoenzymes; most data describing barbiturate drug interactions have been documented with phenobarbital, a strong CYP3A inducer. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Phenobarbital: (Major) Avoid the concomitant use of trabectedin with phenobarbital due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Phenytoin: (Major) Avoid the concomitant use of trabectedin with phenytoin due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Pirfenidone: (Minor) Use caution if coadministration of trabectedin and pirfenidone is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, pirfenidone is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Posaconazole: (Major) Avoid the concomitant use of trabectedin with posaconazole due to significantly increased trabectedin exposure. If short-term posaconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Primidone: (Major) Avoid the concomitant use of trabectedin with primidone due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Quinine: (Moderate) Use caution if coadministration of trabectedin and quinine is necessary, due to the risk of altered trabectedin exposure. Trabectedin is a CYP3A substrate and quinine is a moderate CYP3A inhibitor and, in vitro, a CYP3A inducer. There are no specific recommendations for concomitant use of moderate CYP3A inhibitors or inducers with trabectedin. If concomitant use is necessary, monitor the patient closely for chemotherapeutic efficacy and adverse effects.
    Ranolazine: (Minor) Use caution if coadministration of trabectedin and ranolazine is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, ranolazine is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Regorafenib: (Minor) Use caution if coadministration of trabectedin and regorafenib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, regorafenib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Ribociclib: (Moderate) Use caution if ribociclib is coadministered with trabectedin, as the systemic exposure of trabectedin may increase resulting in trabectedin-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and trabectedin is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if ribociclib is coadministered with trabectedin, as the systemic exposure of trabectedin may increase resulting in trabectedin-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and trabectedin is a CYP3A4 substrate.
    Rifabutin: (Moderate) Use caution if coadministration of trabectedin and rifabutin is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Rifampin: (Major) Avoid the concomitant use of trabectedin with rifampin due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days) decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Rifapentine: (Moderate) Use caution if coadministration of trabectedin and rifapentine is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and rifapentine is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Rifaximin: (Minor) Use caution if coadministration of trabectedin and rifaximin is necessary, due to the potential risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, rifaximin is a CYP3A inducer; however, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A substrates in patients with reduced liver function who have elevated rifaximin concentrations. During pharmacokinetic studies, coadministration of a single dose of trabectedin with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    Ritonavir: (Major) Avoid the concomitant use of trabectedin with ritonavir due to significantly increased trabectedin exposure. If short-term ritonavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Saquinavir: (Major) Avoid the concomitant use of trabectedin with saquinavir due to significantly increased trabectedin exposure. If short-term saquinavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Simeprevir: (Moderate) Use caution if coadministration of trabectedin and simeprevir is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and simeprevir is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of trabectedin with St. John's Wort, hypericum perforatum due to significantly decreased trabectedin exposure. Trabectedin is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), another strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone.
    Streptogramins: (Major) Avoid the concomitant use of trabectedin with dalfopristin; quinupristin due to significantly increased trabectedin exposure. If short-term dalfopristin; quinupristin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and quinupristin is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Tamoxifen: (Moderate) Use caution if coadministration of trabectedin and tamoxifen is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; tamoxifen and some if its active metabolites are inhibitors of CYP3A. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Telaprevir: (Major) Avoid the concomitant use of trabectedin with telaprevir due to significantly increased trabectedin exposure. If short-term telaprevir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and telaprevir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Telithromycin: (Major) Avoid the concomitant use of trabectedin with telithromycin due to significantly increased trabectedin exposure. If short-term telithromycin (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and telithromycin is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and trabectedin is necessary, as the systemic exposure of trabectedin may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of trabectedin; consider increasing the dose of trabectedin if necessary. Trabectedin is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Ticagrelor: (Moderate) Use caution if coadministration of trabectedin and ticagrelor is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and ticagrelor is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tipranavir: (Major) Avoid the concomitant use of trabectedin with tipranavir due to significantly increased trabectedin exposure. If short-term tipranavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Trandolapril; Verapamil: (Moderate) Use caution if coadministration of trabectedin and verapamil is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Valproic Acid, Divalproex Sodium: (Moderate) Use caution if coadministration of trabectedin and valproic acid, divalproex sodium is necessary, due to the risk of altered trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, valproic acid is weak inhibitor and inducer of CYP3A. There are no specific recommendations for concomitant use of weak CYP3A inhibitors or inducers with trabectedin. If concomitant use is necessary, monitor the patient closely for chemotherapeutic efficacy and adverse effects.
    Verapamil: (Moderate) Use caution if coadministration of trabectedin and verapamil is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Voriconazole: (Major) Avoid the concomitant use of trabectedin with voriconazole due to significantly increased trabectedin exposure. If short-term voriconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Zafirlukast: (Minor) Use caution if coadministration of trabectedin and zafirlukast is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, zafirlukast is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, trabectedin may cause fetal harm when administered during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted; however, placental transfer of trabectedin was demonstrated in pregnant rats.

    It is not known whether trabectedin is present in human milk. Many drugs are excreted in human milk including antibodies. Due to the potential for serious adverse reactions in nursing infants from trabectedin, advise women to discontinue breast-feeding during treatment.

    MECHANISM OF ACTION

    Trabectedin causes alkylation by binding guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.

    PHARMACOKINETICS

    Trabectedin is administered by intravenous infusion; it is highly bound to plasma proteins (97%), independent of concentrations ranging from 10 to 100 ng/mL. The steady-state volume of distribution (Vd) is greater than 5,000 liters. The mean clearance is 31.5 L/hour (CV%, 50%) and the terminal elimination half-life is approximately 175 hours. Trabectedin is extensively metabolized, with negligible unchanged drug in urine or feces. Trabectedin is not significantly renally excreted; in patients with solid tumors, 64% of a radiolabeled 3-hour or 24-hour dose was recovered in 24 days, with 6% in urine and 58% in feces.
     
    Affected cytochrome P450 (CYP) isoenzymes: CYP3A
    CYP3A is the predominant enzyme responsible for the hepatic metabolism of trabectedin. In vitro, trabectedin has limited inhibition or induction potential of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

    Intravenous Route

    The pharmacokinetics of trabectedin are characterized by a rapid decline phase at the end of the infusion, and slower exponential phases. Based on population pharmacokinetic analyses, the pharmacokinetics are dose-proportional over a range of 0.024 to 1.8 mg/m2; exposure is time-dependent. Plasma accumulation of trabectedin is not observed when administered every 3 weeks.