Trabectedin

Trabectedin is used for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen.

Trabectedin is available under the following different brand names: Yondelis.

Dosages of Trabectedin:

Dosage Forms and Strengths

Lyophilized Powder for Reconstitution

• 1 mg/vial

Dosage Considerations – Should be Given as Follows:

Soft Tissue Sarcoma

• Indicated for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen
• Premedicate with dexamethasone before each dose
• 1.5 mg/m² intravenously (IV) every 3 weeks until disease progression or unacceptable toxicity
• Infuse over 24 hours via a central venous line
• Note: Patients must have normal bilirubin and AST or ALT up to 2.5 x ULN; there is no recommended dose in patients with serum bilirubin levels above the institutional ULN

Dosage Modifications

Bilirubin greater than ULN: Not studied

Hepatic impairment

• Moderate hepatic impairment (bilirubin levels 1.5 times to 3 times upper limit of normal, and AST and ALT less than 8 times upper limit of normal): 0.9 mg/m²

Renal impairment

• Mild-to-moderate (CrCl 30-89 mL/minute): No dose adjustment required
• Severe (CrCl less than 30 mL/minute) or ESRD: Not studied

Permanently discontinue

• Persistent adverse reactions requiring a delay in dosing of more than 3 weeks
• Adverse reactions requiring dose reduction following the dose of 1 mg/m²
• Severe liver dysfunction including all of the following in the prior treatment cycle
  • Severe hepatic impairment (bilirubin levels greater than 3 times to 10 times upper limit of normal, AND
  • AST or ALT 3 x ULN, WITH
  • Alkaline phosphatase less than 2 x ULN

Dose reductions

• First dose reduction: 1.2 mg/m² every 3 weeks
• Second dose reduction: 1 mg/m² every 3 weeks

Delay next dose for up to 3 weeks

• Platelets: less than 100,000 platelets/mc
• Absolute neutrophil count (ANC): less than 1500 neutrophils/mcL
• Total bilirubin: greater than ULN AST or ALT: greater than 2.5 x ULN
• Alkaline phosphatase: greater than 2.5 x ULN
• Creatinine phosphate (CPK): greater than 2.5 x ULN
• Decreased LVEF: Less than the lower limit of normal or clinical evidence of cardiomyopathy
• Other nonhematologic adverse reactions: Grade 3 or 4

Reduce next dose by one dose level for adverse reaction(s) during the prior cycle

• Platelets: less than 25,000 platelets/mcL
• ANC: less than 1000 neutrophils/mcL with fever/infection
• ANC: less than 500 neutrophils/mcL lasting greater than 5 days
• AST or ALT: greater than 5 x ULN Total bilirubin: greater than ULN
• Alkaline phosphatase: greater than 5 x ULN
• CPK: greater than 5 x ULN
• Decreased LVEF: Absolute decrease of 10% or greater from baseline and less than the lower limit of normal, or clinical evidence of cardiomyopathy
• Other nonhematologic adverse reactions: Grade 3 or 4

Safety and efficacy not established in pediatric patients.

Common side effects of trabectedin include:

• Nausea
• Fatigue
• Vomiting
• Constipation
• Decreased appetite
• Diarrhea
• Swelling of extremities
• Shortness of breath
• Headache
• Joint pain
• Insomnia
• Muscle pain

Laboratory abnormalities

• Anemia
• Increased ALT
• Increased AST
• Increased alkaline phosphatase
• Low white blood cell count (neutropenia)
• Hypoalbuminemia
• Low platelet count (thrombocytopenia)
• Increased creatinine
• Increased CPK
• Hyperbilirubinemia

Postmarketing side effects of trabectedin reported include:

• Capillary leak syndrome

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

Trabectedin has no listed severe interactions with other drugs.

Trabectedin has serious interactions with at least 51 different drugs.

Trabectedin has moderate interactions with at least 44 different drugs.

Trabectedin has no listed mild interactions with other drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

This medication contains trabectedin. Do not take Yondelis if you are allergic to trabectedin or any ingredients contained in this drug.

Contraindications

• Known hypersensitivity, including anaphylaxis, to trabectedin

Effects of Drug Abuse

• No information available

Short-Term Effects

• See "What Are Side Effects Associated with Using Trabectedin?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Trabectedin?"

Cautions

• Neutropenic sepsis, including fatal cases, were reported during clinical trials; assess neutrophil count before administration of each dose and periodically throughout the treatment cycle
• May cause rhabdomyolysis and musculoskeletal toxicity; assess CPK levels before each administration; reduce dose, or permanently discontinue based on the severity of the adverse reaction
• Hepatotoxicity, including hepatic failure, was reported during clinical trials
• Assess liver function tests (LFTs) before each administration and as clinically indicated based on underlying severity of pre-existing hepatic impairment; manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality; not for administration to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT); reduce dose in patients with moderate hepatic impairment
• Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction, can occur; discontinue treatment based on the severity of the adverse reaction
• Extravasation, resulting in tissue necrosis, requiring debridement, can occur; evidence of tissue necrosis can occur more than 1 week after the extravasation; there is no specific antidote for extravasation of trabectedin; administer through a central venous line
• Capillary leak syndrome (CLS) characterized by hypotension, edema, and hypoalbuminemia reported, including serious CLS resulting in death; monitor for signs and symptoms of CLS; discontinue therapy and promptly initiate standard management for patients with CLS, which may include a need for intensive Care
• Based on its mechanism of action, can cause fetal harm when administered to a pregnant woman

Coadministration with strong CYP3A inhibitors and inducers

• Trabectedin is a CYP3A substrate
• Avoid coadministration with strong CYP3A inhibitors or inducers
• Clinical trials showed systemic exposure of trabectedin increased by 66% with ketoconazole, a strong CYP3A inhibitor
• Coadministration with rifampin, a strong CYP3A inducer, decreased the systemic exposure of trabectedin by 31%

Risk of infections

• May increase risk of infection; upper respiratory tract infections, oral candidiasis, conjunctivitis, and tinea infections reported
• Instruct patients to seek medical advice if signs or symptoms of infection occur
• If a serious infection develops or infection is not responding to standard therapy, monitor the patient closely and discontinue therapy until the infection resolves

Tuberculosis evaluation

• Evaluate patients for TB before initiating treatment
• Do not administer to patients with active TB
• Initiate treatment of latent TB before administering therapy
• Consider anti-TB therapy before initiating in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed
• Monitor closely for signs and symptoms of active TB during and after treatment

Drug interaction overview

• Before initiating drug, consider completion of all age-appropriate immunizations; avoid the use of live vaccines; no data are available on the response to live vaccines while taking trabectedin
• Altering CYP450 enzymes
  • The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF-alpha, IFN) during chronic inflammation; thus, trabectedin, an IL-17A antagonist, could normalize the formation of CYP450 enzymes
  • Upon initiating or discontinuing trabectedin in patients receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., warfarin) or drug concentration (e.g., cyclosporine) and consider dosage modification of the CYP450 substrate

Pregnancy and Lactation

Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy. There are no available data on trabectedin use during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats.

Female patients of reproductive potential are advised to use effective contraception during treatment with trabectedin and for 2 months after the last dose. Trabectedin may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Males with a female sexual partner of reproductive potential are advised to use effective contraception during treatment with trabectedin and for 5 months after the last dose. Trabectedin use may result in decreased fertility in males and females.

It is unknown if trabectedin is distributed in human breast milk. Because of the potential for serious adverse reactions from trabectedin in breastfed infants, nursing women to are advised discontinue breastfeeding during treatment.