DRUG INTERACTIONS-(summary)

 CYP3A inhibitors: Avoid concomitant strong CYP3A inhibitors (7.1) ? CYP3A inducers: Avoid concomitant strong CYP3A inducers

DRUG INTERACTIONS -(details)

1. Effect of Cytochrome CYP3A Inhibitors Coadministration of YONDELIS with ketoconazole, a strong CYP3A inhibitor, increases systemic exposure of trabectedin by 66%

. Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS.

Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. If a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion [see Clinical Pharmacology (12.3)].

2. Effect of Cytochrome CYP3A Inducers Coadministration of YONDELIS with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%. Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS 

.

31/15 PRODUCT DETAILS 

Name of the drug-      YONDELIS

Active ingriendents-   Trabectedin

FDA approved use-    To treat specific soft tissue sarcomas(STS)- iposarcoma that cannot be removed by surgery (unresctable) or advanced (metastatic                                                                                                                       

 Date of Approval         10/23/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                             YONDELIS® safely and effectively.

See full prescribing information for YONDELIS. YONDELIS (trabectedin) for injection, for intravenous use

Initial U.S. Approval: 2015 -

INDICATIONS AND USAGE-

 YONDELIS is an alkylating drug indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen

ADVERSE REACTIONS-

The most common (=20%) adverse reactions are nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, headache.

The most common (5%) grades 3-4 laboratory abnormalities are: neutropenia, increased ALT, thrombocytopenia, anemia, increased AST, and increased creatine phosphokinase.

CONTRAINDICATIONS-

 Known hypersensitivity to trabectedin

WARNINGS AND PRECAUTIONS-

 Neutropenic sepsis: Severe, and fatal, neutropenic sepsis may occur. Monitor neutrophil count during treatment.

Withhold YONDELIS for Grade 2 or greater neutropenia

 Rhabdomyolysis: Rhabdomyolysis may occur; withhold YONDELIS for severe or life-threatening increases in creatine phosphokinase level 

Hepatotoxicity: Hepatotoxicity may occur. Monitor and delay and/or reduce dose if needed

Cardiomyopathy: Severe and fatal cardiomyopathy can occur. Withhold YONDELIS in patients with left ventricular dysfunction

 Embryofetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use effective contraception

DOSAGE AND ADMINISTRATION-

 Administer at 1.5 mg/m2 body surface area as a 24-hour intravenous infusion, every 3 weeks through a central venous line

 Premedication: dexamethasone 20 mg IV, 30 min before each infusion

DOSAGE FORMS AND STRENGTHS-

 For injection: 1 mg sterile lyophilized powder in a single-dose vial

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness.

Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness. 

Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion.

Cardiomyopathy: Advise patients to contact their healthcare provider for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations.

Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash

Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site.

Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with YONDELIS

Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 2 months after last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 5 months after the last dose [see Warnings and Precautions (5.6) and Use in Specific Populations (8.3)].

Lactation: Advise females not to breastfeed during treatment with YONDELIS

Manufactured by: Baxter Oncology GmbH Halle/Westfalen Germany Manufactured for: Janssen Products, LP Horsham, PA © Janssen Products, LP. 2015 Under license from Pharma Mar, S.A.

CLINICAL PHARMACOLOGY

1 Mechanism of Action Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove.

Adduct 11 Reference ID: 3837231 formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.

2. Pharmacodynamics Cardiac Electrophysiology The effect of trabectedin on the QT/QTc interval was evaluated in 75 patients who received placebo on day 1 and trabectedin (1.3 mg/m2) as a 3-hour intravenous infusion on day 2.

No patients in the study showed a QTc interval exceeding 500 msec or more than 60 msec increase from baseline, and no large changes in the mean QTc interval (i.e., >20 msec) were observed.

3. Pharmacokinetics-                                                                                                       The pharmacokinetics of trabectedin is characterized by a rapid decline phase at the end of the infusion and slower exponential phases.

Population pharmacokinetic analyses suggest that the pharmacokinetics of trabectedin is dose-proportional (over the dose range of 0.024 to 1.8 mg/m2) and exposure is time-independent. No accumulation of trabectedin in plasma is observed upon repeated administrations every 3 weeks.

Distribution-                                                                                                                  Binding of trabectedin to human plasma proteins was approximately 97%, independent of trabectedin concentrations ranging from 10 ng/mL to 100 ng/mL. Steady state volume of distribution of trabectedin exceeds 5000 L.

Elimination-                                                                                                                         The estimated mean (% coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 175 hours.

Metabolism-                                                                                                                       CYP3A is the predominant CYP enzyme responsible for the hepatic metabolism of trabectedin. Trabectedin was extensively metabolized with negligible unchanged drug in urine and feces following administration of trabectedin to humans.

Excretion-                                                                                                                          In patients with solid tumors, following a 3-hour or a 24-hour intravenous infusion of 14C-labeled trabectedin, 64% of the total administered radioactive dose was recovered in 24 days, with 58% in feces and 6% in urine.

Specific Populations-                                                                                                    The following population characteristics are not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), body surface area (0.9 to 2.8 m2), or mild to moderate renal impairment.

The effect of any degree of 12 Reference ID: 3837231 hepatic impairment, severe renal impairment, or end stage renal disease on trabectedin exposure is unknown.

Drug Interactions-                                                                                                              Effect of Strong CYP3A Inhibitors on Trabectedin Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of YONDELIS (0.58 mg/m2) on day 1 increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to a single YONDELIS dose (1.3 mg/m2) given alone.

Effect of Strong CYP3A Inducers -                                                                                      on Trabectedin Coadministration of multiple doses of rifampin (600 mg daily for 6 days) with a single YONDELIS dose (1.3 mg/m2) on day 6 decreased trabectedin AUC by 31% and Cmax by 21% compared to a single YONDELIS dose (1.3 mg/m2) given alone.

Effect of Trabectedin -                                                                                                         on CYP Enzymes In vitro, trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4)

 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary-

Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy [see Clinical Pharmacology (12.1)].

There are no available data with the use of  YONDELIS during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats.

Advise pregnant woman of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

2 Lactation Risk Summary There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions from YONDELIS in breastfed infants, advise a nursing woman to discontinue nursing during treatment with YONDELIS.

3 Females and Males of Reproductive Potential Contraception Females Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of YONDELIS

 Males YONDELIS may damage spermatozoa, resulting in possible genetic and fetal abnormalities

. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of YONDELIS

 Infertility YONDELIS may result in decreased fertility in males and females

4. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

5. Geriatric Use Clinical studies of YONDELIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects

6. Hepatic Impairment The pharmacokinetics of trabectedin has not been evaluated in patients with a total bilirubin greater than the upper limit of normal

7. Renal Impairment No dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min] or moderate (CLcr of 30-59 mL/min) renal impairment. The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease 

 OVERDOSAGE-

There is no specific antidote for YONDELIS. Hemodialysis is not expected to enhance the elimination of YONDELIS because trabectedin is highly bound to plasma proteins (97%) and not significantly renally excreted.