YONDELIS (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Trabectedin is genotoxic in both in vitro and in vivo studies. Long-term carcinogenicity studies have not been performed.

Fertility studies with trabectedin were not performed. In male rats there were limited histopathological signs of hemorrhage and degeneration in the testes following repeated administration of trabectedin at doses approximately 0.2 times the 1.5 mg/m2 human dose based on body surface area.

14 CLINICAL STUDIES

The clinical efficacy and safety of YONDELIS in patients with metastatic or recurrent leiomyosarcoma or liposarcoma were demonstrated in Trial ET743-SAR-3007 (NCT01343277), a randomized (2:1), open-label, active-controlled trial comparing treatment with YONDELIS 1.5 mg/m2 as a 24-hour continuous intravenous infusion once every 3 weeks to dacarbazine 1000 mg/m2 intravenous infusion (20 to 120 minutes) once every 3 weeks. Treatment continued in both arms until disease progression or unacceptable toxicity; all patients in the YONDELIS arm were required to receive dexamethasone 20 mg intravenous injection prior to each YONDELIS infusion. Patients were required to have unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) and previous treatment with an anthracycline- and ifosfamide-containing regimen or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. Randomization was stratified by subtype of soft tissue sarcoma (leiomyosarcoma vs. liposarcoma), ECOG performance status (0 vs. 1), and number of prior chemotherapy regimens (1 vs. ≥2). The efficacy outcome measures were investigator-assessed progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), overall survival (OS), objective response rate (ORR), and duration of response (DOR). Patients in the dacarbazine arm were not offered YONDELIS at the time of disease progression.

A total of 518 patients were randomized, 345 to the YONDELIS arm and 173 patients to the dacarbazine arm. The median patient age was 56 years (range: 17 to 81); 30% were male; 76% White, 12% Black, and 4% Asian; 73% had leiomyosarcomas and 27% liposarcomas; 49% had an ECOG PS of 0; and 89% received ≥2 prior chemotherapy regimens. The most common (≥20%) pre-study chemotherapeutic agents administered were doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%). Approximately 10% of patients had received pazopanib.

Trial ET743-SAR-3007 demonstrated a statistically significant improvement in PFS. An exploratory analysis of independent radiology committee-determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. Efficacy results from Trial ET743-SAR-3007 are presented in the table below.

Table 5: Efficacy Results for Trial ET743-SAR-3007
Efficacy EndpointYONDELISN=345DacarbazineN=173
CR=Complete Response; PR=Partial Response; CI=Confidence Interval, HR=hazard ratio, NE=not estimable.
*
Cox proportional hazards model with treatment group as the only covariate.
Unstratified log rank test.
Based on 384 patients randomized to YONDELIS arm and 193 patients randomized to dacarbazine.
§
Fisher’s exact CI.
Progression-free survival
PFS Events, n (%)217 (63%)112 (65%)
Disease progression204109
Death133
Median (95% CI) (months)4.2 (3.0, 4.8)1.5 (1.5, 2.6)
HR (95% CI)*0.55 (0.44, 0.70)
p-value <0.001
Overall survival
Events, n (%)258 (67%)123 (64%)
Median (95% CI) (months)13.7 (12.2, 16.0)13.1 (9.1, 16.2)
HR (95% CI)*0.93 (0.75, 1.15)
p-value 0.49
Objective Response Rate (ORR: CR+PR)
Number of patients (%)23 (7%)10 (6%)
95% CI §(4.3, 9.8)(2.8, 10.4)
Duration of Response (CR+ PR)
Median (95% CI) (months)6.9 (4.5, 7.6)4.2 (2.9, NE)

Figure 1: Kaplan-Meier Curves of Progression-Free Survival in Trial ET743-SAR-3007

Figure 1
(click image for full-size original)

15 REFERENCES

1.
“OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

YONDELIS is supplied in a single-dose glass vial containing 1 mg trabectedin. Each carton contains one vial (NDC: 59676-610-01).

Storage and Handling

Store YONDELIS vials in a refrigerator at 2°C to 8°C (36°F to 46°F).

YONDELIS is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

17 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.

Capillary leak syndrome: Advise patients to report symptoms such as edema with or without hypotension [see Warnings and Precautions (5.5)].

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 [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

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 (5.7) and Use in Specific Populations (8.3)].

Lactation: Advise females not to breastfeed during treatment with YONDELIS [see Use in Specific Populations (8.2)].

Product of Spain

Manufactured by:
Baxter Oncology GmbH
Halle/Westfalen Germany

Manufactured for:
Janssen Products, LP Horsham, PA

© 2015 Janssen Pharmaceutical Companies

Under license from Pharma Mar, S.A.

PATIENT INFORMATIONYONDELIS® (yon-DEL-ess)(trabectedin)for injection
This Patient Information has been approved by the U.S. Food and Drug Administration. Revised 12/2017
What is YONDELIS? YONDELIS is a prescription medicine used to treat people with liposarcoma or leiomyosarcoma that:
  • cannot be treated with surgery or has spread to other areas of the body, and
  • who have received treatment with certain other medicines.
It is not known if YONDELIS is safe and effective in children.
Who should not receive YONDELIS?
  • You will not be given YONDELIS if you have had a severe allergic reaction to trabectedin, the active ingredient in YONDELIS. See the end of this leaflet for a complete list of ingredients in YONDELIS.
What should I tell my healthcare provider before receiving YONDELIS? Before receiving YONDELIS, tell your healthcare provider about all of your medical conditions, including if you:
  • have liver or kidney problems
  • are pregnant or plan to become pregnant. YONDELIS can harm your unborn baby. You should not become pregnant during treatment with YONDELIS.
    • Females who are able to become pregnant should use an effective form of birth control during treatment with YONDELIS and for 2 months after your last dose of YONDELIS.
    • Males should use an effective form of birth control when having sex with female partners who are able to become pregnant, during your treatment with YONDELIS and for 5 months after your last dose of YONDELIS.
  • are breastfeeding or plan to breastfeed. It is not known if YONDELIS passes into your breast milk.
You should not breastfeed during treatment with YONDELIS.Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive YONDELIS?
  • YONDELIS is given by an intravenous (IV) infusion into a vein over 24 hours. To help avoid irritation at the site where it is infused, YONDELIS is given to you into a large vein through a type of IV line called a central venous line.
  • YONDELIS is usually given every 3 weeks.
  • Your healthcare provider may decrease your dose or delay doses if you have certain side effects. If you have any side effects that are severe, your healthcare provider may stop your treatment with YONDELIS.
  • Before each treatment with YONDELIS, you will receive a steroid medicine to help reduce your risk of getting certain side effects.
  • Your healthcare provider will decide how long you will continue treatment with YONDELIS.
  • Your healthcare provider may do certain tests while you are receiving YONDELIS to check you for side effects, and to see how well you respond to the treatment.
What are the possible side effects of YONDELIS?YONDELIS may cause serious side effects, including:
  • Severe infections due to decreased white blood cells. Decreased low white blood cell count is common with YONDELIS, but it can also lead to severe infections and death. Your healthcare provider may need to decrease your dose of YONDELIS, delay or stop your treatment, if your white blood cell count is too low or you get a serious infection. Call your healthcare provider right away if you develop fever or other signs of infection.
  • Severe muscle problems (rhabdomyolysis). YONDELIS can cause muscle problems that can be severe and lead to death. Tell your healthcare provider right away if you have severe muscle pain or weakness.
  • Liver problems, including liver failure. Tell your healthcare provider right away if you get:
  • yellowing of your skin and whites of your eyes
  • pain in your upper right stomach-area (abdomen)
  • nausea
  • vomiting
  • generally do not feel well
  • problem with concentration
  • confusion
  • sleepiness
  • Heart muscle problems, including heart failure. Your healthcare provider will do a test to check your heart function before you start YONDELIS, and during treatment. If you develop heart muscle problems or heart failure during treatment with YONDELIS, your healthcare provider may stop your treatment. Tell your healthcare provider right away if you develop new chest pain, shortness of breath, tiredness, swelling of your legs, ankles, or feet, or heart palpitations.
  • Leakage of YONDELIS out of your vein during the infusion. If YONDELIS leaks into the tissues around your infusion site, it can cause damage and death of tissue cells around the infusion site. You may need to have surgery to remove any dead tissue. Tell your healthcare provider right away if you see any YONDELIS leaking out of your vein or around the catheter during your infusion, or if you notice any redness, swelling, itching or discomfort at the infusion site at any time.
  • Some people have had allergic reactions to YONDELIS. Some of these reactions were severe. Your healthcare provider may need to stop your treatment with YONDELIS, and may give you medicines to treat the allergic reaction. Signs of an allergic reaction can include: difficulty breathing, chest tightness, wheezing, swelling of the lips, or skin rash.
  • Capillary leak syndrome. YONDELIS can cause fluid to leak from the blood vessels into the body’s tissues. This condition is called “Capillary Leak Syndrome” (CLS). CLS can cause you to have symptoms that may lead to death. Tell your healthcare provider right away if you develop swelling, dizziness or lightheadedness with or without a sudden drop in blood pressure.
The most common side effects of YONDELIS include:
  • nausea
  • tiredness
  • vomiting
  • constipation
  • decreased appetite
  • diarrhea
  • swelling of your hands, ankles, or feet
  • shortness of breath
  • headache
  • decreased red cell count (cells which carry oxygen in the blood). Tell your healthcare provider if you feel more tired than usual or look pale.
  • decreased platelet cell counts (cells which help blood to clot). Tell your healthcare provider if you bruise easily or have bleeding.
  • changes in liver and kidney function blood tests
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of YONDELIS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of YONDELIS Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about YONDELIS that is written for health professionals.
What are the ingredients in YONDELIS?Active ingredient: trabectedinInactive ingredients: potassium dihydrogen phosphate, sucrose, phosphoric acid and potassium hydroxide.Product of Spain Manufactured by: Baxter Oncology GmbH, Halle/Westfalen Germany Manufactured for: Janssen Products, LP, Horsham, PA For more information, call 1-800-526-7736 or go to www.YONDELIS.com.

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