Yondelis

Get emergency medical help if you have signs of an allergic reaction: hives; chest tightness, wheezing, difficult breathing; feeling light-headed; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• pain, burning, irritation, or skin changes where the injection was given;
• heart problems--chest pain, fast or pounding heartbeats, shortness of breath (even with mild exertion), swelling, rapid weight gain;
• breakdown of muscle tissue--unexplained muscle pain, tenderness, or weakness (especially if you also have fever, unusual tiredness, and dark colored urine);
• liver problems--nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, easy bruising, unusual bleeding, feeling tired or light-headed.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• nausea, vomiting, loss of appetite;
• diarrhea, constipation;
• abnormal liver or kidney function tests;
• headache; or
• feeling short of breath.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Yondelis is part of the drug class:

• Other plant alkaloids and natural products

Serious side effects have been reported with Yondelis. See the “Yondelis Precautions” section.

Common side effects of Yondelis include the following:

• nausea
• fatigue
• vomiting
• diarrhea
• constipation
• decreased appetite
• shortness of breath
• headache,
• tissue swelling (peripheral edema)
• a decrease in infection-fighting white blood cells (neutropenia)
• low blood platelet counts (thrombocytopenia)
• low red blood cell count (anemia)
• elevated liver enzymes and decreases in albumin, a protein found in blood.  

This is not a complete list of Yondelis side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• medications that block a protein in the body (CYP3A4) such as some macrolide antibiotics (clarithromycin, telithromycin), some HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (boceprevir, telaprevir), some azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan (Vaprisol), delavirdine (Rescriptor), and nefazodone

• medications that increase the activity of the enzyme CYP3A4 such as carbamazepine (Tegretol, Equetro, Carbatrol), phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), St John's wort, and nimodipine (Nimotop)

This is not a complete list of Yondelis drug interactions. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Yondelis including the following:

Severe infections due to decreased white blood cells. Serious infections can occur with Yondelis due to a low number of white blood cells that typically fight infections. Your healthcare provider will perform blood tests to check your white blood cell count and may lower your dose or stop treatment with Yondelis completely if you develop this side effect. Call your doctor immediately if you develop signs of an infection such as a fever, chills, sore throat, or ongoing cough and congestion.

Rhabdomyolysis (severe muscle problems). Yondelis can cause serious muscle problems. Your doctor will perform blood tests to monitor your level of CPK, which can indicate muscle damage if high. Tell your doctor immediately if you experience any of the following signs or symptoms:

• muscle pain
• muscle weakness
• dark urine
• general weakness
• decreased urine output

Liver problems, including liver failure. Tell your healthcare provider right away if you experience any of the following signs or symptoms of liver damage:

• loss of appetite or start losing weight (anorexia)
• nausea or vomiting
• feel tired
• stomach pain or tenderness
• dark urine or light colored stools
• yellowing of your skin or the whites of your eyes
• fever or rash

Heart muscle problems, including heart failure. Your doctor will check your heart function before starting Yondelis and during treatment. Tell your doctor immediately if you start having any of the following signs or symptoms:

• chest pain
• trouble breathing
• swelling of your legs, ankles, or feet
• feel like your heart is racing or fluttering

Leakage of Yondelis out of your vein during an infusion. Serious tissue damage can occur if Yondelis leaks out of your vein when you are receiving an infusion. Immediately alert your physician if you experience redness, itching, swelling, or pain at the site where you are receiving your infusion of Yondelis.

Allergic reactions. 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.

Do not receive Yondelis if you are allergic to Yondelis or to any of its ingredients.

If Yondelis is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Alkylating antineoplastic agent; a synthetic alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata.1 14 20 21 22 26 28

General

• To help prevent nausea and vomiting and reduce the risk of hepatotoxicity, premedicate with dexamethasone phosphate 20 mg IV 30 minutes before each trabectedin infusion.1 3 9 28 May administer additional antiemetics as needed.9 28

• Monitor neutrophil count prior to administration of each dose of trabectedin and periodically thereafter.1 (See Neutropenic Sepsis under Cautions.)

• Monitor serum CK concentrations and liver function tests prior to administration of each dose of trabectedin.1 (See Rhabdomyolysis and also see Hepatic Toxicity under Cautions.)

• Assess left ventricular ejection fraction (LVEF) by echocardiogram or multiple gated acquisition (MUGA) scan prior to initiation of trabectedin and at 2- to 3-month intervals thereafter.1 (See Cardiomyopathy under Cautions.)

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Restricted Distribution Program

• Available only through specialty distributors.5 Consult the Yondelis website for specific availability information (http://www.yondelis.com/ordering).5

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by continuous IV infusion over 24 hours through central venous line; use an infusion set with a 0.2-mcm polyethersulfone inline filter.1

Do not admix with other drugs.1

Trabectedin powder for injection must be reconstituted and diluted prior to administration.1 Complete infusion within 30 hours following initial reconstitution.1 (See Storage under Stability.)

Diluted solutions are compatible with type I colorless glass vials; PVC and polyethylene bags and tubing; polyethylene and polypropylene mixture bags; polyethersulfone inline filters; titanium, platinum, or plastic ports; silicone and polyurethane catheters; and infusion pumps having contact surfaces made of PVC, polyethylene, or polyethylene/polypropylene.1

Reconstitute vial containing 1 mg of trabectedin with 20 mL of sterile water for injection to provide a solution containing 0.05 mg/mL.1 Shake vial to ensure complete dissolution.1 Discard any partially used vials.1

Dilute appropriate dose in 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 Discard any unused solution.1

Administer over 24 hours.1

Dosage

Adults

1.5 mg/m2 every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

When dosage modification is required, initially reduce dosage to 1.2 mg/m2 every 3 weeks.1 If further dosage reduction is necessary, reduce dosage to 1 mg/m2 every 3 weeks.1

If a dosage of 1 mg/m2 every 3 weeks requires further reduction, permanently discontinue the drug.1

Do not re-escalate dosage following dosage reduction.1

Permanently discontinue therapy if persistent adverse reactions requiring a treatment delay of >3 weeks occur.1

For ANC <1500/mm3 or platelet count <100,000/mm3, interrupt therapy for up to 3 weeks, and then resume at the same dosage.1

If ANC <1000/mm3 and signs or symptoms of infection (e.g., fever) occurred during preceding cycle, reduce dosage.1

If ANC <500/mm3 for >5 days occurred during preceding cycle, reduce dosage.1

If platelet counts <25,000/mm3 occurred during preceding cycle, reduce dosage.1

If life-threatening or prolonged and severe neutropenia occurred during preceding cycle, permanently reduce dosage.1

If total bilirubin concentrations exceeding the ULN or serum hepatic aminotransferase (ALT or AST) or alkaline phosphatase concentrations >2.5 times ULN occur, interrupt therapy for up to 3 weeks, and then resume at the same dosage.1

If total bilirubin concentrations exceeding the ULN, AST or ALT concentrations >5 times ULN, or alkaline phosphatase concentrations >2.5 times ULN occurred during preceding cycle, reduce dosage.1

If severe hepatic dysfunction (total bilirubin concentrations ≥2 times ULN and AST or ALT concentrations ≥3 times ULN with alkaline phosphatase concentrations <2 times ULN) occurred during preceding cycle, permanently discontinue therapy.1

For CK concentrations >2.5 times ULN, interrupt therapy for up to 3 weeks and then resume at the same dosage.1

If CK concentrations >5 times ULN occurred during preceding cycle, reduce dosage.1

If rhabdomyolysis occurs, permanently discontinue therapy.1

If LVEF decreases to less than the lower limit of normal (LLN) or clinical evidence of cardiomyopathy occurs, interrupt therapy for up to 3 weeks and then resume at the same dosage.1

If LVEF decreased below the LLN with absolute decrease from baseline of ≥10% or clinical evidence of cardiomyopathy occurred during preceding cycle, reduce dosage.1

If symptomatic cardiomyopathy or prolonged left ventricular dysfunction (LVEF does not recover to LLN within 3 weeks) occurs, permanently discontinue therapy.1

For any other grade 3 or 4 nonhematologic adverse effects, interrupt therapy for up to 3 weeks, and then resume at the same dosage.1

If any other grade 3 or 4 nonhematologic adverse effects occurred during preceding cycle, reduce dosage.1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with normal serum bilirubin concentrations and serum ALT or AST concentrations up to 2.5 times the ULN1 or in those with liver metastases.3

Serum bilirubin concentrations exceeding the ULN or aminotransferase (ALT or AST) concentrations >2.5 times the ULN: Use not recommended.1 Manufacturer does not provide specific dosage recommendations for patients with serum bilirubin concentrations above the ULN.1 3 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild (Clcr 60–89 mL/minute) or moderate (Clcr of 30–59 mL/minute) renal impairment: No dosage adjustment required.1

Severe renal impairment or end-stage renal disease: Pharmacokinetics not studied; manufacturer does not provide specific dosage recommendations.1

Geriatric Patients

No specific dosage recommendations at this time.1

• Synthetic tetrahydroisoquinoline alkaloid originally isolated from the marine ascidian Ecteinascidia turbinata.1 3 14 20 21 22 26

• Alkylating antineoplastic agent; forms covalent adducts with guanine residues in the minor groove of DNA, bending the helix towards the major groove.1 16 20 21 22 26

• Appears to affect function of DNA binding proteins, including transcription factors and DNA repair pathways, thereby inducing G2/M phase arrest, blocking progression of cells from the S phase, and subsequently inducing cell growth arrest and apoptosis.1 2 21 22 26

• Demonstrated antiproliferative activity in vitro and in vivo against a range of human tumor cell lines and experimental tumors, including sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer, and melanoma.9

• Importance of reading the manufacturer's patient information.1

• Risk of myelosuppression.1 Importance of monitoring ANC prior to each dose of trabectedin and periodically throughout treatment cycle.1 Importance of promptly informing clinician if fever, unusual bruising, bleeding, fatigue, or pallor occurs.1

• Risk of rhabdomyolysis.1 Importance of monitoring CK concentrations.1 Advise patients to promptly inform clinician if they experience severe muscle pain or weakness.1

• Risk of hepatotoxicity.1 Importance of monitoring liver function tests prior to each dose of trabectedin.1 Importance of immediately contacting clinician if possible manifestations of hepatotoxicity (e.g., jaundice, abdominal pain [particularly in the right upper quadrant], severe nausea or vomiting, difficulty concentrating, disorientation, confusion) occur.1

• Risk of cardiomyopathy.1 Importance of cardiac monitoring before initiating trabectedin and periodically during therapy.1 Importance of immediately contacting a clinician if new-onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations occur.1

• Risk of hypersensitivity reactions.1 Advise patients to seek immediate medical attention if symptoms of an allergic reaction (e.g., difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips, rash) occur.1

• Risk of extravasation.1 Importance of contacting a clinician if redness, swelling, pruritus, or discomfort or leakage at the injection site occurs.1

• Risk of fetal harm.1 Necessity of advising women of childbearing potential to use effective contraception during trabectedin therapy and for at least 2 months after the last dose of the drug.1 Necessity of advising men who are partners of such women that they should use effective contraception during trabectedin therapy and for at least 5 months after the last dose of the drug.1 If pregnancy occurs, advise patient of potential risk to the fetus.1

• Importance of advising women to avoid breast-feeding while receiving trabectedin.1 (See Lactation under Cautions.)

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.1

• Importance of advising patients to avoid grapefruit during trabectedin therapy.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You will need to have heart function tests while taking this medicine (Yondelis). Talk with the doctor.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• Low white blood cell counts have happened with drugs like this one. This may lead to a higher chance of getting an infection. Deadly infections have rarely happened. Tell your doctor if you have ever had a low white blood cell count. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• Avoid grapefruit and grapefruit juice.
• This medicine may cause a very bad and sometimes deadly problem called capillary leak syndrome (CLS). CLS may lead to low blood pressure and harm to the body. It may also lead to a heartbeat that is not normal, chest pain or pressure, heart attack, lung or breathing problems, bleeding or lower blood flow in the stomach or bowel, kidney problems, swelling, or feeling confused. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 5 months after care ends. Use birth control that you can trust.
• If you are a man and your sex partner gets pregnant within 5 months after your care has ended, call your doctor right away.
• This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking this medicine (Yondelis) and for at least 2 months after your last dose.
• If you get pregnant while taking this medicine or within 2 months after your last dose, call your doctor right away.

How Supplied

Yondelis is supplied in a 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

Yondelis is injected into a vein through a central line IV. A healthcare provider will give you this injection.

Before you receive a dose of Yondelis, you may need a blood test to check your liver function.

The infusion must be given slowly and can take up to 24 hours to complete.

Yondelis is usually given once every 3 weeks. Your doctor will determine how long to treat you with this medicine.

You may be given steroid medication to prevent certain side effects of Yondelis.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when Yondelis is injected.

Yondelis can lower blood cells that help your body fight infections and help your blood to clot. Serious and sometimes fatal infections may occur during treatment with trabectedin. Your blood will need to be tested often.

Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

Applies to trabectedin: intravenous powder for injection

Hepatic

Very common (10% or more): Increased ALT (up to 96.1%), increased AST (up to 89.5%), increased alkaline phosphatase (up to 70%), hyperbilirubinemia (up to 25.2%), increased gamma-glutamyltransferase (% unavailable)
Common (1% to 10%): Drug-induced liver injury
Uncommon (0.1% to 1%): Hepatotoxicity
Frequency not reported: Hepatic failure, increased conjugated bilirubin[Ref]

Hematologic

Very common (10% or more): Anemia (up to 96%), neutropenia (up to 91.6%), leukopenia (up to 94.9%), thrombocytopenia (up to 63.7%)
Common (1% to 10%): Febrile neutropenia, neutropenic sepsis, pancytopenia, bone marrow failure, granulocytopenia
Uncommon (0.1% to 1%): Neutropenic infection[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 75%), vomiting (up to 51.7%), constipation (up to 37%), diarrhea (up to 35%), stomatitis (up to 19.2%),
Common (1% to 10%): Abdominal pain, dyspepsia, upper abdominal pain[Ref]

Other

Very common (10% or more): Fatigue/asthenia/malaise (up to 69%), peripheral edema (up to 28%), mucosal inflammation (up to 11.4%), pyrexia (up to 10.2%)
Common (1% to 10%): Infection, edema, injection site reaction
Uncommon (0.1% to 1%): Septic shock
Frequency not reported: Multi-organ failure, catheter site reactions
Postmarketing reports: Extravasation/tissue necrosis[Ref]

Metabolic

Very common (10% or more): Hypoalbuminemia (up to 63%), decreased appetite (up to 37%), anorexia (up to 28.8%)
Common (1% to 10%): Dehydration, hypokalemia, decreased weight[Ref]

Renal

Very common (10% or more): Increased creatinine (up to 46%)
Common (1% to 10%): Renal failure[Ref]

Musculoskeletal

Very common (10% or more): Elevated creatine phosphokinase (up to 33%), arthralgia (up to 15%), myalgia (up to 12%)
Common (1% to 10%): Back pain
Uncommon (0.1% to 1%): Rhabdomyolysis
Frequency not reported: Musculoskeletal pain[Ref]

Respiratory

Very common (10% or more): Dyspnea (up to 25%)
Common (1% to 10%): Cough, pulmonary embolism
Uncommon (0.1% to 1%): Pulmonary edema[Ref]

Nervous system

Very common (10% or more): Headache (up to 25%)
Common (1% to 10%): Peripheral neuropathy, dysgeusia, dizziness, paresthesia
Uncommon (0.1% to 1%): Syncope
Frequency not reported: Hypoesthesia[Ref]

Dermatologic

Very common (10% or more): Palmar-plantar erythrodysesthesia (up to 24%), alopecia (up to 12%)
Common (1% to 10%): Rash, skin hyperpigmentation[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 15%)[Ref]

Cardiovascular

Common (1% to 10%): Cardiomyopathy, decreased ejection fraction, hypotension, flushing
Uncommon (0.1% to 1%): Left ventricular dysfunction[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity reactions[Ref]

Some side effects of Yondelis may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.