Trabectedin (Yondelis) is a chemotherapeutic drug (alkylating agent) that is used to treat soft tissue and ovarian tumors.

Indications of Trabectedin (Yondelis):

• Soft tissue sarcoma:
  • It is indicated for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma) in patients who have received a prior anthracycline-containing regimen [Ref].
• Off Label Use of Trabectedin in Adults:
  • Relapsed Ovarian cancer (platinum sensitive).

Trabectedin (Yondelis) dose in adults:

Before each treatment:

• Check blood counts. Make sure:
  • White blood cell count (ANC) is at least 1,500.
  • Platelet count is at least 100,000.
• Liver tests need to be in normal range or slightly higher (but not more than 2.5 times the normal).

Before the drug is given:

• Give dexamethasone (a medication) through an IV 30 minutes before.
• The drug can cause nausea. You might need more medication to help with that.

Trabectedin (Yondelis) dose in the treatment of unresectable/ metastatic Soft tissue sarcoma:

• The dose is given through an IV.
• It's 1.5 mg for every square meter of a person's body surface area.
• The infusion takes 24 hours.
• Repeat it every 3 weeks.
• Keep doing this until either the disease gets worse or the side effects are too much.

Trabectedin (Yondelis) dose in the treatment of relapsed platinum-sensitive Ovarian cancer (off-label):

• Trabectedin is given through an IV.
• The dose is 1.1 mg for every square meter of body surface area.
• It takes 3 hours for the infusion.
• Repeat it every 3 weeks.
• Keep doing this as long as it's helping the patient or until the disease gets worse.
• If there are side effects, treatment might be delayed, or the trabectedin dose might be reduced (first to 0.9 mg/m and then to 0.75 mg/m).
• If a second dose reduction isn't tolerated well, treatment might be stopped.

Use in children:

The safety and efficacy of the drug in children have not been established.

Trabectedin (Yondelis) Pregnancy Risk Category: D

• Trabectedin can harm an unborn baby if a pregnant person takes it.
• Before starting this treatment, doctors should check if a woman could become pregnant.
• Women who could become pregnant should use birth control while they're on this treatment and for at least 2 months after they stop taking it.
• Men who could make someone pregnant should also use birth control while on this treatment and for at least 5 months after they stop.
• Trabectedin might make it harder for both men and women to have children.

Use while breastfeeding

• It's uncertain if trabectedin gets into breast milk.
• Because of possible serious risks to a baby who is breastfed, it's suggested that mothers stop breastfeeding while taking trabectedin.

Trabectedin (Yondelis) Dose adjustment in renal disease:

• If your kidneys filter at least 30 mL/minute, you don't need to change the drug dose.
• If your kidneys filter less than 30 mL/minute or you have severe kidney disease, the drug company hasn't given any guidance on dosage because they haven't studied it in such cases.
• If you're on hemodialysis (a treatment for kidney failure), it won't remove trabectedin from your body.

Trabectedin (Yondelis) Dose adjustment in liver disease:

Before Starting Treatment:

• Mild liver issue (bilirubin slightly raised but not double): Regular dose is okay.
• Moderate liver issue (bilirubin raised more but not too high, and AST or ALT not super high): Lower the dose to 0.9 mg/m^2.
• Severe liver issue (really high bilirubin and any AST or ALT level): Don't use the drug.

If Liver Problems Occur During Treatment:

For patients who had mild or moderate liver issues at the start:

• Mild liver issue:
  • First lower the dose to 1.2 mg/m^2 every 3 weeks.
  • If more issues, then lower again to 1 mg/m^2 every 3 weeks.
• Moderate liver issue:
  • First lower the dose to 0.6 mg/m^2 every 3 weeks.
  • If more issues, then lower again to 0.3 mg/m^2 every 3 weeks.
• If bilirubin goes over the normal limit: Wait up to 3 weeks and then lower the dose.
• If AST or ALT goes up but isn't super high: Wait up to 3 weeks before the next dose.
• If AST or ALT gets really high or alkaline phosphatase rises: Wait up to 3 weeks and then lower the dose.

When to Stop the Drug Completely:

• Severe liver dysfunction: If certain liver tests go way above the normal range and you had normal liver function at the start: Stop the drug.
• Worsening liver function in those with moderate liver issue at the start: Stop the drug.
• Bad side effects at doses of 1 mg/m^2 (for those with normal or mild liver issues) or 0.3 mg/m^2 (for those with moderate liver issues) and need to lower the dose even more: Stop the drug.

Common Side Effects of Trabectedin (Yondelis):

• Cardiovascular:
  • Peripheral Edema
• Central Nervous System:
  • Fatigue
  • Headache
  • Insomnia
• Endocrine & Metabolic:
  • Hypoalbuminemia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Constipation
  • Decreased Appetite
  • Diarrhea
• Hematologic & Oncologic:
  • Anemia
  • Neutropenia
  • Thrombocytopenia
• Hepatic:
  • Increased Serum ALT
  • Increased Serum AST
  • Increased Serum Alkaline Phosphokinase
  • Hyperbilirubinemia
• Neuromuscular & Skeletal:
  • Increased Creatine Phosphokinase
  • Arthralgia
  • Myalgia
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Dyspnea

Uncommon Side Effects of Trabectedin (Yondelis):

• Cardiovascular:
  • Pulmonary Embolism
  • Cardiomyopathy
• Central Nervous System:
  • Hypoesthesia
  • Paresthesia
  • Peripheral Neuropathy

Rare side effects of Trabectedin (Yondelis):

• Hepatic:
  • Hepatic Failure
• Hypersensitivity:
  • Anaphylaxis

Contraindication to Trabectedin Include:

• Severe Allergic Reaction: If someone has had a severe allergic reaction (including anaphylaxis) to trabectedin or any part of the medication before, they shouldn't use it.

• Canada-Specific Contraindications: In Canada, trabectedin should not be used if there is an active, serious, or uncontrolled infection. Additionally, breastfeeding while taking trabectedin is not recommended in Canada. These specific contraindications may not apply in the United States.

Warnings/Precautions

Bone marrow suppression:

• Trabectedin can lead to problems in the bone marrow, which is responsible for making blood cells.
• This can cause:
  • Anemia (low red blood cell count),
  • Neutropenia (low white blood cell count, specifically neutrophils),
  • Thrombocytopenia (low platelet count).
• Sometimes, neutropenia can lead to fever and serious infections, which can even be fatal.
• The severe neutropenia typically starts around 16 days after starting the treatment and can last for about 13 days, but it can vary.
• Doctors need to check blood counts regularly, both before and during treatment.
• If these blood problems are severe, treatment might need to be stopped temporarily, or the dose might be reduced.

Capillary leak syndrome:

• CLS is a rare but serious condition that has been reported in some people who take trabectedin.
• Symptoms of CLS can include low blood pressure (hypotension), swelling (edema), and low levels of a protein called albumin in the blood (hypoalbuminemia).
• If someone shows signs or symptoms of CLS while taking trabectedin, doctors should stop the treatment and provide appropriate care.
• CLS can be severe and, in some cases, even fatal. So, it's crucial to monitor for these symptoms and act promptly if they occur.

Cardiovascular events:

• Trabectedin can affect the heart, leading to cardiomyopathy, which includes problems like heart failure, reduced ejection fraction (how well the heart pumps blood), diastolic dysfunction (a problem with heart relaxation), or right ventricular dysfunction (problems with the right side of the heart).
• Some of these heart issues can be quite severe (grades 3 and 4).
• These heart problems typically appear around 5 months after starting the treatment, but the timing can vary.
• The risk of heart issues might be higher in people who have:
  • A low left ventricular ejection fraction (LVEF) before starting treatment.
  • Received a high lifetime dose of another chemotherapy drug called anthracycline (300 mg/m^2 or more).
  • Are over the age of 65.
  • Have a history of heart problems.
• Doctors should regularly check the LVEF with tests like echocardiograms or MUGA scans before and during trabectedin treatment (every 2 to 3 months) until the treatment ends.
• If someone develops severe heart problems (grade 3 or 4 cardiomyopathy) or if their LVEF drops below the normal range, the treatment should be stopped permanently.
• People with a history of moderate to severe heart failure or abnormal LVEF were not included in the sarcoma study for this medication.

Extravasation:

• Trabectedin is a strong medicine that can harm the tissues if it leaks out of the vein during the infusion. This is called extravasation.
• To prevent this, doctors should make sure the needle or catheter used for the infusion is placed correctly.
• Ideally, trabectedin should be given through a central line, which is a special type of IV.
• Avoiding extravasation is crucial because it can lead to tissue damage, and signs of damage might not appear until a week later.
• If extravasation happens, there are no specific medicines that can reverse the harm. So, it's essential to prevent it from occurring in the first place.

GI events:

• Trabectedin can often cause nausea and vomiting.
• It's advised to take anti-nausea medicines to prevent these symptoms.
• A steroid medicine like dexamethasone is suggested to help with the nausea and vomiting. Sometimes, other anti-nausea medicines might be needed too.
• Trabectedin can also cause constipation and diarrhea, but these are usually mild.

Hepatotoxicity:

• Trabectedin can cause liver problems, and in rare cases, even severe liver failure.
• Many people have seen significant increases in their liver function tests (LFTs), which are markers of liver health.
• Typically, severe increases in these LFTs start about a month after beginning the treatment. It usually takes around two weeks for these levels to return to normal, but it can vary.
• Some patients had instances where their liver tests showed severe damage, with significant elevations.
• It's essential to check liver health before each dose of trabectedin, and even more frequently if there are concerns about liver health.
• If the liver tests show significant abnormalities, doctors might need to pause the treatment, reduce the dose, or stop the medication altogether.
• Taking dexamethasone (a steroid) the day before receiving trabectedin can help reduce the chances of these liver issues.
• People with high bilirubin levels or very high AST or ALT levels were not included in the study that tested trabectedin on sarcoma patients.

Hypersensitivity:

• Trabectedin can cause allergic reactions in some people.

Rhabdomyolysis:

• Trabectedin can cause rhabdomyolysis, a serious condition where muscle tissue breaks down.
• This muscle breakdown can release a protein into the blood that can harm the kidneys.
• About one-third of people taking trabectedin had elevated levels of a muscle enzyme called CPK, which indicates muscle damage.
• Severe increases in CPK levels happened in some patients and some had complications like kidney failure.
• The significant rise in CPK levels usually started around 2 months after beginning treatment. It generally took about 2 weeks for these levels to get back to normal.
• Doctors should check CPK levels before each dose of trabectedin.
• If CPK levels are very high, the treatment might need to be paused, the dose reduced, or the medication stopped completely.

Thromboembolic events:

• Trabectedin has been linked to the formation of blood clots in the lungs, known as pulmonary embolism.

Trabectedin: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May increase the serum concentration of Trabectedin. Exceptions: Grapefruit Juice.
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
HMG-CoA Reductase Inhibitors (Statins)	May enhance the myopathic (rhabdomyolysis) effect of Trabectedin.
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Leflunomide	Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Lenograstim	Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Palifermin	May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
Alcohol (Ethyl)	May enhance the hepatotoxic effect of Trabectedin.
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Trabectedin.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Trabectedin.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
St John's Wort	May decrease the serum concentration of Trabectedin.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

Monitoring parameters:

Blood Tests:

• Complete Blood Count (CBC) with differential:
  • Check before treatment, before each dose, and regularly during treatment cycles.

Liver Tests:

• Total bilirubin, ALT, AST, and alkaline phosphatase:
  • Check before each treatment cycle and more often if there are concerns about liver health.

Kidney Health:

• Check kidney function at the beginning and periodically during treatment.

Muscle Health:

• CPK (indicates muscle damage):
  • Check before each treatment cycle.

Heart Health:

• LVEF (How well the heart pumps blood):
  • Check using MUGA or echocardiogram:
    • At the beginning and then every 2 to 3 months.

Reproductive Health:

• Pregnancy Test:
  • Women who could become pregnant should have a pregnancy test before starting treatment.

Observation for Other Concerns:

• Capillary Leak Syndrome:
  • Watch out for signs/symptoms (like sudden swelling or low blood pressure).

Extravasation (Drug Leaking Outside the Vein):

• Check the site where the drug is given for any signs or symptoms of leakage.

How to administer Trabectedin (Yondelis)?

Nausea & Vomiting:

• Trabectedin can cause nausea and vomiting.
• It's recommended to take anti-nausea medicines before getting the treatment.

How to Give Trabectedin:

• Use an IV and make sure it goes through a central line with a specific filter (0.2 micron polyethersulfone).
• Once the drug is prepared, it needs to be given within 30 hours.
• Take a steroid, like dexamethasone (20 mg IV), 30 minutes before the treatment. You might also need other anti-nausea medicines.
• For Soft Tissue Sarcoma: Give trabectedin as a continuous drip over 24 hours.
• For Ovarian Cancer (not the usual use):
  • First, give doxorubicin liposomal. After that's done and the line is flushed, give trabectedin over 3 hours.

Beware of Extravasation:

• Trabectedin is a vesicant, meaning it can damage tissue if it leaks out of the vein.
• It's crucial to make sure the needle or catheter is placed correctly.

If Extravasation Happens:

• Stop the drug drip immediately but don't remove the needle or catheter right away.
• Try to gently pull out any leaked drug (without pushing any more fluid in).
• After that, you can remove the needle or catheter.
• Lift the affected arm or leg to help with swelling.

Mechanism of action of Trabectedin (Yondelis):

• Trabectedin is a drug derived from marine sources.
• It's a type of chemical (alkylating agent) that interferes with how cells grow and divide.
• It specifically stops the cell cycle at a particular stage called the G/M phase.
• It does this by attaching itself to the DNA, bending it in a certain way, and disrupting how DNA is read and copied.
• This interference affects the activity of various DNA-related processes, including DNA binding, transcription (making copies of genetic information), and DNA repair.
• All of these disruptions ultimately lead to the death of the cells.

Distribution:

• Trabectedin spreads out in the body in a large volume, more than 5,000 liters.

Binding in the Blood:

• About 97% of trabectedin binds to proteins in the blood.

How it's Broken Down:

• The liver does most of the work in breaking down trabectedin.
• A specific enzyme called CYP3A4 is responsible for this.

How Long it Lasts in the Body:

• The half-life of trabectedin is approximately 175 hours.
• This means after 175 hours, half of the drug is eliminated from the body.

How it's Removed from the Body:

• About 58% is removed through feces, but only a tiny amount of this is the unchanged drug.
• About 6% is removed through urine, and again, only a very small part of this is the unchanged drug.

Trabectedin Brand Names (International):

• Yondelis

Trabectedin Brand Names in Pakistan:

No Brands Available in Pakistan.