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:
Note: Prior to each treatment cycle, absolute neutrophil count should be ≥1,500/mm³, platelets ≥100,000/mm³ total bilirubin ≤ upper normal limit, and alkaline phosphatase, ALT, AST, and CPK ≤2.5 times upper normal limit. Premedications: Antiemetics and dexamethasone 20 mg half hour before each infusion.
Trabectedin (Yondelis) dose in the treatment of unresectable/ metastatic Soft tissue sarcoma:
- 1.5 mg/m² intravenous as a continuous infusion over 24 hours once every 3 weeks;
- continue until disease progression or unacceptable toxicity.
Trabectedin (Yondelis) dose in the treatment of relapsed platinum-sensitive Ovarian cancer (off-label):
- 1.1 mg/m² intravenous over 3 hours every 3 weeks (in combination with doxorubicin liposomal),
- continue as long as clinical benefit is demonstrated or until disease progression or confirmed complete response or for 2 or more cycles beyond complete response.
- A dose reduction or delaying is required in case of toxicity.
Use in children:
The safety and efficacy of the drug in children have not been established.
Trabectedin (Yondelis) Pregnancy Risk Category: D
- Because trabectedin can cause harm to fetus, it is important for females to use effective contraception during treatment as well as for at least two months after receiving the last dose of trabectedin.
- Effective contraception should be used by males during treatment, and at least for 5 months following the last dose.
- It is possible to see a decrease in fertility for males and females.
Use while breastfeeding
- It is unknown if breastmilk contains any trace amounts of trabectedin.
- Due to the possibility of fatal side effects, the manufacturer suggests that you stop breastfeeding while receiving trabectedin treatment.
Trabectedin (Yondelis) Dose adjustment in renal disease:
-
Creatinine clearance ≥30 mL/minute:
- No dosage adjustment is necessary.
-
Creatinine clearance <30 mL/minute or ESRD:
- There is no dosage adjustment provided in the manufacturer's labeling.
-
Hemodialysis:
- Hemodialysis is not expected to enhance the elimination of trabectedin.
Trabectedin (Yondelis) Dose adjustment in liver disease:
-
Hepatic impairment(per the manufacturer’s labeling):
-
Mild impairment (bilirubin >1 to 1.5 times upper normal limit and any AST or ALT):
- No initial dosage adjustment necessary.
-
Moderate impairment (bilirubin >1.5 to 3 times upper normal limit and AST or ALT <8 times ULN):
- Reduce dose from 1.5 mg/m to 0.9 mg/m².
-
Severe impairment: (bilirubin >3 times upper normal limit and any AST or ALT):
- Should not be administered.
-
-
Hepatotoxicity during treatment:
- Dose reduction is required in patients with mild or moderate hepatic impairment at baseline (once a dose is reduced it should not be increased in subsequent cycles):
-
Mild impairment:
- First dose reduction: 1.2 mg/m once every 3 weeks.
- Second dose reduction: 1 mg/m once every 3 weeks.
-
Moderate impairment:
- First dose reduction:
- 0.6 mg/m once every 3 weeks.
- Second dose reduction:
- 0.3 mg/m² once every 3 weeks.
- Total bilirubin >ULN:
- Delay dose for up to 3 weeks and reduce the next dose by one dose level
- AST or ALT >2.5 times ULN:
- Delay dose for up to 3 weeks
- AST or ALT >5 times ULN during the prior cycle:
- Delay dose for up to 3 weeks and reduce the next dose by one dose level
- Alkaline phosphatase >2.5 times ULN:
- Delay dose for up to 3 weeks and reduce the next dose by one dose level
- First dose reduction:
-
Severe liver dysfunction (bilirubin 2 times ULN and AST or ALT 3 times ULN and alkaline phosphatase <2 times ULN in prior treatment cycle in patients with normal hepatic function at baseline):
- Permanently discontinue.
-
Exacerbation of hepatic dysfunction in patients with preexisting moderate impairment:
- Permanently discontinue.
-
Adverse reactions with trabectedin administered at 1 mg/m² (in patients with normal hepatic function or mild hepatic impairment) or at 0.3 mg/m² (in patients with moderate hepatic impairment) and requiring further dose reduction:
- Permanently discontinue.
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
Trabectedin: Drug Interaction
|
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 |
|
|
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:
- Complete blood count
- Liver function tests
- Renal function tests
- CPK (prior to each treatment cycle)
- Pregnancy test (prior to treatment in females of reproductive potential)
- Echocardiogram or MUGA scan
- Signs/symptoms of capillary leak syndrome
- Signs/symptoms of extravasation
How to administer Trabectedin (Yondelis)?
It should be administered intravenously infusion via a central line equipped with a 0.2 micron polyethersulfone filter. Half an hour prior to treatment, antiemetics and dexamethasone 20mg IV should be taken.
Soft tissue sarcoma
- Continuous infusion for 24 hours with a single agent.
Ovarian cancer (off the label use)Combination therapy with doxorubicin Liposomal
- Doxorubicin liposomal: First flush with D W), then infusion of trabectedin over three hours.
To avoid extravasation, it is important to properly position the needle before and during infusion.
Extravasation management
- It is important to stop the infusion immediately. Gentle aspiration should be done of any extravasated solution, without flushing the line. The cannula must be removed and the extremity elevated.
Mechanism of action of Trabectedin (Yondelis):
- Trabectedin, an alkylating agent, acts by blocking the cell's G/M phase.
- It covalently binds to the minor DNA groove.
- This bends the helix towards the major groove and alters DNA transcription.
- It can interfere with the activity of DNA binding proteins, transcription factor, and DNA-repair, resulting in cell death.
Protein binding: 97%; to plasma proteins
Metabolism: Extensively occurs in liver; via CYP3A4
Half-life elimination: 175 hours
Excretion: Feces (58%; only negligible amounts as unchanged drug); urine (6%; only negligible amounts as unchanged drug)
Trabectedin Brand Names (International):
- Yondelis
Trabectedin Brand Names in Pakistan:
No Brands Available in Pakistan.
.png)
