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trabectedin
Trabectedin was originally derived from the Caribbean marine tunicate, Ecteinascidia turbinate, and is now produced synthetically. This antineoplastic is a tetrahydroisoquinoline alkaloid which binds to the minor groove of the DNA, bending DNA towards the major groove. The changed conformation interferes with several DNA transcription factors, repair pathways and cell proliferation.
Pharmacokinetics are dose-proportional up to 1.8 mg/m2. No accumulation observed when administered every 3 weeks. Extensively distributed into peripheral tissues
| PPB | 97 % |
| Cross blood brain barrier? | No information found. |
Extensive metabolism, mainly by CYP 3A4. Does not induce or inhibit major CYP 450 enzymes. No appreciable glucuronidation.
| Active metabolites | No information found |
| Inactive metabolites | Yes |
Multiple compartment disposition. Mainly fecal elimination, with <1% excreted unchanged. Clearance not influenced by total body weight, body surface area, age or gender.
| Half-life | terminal half-life: 175 hours |
| Urine | (renal) < 9 % |
| Feces | 58 % |
- In combination with pegylated liposomal doxorubicin (Caelyx®) for the treatment of platinum-sensitive ovarian cancer patients, for whom one first-line platinum-based chemotherapy (including adjuvant) has failed, and who are not expected to benefit, are ineligible or not willing to receive retreatment with platinum-based chemotherapy.
- For the treatment of patients with metastatic liposarcoma or leiomyosarcoma after failure of prior anthracycline and ifosfamide chemotherapy.
NOTES:
Approval in ovarian cancer was based on progression-free survival benefit; however, overall survival and quality of life benefits have not been demonstrated. Approval in soft tissue sarcoma was based on a progression-free survival in a randomized study comparing 2 doses of trabectedin; survival prolongation was not demonstrated and quality of life was not assessed.
Emetogenic Potential:
Extravasation Potential: Vesicant
These are mainly from single agent studies. Other events that are reported at a higher (>2%) incidence in combination compared to pegylated liposomal doxorubicin (Caelyx®) alone are also reported.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiotoxicity (2%) | E D | |||
| Hypotension (rare) | E | ||||
| Palpitations (4%) | E | ||||
| Venous thromboembolism (5%) | E | ||||
| Dermatological | Alopecia (3%) (mostly mild) | E | |||
| Skin hyperpigmentation (6%) | E | ||||
| Gastrointestinal | Abdominal pain (5%) | E | |||
| Anorexia (19%) | E | ||||
| Constipation (18%) | E | ||||
| Dehydration (5%) | E | ||||
| Diarrhea (15%) | E | ||||
| Dyspepsia (5%) | E | ||||
| Mucositis (1%) | E | ||||
| Nausea, vomiting (72%) | I E | ||||
| General | Edema (5%) | E | |||
| Fatigue (53%) | E | ||||
| Fever (5%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (35%) (severe) | E | |||
| Hepatobiliary | ↑ LFTs (39%) (severe) | E | |||
| Hypersensitivity | Hypersensitivity (2%) | I | |||
| Injection site | Phlebitis (15%) | I E | |||
| Metabolic / Endocrine | ↓ K (5%) | E | |||
| Musculoskeletal | Musculoskeletal pain (10%) | E | |||
| ↑CPK (26%) (4% severe) | E | ||||
| Rhabdomyolysis (<1%) | E | ||||
| Nervous System | Dizziness (5%) | E | |||
| Dysgeusia (8%) | E | ||||
| Headache (15%) | E | ||||
| Insomnia (6%) | E | ||||
| Peripheral neuropathy (1%) | E | ||||
| Renal | Creatinine increased (5%) (may be severe) | E | |||
| Respiratory | Dyspnea (5%) | E | |||
| Vascular | Capillary leak syndrome (rare) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects of trabectedin include fatigue, myelosuppression, GI effects, headache, musculoskeletal pain, elevated LFTs or CPK. In the pivotal ovarian cancer clinical trial, 42% of patients received filgrastim, and there was an 8% rate of febrile neutropenia (1% fatal).
Grade 3 or 4 LFT elevations are common, usually occur in the first week, and recover prior to the next planned dose. Pretreatment with corticosteroids reduces the incidence. Hepatotoxcity may be cumulative and worsen with successive cycles. Hepatic failure has been reported.
CPK elevations are common; however, rhabdomyolysis is rare, but may be fatal. It is usually associated with myelotoxicity, severe hepatic or renal impairment. Trabectedin should be discontinued and aggressive treatment instituted if rhabdomyolysis occurs.
Phlebitis may occur even when a central line is used.
Hypersensitivity is generally mild to moderate; however, fatal cases have also been reported.
Capillary leak syndrome has been reported and may present with hypotension, edema and rapidly falling albumin.
Clinically significant cardiac events were reported in combination with liposomal doxorubicin in patients with ovarian cancer. Cardiac dysfunction was also reported in patients with liposarcoma and leiomyosarcoma who received prior anthracyclines. The incidence was higher in patients who received trabectedin (5%) compared to those who received dacarbazine (2%). Monitoring of LVEF is recommended, especially in patients at risk from previous anthracycline exposure or those with symptoms of cardiac dysfunction.
Refer to protocol by which patient is being treated. Premedication with corticosteroids such as dexamethasone 20mg IV 30 minutes before each trabectedin dose is required, for hepatoprotective and anti-emetic effects. Supportive care/colony stimulating factors for myelosuppression should be considered per institutional guidelines.
List A:
The following criteria must be met before EACH trabectedin treatment.
- ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 90 g/L
- Bilirubin ≤ ULN, AST and ALT ≤ 2.5 x ULN
- Albumin ≥ 25 g/L
- Creatinine clearance ≥ 30 mL/min (monotherapy)
- Creatinine ≤ 132.6 µmol/L or Creatinine clearance ≥ 60 mL/min (combination therapy)
- ALP (of non-osseous origin) ≤ 2.5 x ULN (consider hepatic isoenzymes 5' nucleotidase or GGT, to distinguish elevations that can be osseous in origin)
- CPK ≤ 2.5 x ULN
Ovarian Cancer:
q3w: 1.1 mg/m2 IV over 3 hours on day 1, after pegylated liposomal doxorubicin 30 mg/m2 IV over 90 minutes
Liposarcoma or Leiomyosarcoma
q3w: 1.5 mg/m2 IV over 24 hours
Reduced doses are not re-escalated. Discontinue if toxicity recurs after 2 dose reductions.
|
|
Liposarcoma or Leiomyosarcoma |
Ovarian Cancer |
|
|
Dose |
Trabectedin |
Trabectedin |
Pegylated Liposomal Doxorubicin |
|
Starting dose |
1.5 mg/m2 |
1.1 mg/m2 |
30 mg/m2 |
|
First reduction |
1.2 mg/m2 |
0.9 mg/m2 |
25 mg/m2 |
|
Second reduction |
1 mg/m2 |
0.75 mg/m2 |
20 mg/m2 |
Table B - Dose Modifications for Toxicity:
|
Counts / Toxicity (worst in previous cycles) |
Trabectedin Dose** |
| Grade 4 ANC≥ 5 days or Febrile neutropenia or Platelets < 25 x 109/L |
↓ 1 dose level |
|
Alkaline phosphatase > 2.5 x ULN (non-osseous) |
↓ 1 dose level |
| AST/ALT > 2.5 x ULN (monotherapy), or >5 ULN (combination therapy) & not recovered by Day 21 or bilirubin > ULN*** |
↓ 1 dose level |
|
≥ grade 3 non-hematological/organ toxicity |
↓ 1 dose level |
|
Any grade rhabdomyolysis or CPK > 2.5 ULN |
Hold until recovery, consider discontinuing |
| Severe hypersensitivity | Discontinue |
| Capillary leak syndrome | Hold if suspected; discontinue if confirmed and treat according to institutional practice |
|
**Do not treat until laboratory values meet conditions listed in List A and organ/non-hematologic toxicities have recovered to ≤ grade 2. Delay for a maximum of 3 weeks – if not recovered, discontinue. ***Hold trabectedin until normalizes and restart at reduced dose. If not recovered by day 21, discontinue. |
|
At baseline:*
| Parameter |
≥ ULN - < 2.5 x ULN |
≥ 2.5 ULN |
| Bilirubin |
Do not treat |
Do not treat |
| AST/ALT |
No change |
Do not treat |
| Alkaline Phosphatase |
No Change |
Do not treat |
|
CrCl (ml/min |
Single Agent Trabectedin |
Combination with Pegylated liposomal doxorubicin |
|
30-60 |
No change |
Discontinue |
|
< 30 |
Discontinue |
Discontinue |
No dose adjustment needed. No differences in safety or effectiveness were seen in patients > 65 years of age versus younger patients.
Increased myelotoxicity has been reported in Asian patients. Rates of infection were similar between white and Asian cohorts.
Safety and effectiveness have not been established. A phase II study showed no efficacy in pediatric patients with sarcomas. Trabectedin should not be used in children and adolescents.
- Avoid alcohol intake while on trabectedin treatment to prevent hepatotoxicity.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products (as well as other inhibitors of CYP3A4) during treatment (see Interactions section)
- MUST be administered via central intravenous line.
- Patients must receive corticosteroid premedication 30 minutes before each trabectedin dose (i.e. dexamethasone 20mg IV), as an antiemetic and to protect the liver.
- Reconstitute with sterile water for injection as directed.
- Further dilute in 500mL Normal Saline or D5W.
- Compatible with PVC, glass, polyethylene (PE) containers and tubing.
- After completion of the pegylated liposomal doxorubicin infusion, the IV line should be flushed with D5W before trabectedin administration.
- Do not mix or dilute with other drugs or solutions.
- Refrigerate unopened vials at 2-8°C.
- patients who have a hypersensitivity to trabectedin or any of its components
- patients who have active, serious or uncontrolled infections
- patients who have left ventricular injection fraction below the lower limit of normal
- patients with active hepatitis, elevated bilirubin, or who have CPK > 2.5 times the upper limit of normal.
Other Warnings/Precautions:
- exercise caution in patients with a history of ischemic heart disease or tachyarrhythmia, as trabectedin has been associated with transient heart rate increases
- avoid live vaccines
- avoid alcohol, concomitant use of other hepatotoxic drugs or drugs known to cause rhabdomyolysis
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
Yes
-
Mutagenicity:
Yes
Trabectedin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose for females (5 months for males) -
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment and for 3 months after the last dose. -
Fertility effects:
Probable
Trabectedin does not appear to induce or inhibit major CYP450 enzymes, but is metabolized by CYP3A4.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Pegylated liposomal doxorubicin | ↓ trabectedin clearance by 16-31% | Unknown | monitor |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ trabectedin concentrations and/or toxicity (↑ AUC 66% with ketoconazole) | ↓ trabectedin metabolism | Monitor closely; avoid strong CYP3A4 inhibitors if possible or consider dose reduction |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ trabectedin concentrations and effectiveness (↓ AUC 31% with rifampin) | ↑ trabectedin metabolism and clearance | Monitor; avoid strong CYP3A4 inducers if possible |
| P-glycoprotein inducers (i.e. rifampin, dexamethasone, indinavir) | Possibly ↓ trabectedin concentrations and effectiveness | ↑ trabectedin metabolism and clearance | Caution |
| P-glycoprotein inhibitors (i.e. quinidine, verapamil, cyclosporine) | Possibly ↑ trabectedin concentrations and/or toxicity | ↓ trabectedin metabolism | Caution |
| phenytoin (high dose) | ↑ free trabectedin concentration (28%) | Displacement of trabectedin from protein binding | Avoid; monitor closely if must use |
| phenytoin (high dose) | ↑ risk of seizures | ↓ phenytoin absorption | Avoid; monitor closely if must use |
| Hepatotoxic drugs (i.e. alcohol, methotrexate, isoniazid, nefazodone) | May ↑ hepatotoxicity | Additive effect | Avoid |
| Drugs that may cause muscle damage (i.e. statins, levofloxacin) | May ↑ risk of rhabdomyolysis | Additive effect | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
LVEF |
baseline and periodic (especially in patients at risk of cardiac dysfunction) |
| CBC | baseline, prior to each cycle, and weekly for first 2 cycles, then once between cycles |
| Liver function tests and CPK | baseline and prior to each cycle, and weekly for the first 2 cycles, then once between cycles |
| Renal function tests | baseline and regular |
Clinical toxicity assessment for cardiac, musculoskeletal, GI, hepatic and local toxicity, as well as VTE, infection and bleeding; regular |
At each visit |
Albumin |
If capillary leak syndrome suspected |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Product Monograph: Yondelis® (trabectedin). Janssen-Ortho Inc., April 21, 2017.
Carter NJ and Keam SJ. Trabectedin: a review of its use in the management of soft tissue sarcoma and ovarian cancer. Drugs 2007; 67 (15): 2257-76.
Chuk MK, Balis FM, Fox E. Trabectedin. The Oncologist 2009;14:794–9.
Grosso F, Dileo P, Sanfilippo R, et al. Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma. Eur J Cancer 2006;42(10):1484-90.
Kim RB. Drugs as p-glycoprotein substrates, inhibitors, or inducers. Drug Metab Rev 2002; 34(1-2): 47-54.
Trabectedin (Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766). Drugs R D 2006; 7(5): 317-28.
November 2017 Added description of capillary leak syndrome (CLS) to adverse effects, added CLS to dose modification table, changed monitoring section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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