Chemical formula: C₃₉H₄₃N₃O₁₁S Molecular mass: 761.837 g/mol PubChem compound: 108150
Trabectedin interacts in the following cases:
Special caution is advised and dose adjustments may be necessary in patients with hepatic impairment since systemic exposure to trabectedin is increased and the risk of hepatotoxicity might be increased. Patients with elevated serum bilirubin levels at baseline must not be treated with trabectedin. Liver function tests should be monitored during treatment with trabectedin as dose adjustments may be indicated.
Patients must meet specific criteria on hepatic function parameters to start treatment with trabectedin. Since the systemic exposure to trabectedin is on average approximately doubled due to hepatic impairment and therefore the risk of toxicities might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose adjusted if needed. Patients with elevated serum bilirubin levels must not be treated with trabectedin.
Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients. Τrabectedin must not be used in patients with elevated bilirubin. Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate dose adjustments.
Studies including patients with renal insufficiency (creatinine clearance <30 ml/min for the monotherapy, and <60 ml/min for the combination regimen) have not been conducted and therefore trabectedin must not be used in this patient population. Considering the pharmacokinetic characteristics of trabectedin, no dose adjustments are warranted in patients with mild or moderate renal impairment.
Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of the medicinal product.
Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or elimination. The relevance of this interaction e.g. central nervous system (CNS) toxicity has not been established. Caution should be taken in such situations.
Since trabectedin is metabolised mainly by CYP3A4, the concentrations of trabectedin in plasma are likely to be increased in patients who are co-administered drugs that potently inhibit the activity of this isoenzyme. Similarly, the co-administration of trabectedin with potent inducers of CPY3A4 may increase the metabolic clearance of trabectedin. Two in vivo drug-drug interaction phase 1 studies have confirmed trends toward increased and decreased trabectedin exposures when administered with ketoconazole and rifampicin, respectively.
When ketoconazole was co-administered with trabectedin, the plasma exposure of trabectedin was increased by approximately 21% for Cmax and 66% for AUC, but no new safety concerns were identified. Close monitoring of toxicities is required in patients receiving trabectedin in combination with potent CYP3A4 inhibitors (e.g. oral ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant) and such combinations should be avoided if possible. If such combinations are needed, appropriate dose adjustments should be applied in the event of toxicities.
When rifampicin was co-administered with trabectedin, it resulted in reduced plasma exposure of trabectedin by approximately 22% for Cmax and 31% for AUC. Therefore, the concomitant use of trabectedin with strong CYP3A4 inducers (e.g., rifampicin, phenobarbital, Saint John’s Wort) should be avoided if possible.
Men in fertile age must use effective contraception during treatment and 5 months after treatment.
Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with trabectedin.
Genetic counselling is also recommended for patients wishing to have children after therapy.
Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to an exacerbation of convulsions. Combination of trabectedin with phenytoin is not recommended.
Patients should be monitored for cardiac-related adverse events or myocardial dysfunction.
A thorough cardiac assessment including determination of left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan (MUGA) should be conducted before initiation of trabectedin and at 2 to 3-month intervals thereafter until trabectedin is discontinued.
Patients with LVEF less than the lower limit of normal (LVEF < LLN), prior cumulative anthracycline dose of >300 mg/m², aged >65 years, or a history of cardiovascular disease (especially in those with cardiac medication) may be at increased risk of cardiac dysfunction at treatment with trabectedin as monotherapy or in combination with doxorubicin.
For patients with Grade 3 or 4 cardiac adverse events indicative of cardiomyopathy or for patients with a LVEF that decreases below the LLN (assessed as either an absolute decrease of LVEF of ≥15% or <LLN with an absolute decrease of ≥5%), trabectedin should be discontinued.
Trabectedin must not be used in patients with CPK >2.5 x ULN. Rhabdomyolysis has been uncommonly reported, usually in association with myelotoxicity, severe liver function test abnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with trabectedin should be discontinued until the patient fully recovers.
Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins), are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased.
Grades 3 or 4 neutropenia and thrombocytopenia associated with trabectedin therapy have been very commonly reported. A full blood cell count including differential and platelet count must be performed at baseline, weekly for the first two cycles and then once between cycles. Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately.
Trabectedin should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³ and platelets count of less than 100,000 cells/mm³. If severe neutropenia (ANC <500 cells/mm³) lasting more than 5 days or associated with fever or infection occurs, dose reduction is recommended.
Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases with fatal outcomes). If symptoms of possible CLS develop, such as unexplained oedema with or without hypotension, the treating physician should reassess serum albumin level. A rapid decline in serum albumin level may be indicative of CLS. If a diagnosis of CLS is confirmed after exclusion of other causes, the treating physician should discontinue trabectedin and initiate CLS treatment according to institutional guidelines.
No sufficient clinical data on exposed pregnancies are available. However, based on its known mechanism of action, trabectedin may cause serious birth defects when administered during pregnancy. Trabectedin crossed the placenta when administered to pregnant rats. Trabectedin should not be used during pregnancy. If pregnancy occurs during treatment, the patient must be informed of the potential risk to the foetus and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns.
It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been studied in animals. Breast-feeding is contraindicated during treatment and 3 months thereafter.
Women of childbearing potential must use effective contraception during treatment and 3 months thereafter, and immediately inform the treating physician if a pregnancy occurs.
If pregnancy occurs during treatment the possibility of genetic counselling should be considered.
Men in fertile age must use effective contraception during treatment and 5 months after treatment.
Trabectedin can have genotoxic effects. Advice on conservation of ovules or sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with trabectedin. Genetic counselling is also recommended for patients wishing to have children after therapy.
No studies on the effects of the ability to drive and to use machines have been performed. However, fatigue and/or asthenia have been reported in patients receiving trabectedin. Patients who experience any of these adverse reactions during therapy must not drive or operate machines.
Most patients treated with trabectedin can be expected to have adverse reactions of any grade (91% in monotherapy and 99% in combination therapy) and less than one third serious adverse reactions of grade 3 or 4 severity (10% in monotherapy and 25% in combination therapy). The most common adverse reactions of any severity grade were neutropenia, nausea, vomiting, increase in AST/ALT, anaemia, fatigue, thrombocytopenia, anorexia and diarrhoea.
Fatal adverse reactions have occurred in 1.9% and 0.9% of patients treated with the monotherapy and combination regimens respectively. They were often the result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal or multiorgan failure and rhabdomyolysis.
The following safety profile of trabectedin is based on adverse reactions reported in clinical trials, post- authorisation safety studies and spontaneous reporting.
The list below displays the adverse reactions reported in patients with soft tissue sarcoma and ovarian cancer that were treated with trabectedin recommended regimen in each indication. Both adverse reactions and laboratory values have been used to provide frequencies.
Adverse reactions are listed by System Organ Class and frequency. The frequencies are classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000).
Very Common: Neutropenic infection
Common: Sepsis
Uncommon: Septic shock
Very Common: Neutropenia, Thrombocytopenia, Anaemia, Leukopenia
Common: Febrile neutropenia
Common: Hypersensitivity
Very Common: Decreased appetite
Common: Dehydration, Hypokalaemia
Very Common: Insomnia
Very Common: Headache
Common: Dizziness, Dysgeusia, Peripheral sensory neuropathy, Syncope*
Common: Palpitations*, Left ventricular dysfunction*
Common: Hypotension, Flushing
Uncommon: Capillary leak syndrome
Very Common: Dyspnoea, Cough
Common: Pulmonary embolism*
Uncommon: Pulmonary oedema
Very Common: Abdominal pain, Nausea, Vomiting, Constipation, Diarrhoea, Stomatitis
Common: Dyspepsia
Very Common: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood bilirubin increased
Common: Gamma-glutamyltransferase increased
Rare: Hepatic failure
Very Common: Palmar-plantar erythrodysaesthesia syndrome*
Common: Rash, Alopecia, Skin hyperpigmentation*
Very Common: Arthralgia, Back pain, Blood creatine phosphokinase increased
Common: Myalgia
Uncommon: Rhabdomyolysis
Very Common: Fatigue, Pyrexia, Oedema, Mucosal inflammation*
Common: Injection site reactions
Uncommon: Extravasation, Soft tissue necrosis
Very Common: Blood creatinine increased, Blood albumin decreased
Common: Weight decreased
* Adverse drug reaction only for Ovarian cancer
In the trabectedin + PLD arm, non-white (mainly Asian) patients had a higher incidence than white patients in grade 3 or 4 adverse reactions (96% versus 87%), and serious adverse reactions (44% versus 23% all grades). The differences were mainly observed in relation with neutropenia (93% versus 66%), anaemia (37% versus 14%) and thrombocytopenia (41% versus 19%). However, the incidences of clinical complications related to haematological toxicity such as severe infections or bleeding, or those leading to death or treatment termination, were similar in both subpopulations.
Neutropenia: Neutropenia is the most common haematological toxicity. It followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection. Neutrophil nadirs occurred at a median of 15 days and recovered within a week. The analysis per cycle performed in patients treated with the monotherapy regimen showed neutropenia of grade 3 and 4 in approximately 19% and 8% of cycles respectively. In this population febrile neutropenia occurred in 2% of patients and in <1% of cycles.
Thrombocytopenia: Bleeding events associated to thrombocytopenia occurred in <1% of patients treated with the monotherapy regimen. The analysis per cycle performed in these patients showed thrombocytopenia of grade 3 and 4 in approximately 3% and <1% of cycles respectively.
Anaemia: Anaemia occurred in 93% and 94% of patients treated with the monotherapy and combination regimens respectively. The percentages of patients anaemic at baseline were 46% and 35% respectively. The analysis per cycle performed in patients treated with the monotherapy regimen showed anaemia of grade 3 and 4 in approximately 3% and 1% of cycles respectively.
AST/ALT increases: The median time to reach the peak values was 5 days for both AST and ALT. Most of the values had decreased to grade 1 or resolved by day 14-15. The analysis per cycle performed in patients treated with the monotherapy regimen showed grade 3 elevations of AST and ALT in 12% and 20% of cycles respectively. Grade 4 elevations of AST and ALT occurred in 1% and 2% of cycles respectively. Most transaminase elevations improved to grade 1 or to pre-retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25 days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.
Hyperbilirubinemia: Bilirubin peaks approximately a week after onset and resolves approximately two weeks after onset.
Liver function tests predicting severe toxicity (meeting Hy’s law) and clinical manifestations of severe hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in less than 1% of patients in both regimens.
Rare cases of hepatic failure (including cases with fatal outcomes) have been reported in patients with serious underlying medical conditions treated with trabectedin, both in clinical trials and in post marketing setting. Some potential risk factors that may have contributed to increased trabectedin toxicity observed in these cases were dose management inconsistent with recommended guidelines, potential CYP3A4 interaction due to multiple competing CYP3A4 substrates or CYP3A4 inhibitors, or lack of dexamethasone prophylaxis.
Cases of Capillary Leak Syndrome (CLS) have been reported with trabectedin (including cases with fatal outcomes).
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