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Trabectedin Accord is a brand name for Trabectedin. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Trabectedin Accord is indicated for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients. Trabectedin Accord in combination with pegylated…
Verbatim from this product's EMA label. Tap a section to expand.
Trabectedin Accord must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents.
5 mg/m2 body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles. 1 mg/m2, immediately after PLD 30 mg/m2. To minimize the risk of PLD infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute.
If no infusion reaction is observed, subsequent PLD infusions may be administered over a 1-hour period (see also PLD Summary of Product Characteristics [SmPC] for specific administration advice). g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or trabectedin (in monotherapy); not only as anti-emetic prophylaxis, but also because it appears to provide hepatoprotective effects.
Additional anti-emetics may be administered as needed. 5 x ULN (consider hepatic isoenzymes 5-nucleotidase or gamma glutamyl transpeptidase (GGT), if the elevation could be osseous in origin). 5 x ULN - Haemoglobin ≥ 9 g/dl The same criteria as above must be met prior to re-treatment.
Otherwise treatment must be delayed for up to 3 weeks until the criteria are met. Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.
The same dose should be given for all cycles provided that no grade 3-4 toxicities are seen and that the patient fulfils the re-treatment criteria. Dose adjustments during treatment Prior to re-treatment, patients must fulfil the baseline criteria defined above.
5 x ULN (monotherapy) or > 5 x ULN (combination therapy), which has not recovered by day 21 - Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue) Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended.
If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.
4% 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.
6% 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.
Tabulated summary of adverse reactions The following safety profile of trabectedin is based on adverse reactions reported in clinical trials, post- authorisation safety studies and spontaneous reporting. The table 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. 9 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).
1 mg/m2) every 3 weeks or PLD alone (50 mg/m2) every 4 weeks. In the ET743-OVA-301 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.
Hepatic impairment Patients must meet specific criteria on hepatic function parameters to start treatment with Trabectedin Accord. 2) 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.
2). Renal impairment Creatinine clearance must be monitored prior to and during treatment. 2). Neutropenia and thrombocytopenia Grades 3 or 4 neutropenia and thrombocytopenia associated with trabectedin therapy have been very commonly reported.
2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately. Trabectedin Accord 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.
2). 2). 2). 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 Accord should be discontinued until the patient fully recovers.
g. statins), are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased 6 Liver Function Test (LFT) abnormalities Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients.
Trabectedin Accord must not be used in patients with elevated bilirubin. 2). 2). Patients may develop a potentially severe injection site reaction when trabectedin is administered through a peripheral venous line. Trabectedin extravasation may cause tissue necrosis requiring debridement.
4)
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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75 mg/m2 20 mg/m2 See the PLD SmPC for more detailed information on PLD dose adjustments. In the event that further dose reductions are necessary, treatment discontinuation should be considered. Duration of treatment In clinical trials, there were no pre-defined limits to the number of cycles administered.
Treatment continued whilst clinical benefit was noted. 5% and 52% of patients treated with the monotherapy and combination dose and schedule respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles respectively.
No cumulative toxicities have been observed in patients treated with multiple cycles. 1 for results of paediatric sarcoma study). Elderly No specific studies in older people have been performed. Overall 20% of the 1,164 patients in the integrated safety analysis of monotherapy clinical trials were over 65 years.
Of the 333 patients with ovarian cancer who received trabectedin in combination with PLD, 24% were 65 years of age or older and 6% were over 75 years. No relevant differences in the safety profile were seen in this patient population.
It seems that plasma clearance and distribution volume of trabectedin are not influenced by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended. Hepatic impairment 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 Accord . 4). Renal impairment Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the monotherapy, and < 60 ml/min for the combination regimen) […]
Description of selected adverse reactions Most frequent adverse reactions Blood and lymphatic system disorders 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.
Hepatobiliary disorders AST/ALT increases:
The median time to reach the peak values was 5 days for both AST and ALT. 4). 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 11 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 […]
There is no specific antidote for extravasation of trabectedin. Extravasation should be managed by local standard practice. 8). Cardiac Dysfunction 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.
Capillary Leak Syndrome (CLS) 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. 8). 5). If this is not possible, close monitoring of toxicities are required and dose reductions of trabectedin should be considered. Caution should be taken if medicinal products associated with hepatotoxicity are administered concomitantly with trabectedin, since the risk of hepatotoxicity may be increased.
7 Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to an exacerbation of convulsions. Combination of trabectedin with phenytoin or live attenuated vaccines is not recommended and with yellow fever vaccine is specifically […]