1. Name Of The Medicinal Product
0.25 mg vial
1 mg vial
2. Qualitative And Quantitative Composition
0.25 mg vial
Each vial contains 0.25 mg of trabectedin.
1 mg vial
Each vial contains 1 mg of trabectedin.
0.25 mg and 1 mg vials
1 ml of reconstituted solution contains 0.05 mg of trabectedin.
Excipients with known effect:
0.25 mg vial
Each vial contains 2 mg of potassium and 0.1 g of sucrose.
1 mg vial
Each vial contains 8 mg of potassium and 0.4 g of sucrose.
0.25 mg and 1 mg vials
For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion.
White to off-white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Yondelis is indicated for the treatment of 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.
Yondelis in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer.
4.2 Posology And Method Of Administration
Yondelis 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.
Posology
For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m2 body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles.
For the treatment of ovarian cancer Yondelis is administered every three weeks as a 3-hour infusion at a dose of 1.1 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 Product Characteristics for specific administration advice).
All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or Yondelis (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.
The following criteria are required to allow treatment with Yondelis:
- Absolute neutrophil count (ANC) 3
- Platelet count 3
- Bilirubin
- Alkaline phosphatase
- Albumin
- Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)
- Creatinine clearance
- Creatine phosphokinase (CPK)
- Haemoglobin
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. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to table 1 below, for subsequent cycles:
- Neutropenia < 500/mm3 lasting for more than 5 days or associated with fever or infection
- Thrombocytopenia < 25,000/mm3
- Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN
- Increase of aminotransferases (AST or ALT) > 2.5 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 hematologic toxicity according to local standard practice.
Table 1 Dose modification table for Yondelis (as single agent for STS or in combination for ovarian cancer) and PLD
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See the PLD SPC 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. Yondelis has been administered for 6 or more cycles in 29.5% 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.
Paediatric population
The safety and efficacy of trabectedin in the paediatric population have not yet been established. No data are available.
Elderly patients
No specific studies in elderly patients have been performed. Overall 20% of the 1164 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.
Patients with hepatic impairment
No studies with the proposed regimen have been conducted in patients with liver dysfunction. Thus, data are not available to recommend a lower starting dose in patients with hepatic impairment. However, special caution is advised and dose adjustments may be necessary in these patients since systemic exposure is probably increased and the risk of hepatotoxicity might be increased. Patients with elevated bilirubin must not be treated with Yondelis (see section 4.4).
Patients with renal impairment
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 Yondelis must not be used in this patient population (see section 4.4). Considering the pharmacokinetic characteristics of trabectedin (see section 5.2), no dose adjustments are warranted in patients with mild or moderate renal impairment.
Method of administration
Administration through a central venous line is strongly recommended (see section 6.6).
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
- Hypersensitivity to trabectedin or to any of the excipients listed in section 6.1
- Concurrent serious or uncontrolled infection
- Breast-feeding (see section 4.6)
- Combination with yellow fever vaccine (see section 4.4)
4.4 Special Warnings And Precautions For Use
Hepatic impairment
Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since systemic exposure to trabectedin is probably increased due to hepatic impairment and therefore the risk of hepatotoxicity 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 bilirubin must not be treated with trabectedin (see section 4.2).
Renal impairment
Creatinine clearance must be monitored prior to and during treatment. Yondelis monotherapy and combination regimens must not be used in patients with creatinine clearance < 30 ml/min and < 60 ml/min respectively (see section 4.2).
Neutropenia and thrombocytopenia
Grades 3 or 4 neutropenia and thrombocytopenia associated with Yondelis 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 (see section 4.2). Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately.
Yondelis 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 (see section 4.2).
Nausea and vomiting
Anti-emetic prophylaxis with corticosteroids such as dexamethasone must be administered to all patients (see section 4.2).
Rhabdomyolysis and severe CPK elevations ( > 5 x ULN)
Trabectedin must not be used in patients with CPK > 2.5 x ULN (see section 4.2). 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 Yondelis 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
Liver Function Test (LFT) abnormalities
Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients. Yondelis must not be used in patients with elevated bilirubin. Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate dose reduction (see section 4.2).
Injection site reactions
The use of central venous access is strongly recommended (see section 4.2). 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. There is no specific antidote for extravasation of trabectedin. Extravasation should be managed by local standard practice.
Others
Co-administration of Yondelis with potent inhibitors of the enzyme CYP3A4 should be avoided (see section 4.5). 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.
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 contraindicated (see section 4.3).
The concomitant use of trabectedin with alcohol must be avoided (see section 4.5).
Men in fertile age and women of childbearing potential must use effective contraception during treatment and 3 months thereafter for women and immediately inform the treating physician if a pregnancy occurs, and 5 months after treatment for men (see section 4.6).
This medicine contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially “potassium-free”.
See also PLD Summary of Product Characteristics for more detailed information on warnings and precautions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effects of other substances on trabectedin
In vivo interaction studies have not been performed. Since trabectedin is metabolised mainly by CYP3A4, co-administration of substances that inhibit this isoenzyme e.g. ketoconazole, fluconazole ritonavir, clarithromycin or aprepitant could decrease metabolism and increase trabectedin concentrations. If such combinations are needed, close monitoring of toxicities is required (see section 4.4). Likewise co-administration with potent inducers of this enzyme (e.g. rifampicin, phenobarbital, Saint John's Wort) may decrease the systemic exposure to trabectedin.
Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of the medicinal product (see section 4.4).
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. CNS toxicity has not been established. Caution should be taken in such situations.
4.6 Pregnancy And Lactation
Pregnancy
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 should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus (see section 5.3) and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns.
Breast-feeding
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 (see section 4.3).
Fertility
Men in fertile age and women of childbearing potential must use effective contraception during treatment and 3 months thereafter for women and immediately inform the treating physician if a pregnancy occurs (see section 5.3) and 5 months after treatment for men (see section 4.4).
Trabectedin can have genotoxic effects. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Yondelis.
If pregnancy occurs during treatment the possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy.
4.7 Effects On Ability To Drive And Use Machines
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 events during therapy must not drive or operate machines.
4.8 Undesirable Effects
Unless otherwise specified, the following safety profile of Yondelis is based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for both indications.
Most patients treated with Yondelis 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, increases in AST/ALT, anemia, 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.
Adverse reactions
The frequencies of the adverse reactions reported below are classified as very common (
The table below displays the adverse reactions reported in 2, 24 hour infusion every 3 weeks) according to the standard MedDRA system organ class. Both adverse reactions and laboratory values have been used to provide frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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* Derived from laboratory data
The table below provides the frequency and severity of undesirable effects considered possibly related to study drug and reported in 2/PLD 30 mg/m2 or PLD 50 mg/m2 in the pivotal trial ET743-OVA-301. Both adverse reactions and laboratory values have been used. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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