Yondelis

Yondelis

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Trabectedin.
Description
Each mL of reconstituted solution contains trabectedin 0.05 mg.
Each vial also contains the following excipients: Sucrose, potassium dihydrogen phosphate, phosphoric acid and potassium hydroxide for pH adjustment.
Action
Pharmacotherapeutic Group: Antineoplastic agent. ATC Code: L01CX01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Trabectedin binds to the minor groove of DNA, bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA-binding proteins and DNA-repair pathways, resulting in perturbation of the cell cycle. Trabectedin has been shown to exert antiproliferative in vitro and in vivo activity against a range of human tumour cell lines and experimental tumours, including malignancies eg, sarcoma, breast, nonsmall cell lung, ovarian and melanoma.
Clinical Efficacy: The efficacy and safety of trabectedin is based in a randomized trial in patients with locally-advanced or metastatic liposarcoma, or leiomyosarcoma, whose disease had progressed or relapsed after treatment with at least anthracyclines and ifosfamide. In this trial, trabectedin was administered either at 1.5 mg/m2 as a 24-hr IV infusion every 3 weeks or at 0.58 mg/m2 weekly as a 3-hr IV infusion for 3 weeks of a 4-week cycle. There were no predefined limits to the number of cycles administered. Treatment continued while clinical benefit was noted. No cumulative toxicities were observed in patients treated with multiple cycles. The protocol specified final time of progression (TTP) analysis showed a 26.6% reduction in the relative risk of progression for patients treated in the 24-hr every 3-week group (hazard ratio=0.734; CI: 0.554-0.974). Median TTP values were 3.7 months (CI: 2.1-5.4 m) in the 24-hr every 3-week group and 2.3 months (CI: 2-3.5 m) in the 3-hr every week group (p=0.0302). No significant differences were detected in overall survival (OS). Median OS with the 24-hr every 3-week regimen was 13.8 months (CI: 12.5-17.9) and 60.6% of patients were alive at 1 year (CI: 52.3-68.9%).
Additional efficacy data are available from 3 single-arm, phase II trials with similar populations treated with the same regimen. These trials evaluated a total of 100 patients with lipo- and leiomyosarcoma, and 83 patients with other types of sarcoma.
Pharmacokinetics: Systemic exposure after administration as a constant rate IV infusion is dose proportional at doses up to and including 1.8 mg/m2. The pharmacokinetic profile is consistent with a multiple-compartment disposition model, including a terminal half-life (t½) in plasma of 175 hrs. The concentrations of trabectedin in plasma do not accumulate when administered every 3 weeks.
Distribution: Trabectedin has a large volume of distribution (>5000 L), consistent with extensive distribution into peripheral tissues.
Trabectedin is highly bound to plasma proteins. The mean free (unbound) fraction in plasma is 2.23% and 2.72% at a total plasma concentration of 10 ng/mL and 100 ng/mL, respectively.
Metabolism: Trabectedin is extensively metabolized. Cytochrome P-450 3A4 is the major cytochrome P-450 isozyme responsible for the oxidative metabolism of trabectedin at clinically relevant concentrations. The contribution of other P450 enzymes to the metabolism of trabectedin cannot be ruled out. No appreciable glucuronidation of trabectedin has been observed.
Elimination: The mean standard deviation (SD) recovery of total radioactivity was 58% (17%), and 5.8% (1.73%) in the feces (24 days) and urine (10 days), respectively, after a dose of radiolabeled trabectedin was administered to 8 cancer patients. Negligible quantities (<1% of the dose) of unchanged drug are excreted in the feces and in urine. The clearance of trabectedin in whole blood is approximately 35 L/hr. This value is approximately ½ the rate of human hepatic blood flow. Thus, the trabectedin extraction ratio can be considered moderate. The interpatient variability of the population estimate for plasma clearance of trabectedin was 49% and intrapatient variability was 28%.
Special Populations: A population pharmacokinetic analysis indicated that the plasma clearance of trabectedin is not influenced by total bodyweight (36-148 kg), body surface area (0.9-2.8 m2), age (19-83 years) or gender. The effects of race and ethnicity on trabectedin pharmacokinetics have not been studied.
Impaired Renal Function: There is no relevant influence of renal function measured by creatinine clearance on trabectedin pharmacokinetics within the range of values (≥30.3 mL/min) present in the patients included in the clinical studies. No data are available in patients with a creatinine clearance of <30.3 mL/min. The low recovery (<9% in all studied patients) of total radioactivity in the urine after a single dose of 14C-labelled trabectedin suggests that renal impairment would have little influence on the elimination of trabectedin or its metabolites.
Impaired Hepatic Function: The clearance of trabectedin may be decreased in patients with hepatic impairment; resulting in higher concentrations of trabectedin in plasma. Close monitoring of toxicity is warranted when administering trabectedin to patients with impaired hepatic function.
Toxicology: Preclinical Safety Data: Preclinical data indicate that trabectedin has limited effect on the cardiovascular, respiratory and central nervous system at exposures below the therapeutic clinical range in terms of AUC.
The effects of trabectedin on cardiovascular and respiratory functions have been investigated in vivo (anesthetized Cynomolgus monkeys). A 1-hr infusion schedule was selected to attain maximum plasma levels (Cmax values) in the range of those observed in the clinic. The plasma trabectedin levels attained were 10.6±5.4 (Cmax), similar to those reached after administration of 1.1 mg/m2 in a 3-hr infusion (Cmax of 7.9±2 ng/mL).
Myelosuppression and hepatotoxicity were identified as the primary toxicity for trabectedin. Findings observed included haematopoietic toxicity (severe leukopenia, anaemia, and lymphoid and bone marrow depletion) as well as increases in liver function tests, hepatocellular degeneration, intestinal epithelial necrosis and severe local reactions at the injection site.
Renal toxicological findings were detected in multicycle toxicity studies conducted in monkeys. These findings were secondary to severe local intolerance at the administration site (ie, catheter tip location), with severe damage of surrounding tissues (eg, the kidneys) and therefore uncertainly attributable to trabectedin; however, caution must be exercised in the interpretation of these renal findings and treatment-related toxicity cannot be excluded.
Trabectedin is genotoxic both in vitro and in vivo. Long-term carcinogenicity studies have not been performed.
Fertility studies with trabectedin were not performed but limited histopathological changes were observed in the gonads in the repeat-dose toxicity studies. Considering the nature of the compound (cytotoxic and mutagenic), it is likely to affect the reproductive capacity.
Indications/Uses
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.
Dosage/Direction for Use
Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to personnel specialized in the administration of cytotoxic agents.
Recommended Starting Dose: 1.5 mg/m2 body surface area, administered as an IV infusion over 24 hrs with a 3-week interval between cycles.
Administration through a central venous line is strongly recommended (see Instructions for Use, Handling and Disposal under Cautions for Usage).
All patients must be premedicated with corticosteroids eg, dexamethasone IV 20 mg, 30 min before each Yondelis infusion; not only as antiemetic prophylaxis but also because it appears to provide hepatoprotective effects. Additional antiemetics may be administered as needed.
The following criteria are required to allow treatment with Yondelis: Absolute neutrophil count (ANC) ≥1500/mm3; platelet count ≥100,000/mm3; bilirubin ≤upper limit of normal (ULN); alkaline phosphatase ≤2.5 x ULN [consider hepatic isoenzymes 5-nucleotidase or γ-glutamyl transpeptidase (GGT), if the elevation could be osseous in origin]; albumin ≥25 g/L; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN; creatinine clearance ≥30 mL/min; creatine phosphokinase (CPK) ≤2.5 x ULN; haemoglobin ≥9 g/dL.
The same criteria as mentioned previously (except if CPK >2.5 x ULN) must be met prior to initiation of next cycles. Otherwise, treatment must be delayed for up to 3 weeks until the criteria are met. If these toxicities persist beyond 3 weeks, treatment discontinuation should be considered.
Additional monitoring of haematological parameters [alkaline phosphatase, bilirubin, CPK and aminotransferases (AST and ALT)] should occur weekly during the first 2 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 fulfills the re-treatment criteria.
Dose Adjustments During Treatment: Prior to re-treatment, patients must fulfill the baseline criteria as previously mentioned. If any of the following events occur at any time between cycles, the dose must be reduced to 1.2 mg/m2 for subsequent cycles: Neutropenia <500/mm3 lasting for >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 which has not recovered by day 21; any other grade 3 or 4 adverse reactions (eg, 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 to 1 mg/m2. In the event that further dose reductions are necessary, treatment discontinuation should be considered.
For instructions on reconstitution and dilution of Yondelis before administration, see Instructions for Use, Handling and Disposal under Cautions for Usage.
Duration of Treatment: In clinical trials, there were no predefined limits to the number of cycles administered.
Treatment continued whilst clinical benefit was noted. Trabectedin has been administered for 6 or more cycles in 168 out of 569 (29.5%) patients treated with the proposed dose and schedule. This regimen has been used for up to 38 cycles. No cumulative toxicities have been observed in patients treated with multiple cycles.
Special Patient Populations: Children: The safety and efficacy of trabectedin in children have not yet been established. Therefore, Yondelis should not be used in children and adolescents until further data become available.
Elderly: No specific studies in elderly patients have been performed. Overall, 19% of the 1132 patients in the integrated safety analysis were >65 years. No relevant differences in the safety profile were seen in this patient population. Results from population pharmacokinetic analyses indicate that the 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: Patients with hepatic impairment may be at increased risk for toxicity. Recommendations for a starting dose in these patients cannot be made since the use of trabectedin in patients with impaired hepatic function has not been adequately studied. 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 at the time of cycle initiation must not be treated with Yondelis (see Precautions).
Renal Impairment: Studies including patients with severe renal insufficiency (creatinine clearance <30 mL/min) have not been conducted and therefore, Yondelis must not be used in this patient population (see Precautions). The pharmacokinetics of trabectedin are not expected to be impacted by mild to moderate renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
There is limited data on the effects of trabectedin overdosage. The major anticipated toxicities are gastrointestinal, bone marrow suppression and hepatic toxicity. There is no specific antidote for trabectedin currently available. In the event of an overdosage, patients should be closely monitored and symptomatic supportive care measures instituted as required.
Contraindications
Hypersensitivity to trabectedin or to any of the components of Yondelis; patients with an active serious or uncontrolled infection.
Use in lactation: Yondelis should not be administered to breastfeeding women.
It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been studied in animals. Breastfeeding is contraindicated during treatment and 3 months thereafter.
Special Precautions
Hepatic Impairment: Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since systemic exposure to trabectedin may be increased due to hepatic impairment and therefore the risk of hepatotoxicity might be increased, patients with clinically relevant liver diseases eg, active chronic hepatitis, must be closely monitored and the dose adjusted if needed. Patients with elevated bilirubin at the time of cycle initiation must not be treated with trabectedin (see Dosage & Administration).
Renal Impairment: Creatinine clearance must be monitored prior to and during treatment. Trabectedin must not be used in patients with creatinine clearance <30 mL/min (see Dosage & Administration).
Neutropenia and Thrombocytopenia: Grade 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 2 cycles and then once between cycles (see Dosage & Administration). Yondelis should not be administered to patients with baseline neutrophil counts of <1500 cells/mm3 and platelet count <100,000 cells mm3. If severe neutropenia (ANC <500 cells/mm3) lasting >5 days or associated with fever or infection occur, dose reduction is recommended (see Dosage & Administration).
Nausea and Vomiting: Grade 3 or 4 vomiting and nausea were reported commonly. All patients must be premedicated with corticosteroids eg, dexamethasone. Additional antiemetics may be administered as needed (see Dosage & Administration).
Rhabdomyolysis and Severe Creatine Phosphokinase (CPK) Elevations (>5 x ULN): Trabectedin must not be used in patients with CPK >2.5 ULN (see Dosage & Administration). Rhabdomyolysis has been uncommonly reported and severe CPK elevation was observed in 4% of patients treated with Yondelis monotherapy, usually in association with myelotoxicity, severe liver function test abnormalities and/or renal 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 eg, parenteral hydration, urine alkalinization 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 (eg, statins), are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased.
Liver Function Test (LFT) Abnormalities: Reversible acute increases in AST and ALT have been reported in patients treated with Yondelis monotherapy. Grade 3 or 4 transaminase elevations occurred very commonly; grade 4 elevations occurred commonly. The median time to the occurrence of ALT or AST increase to grade 3 or 4 levels was 8 days. Elevated levels decreased below grade 3 or 4 in about 8 days. Transaminase elevations were noncumulative and decreased in magnitude, and incidence with each subsequent cycle. Yondelis must not be used in patients with elevated bilirubin at the time of initiation of cycle. Patients with increased AST, ALT and alkaline phosphatase between cycles may necessitate dose reduction (see Dosage & Administration).
Injection Site Reactions: The use of central venous access is strongly recommended (see Dosage & Administration). Patients may develop a potentially severe injection site reaction when trabectedin is administered through a peripheral venous line.
There have been few reported cases of trabectedin extravasation, with subsequent tissue necrosis requiring debridement. There is no specific antidote for extravasation of trabectedin. Extravasation should be managed by local standard practice (see Pharmacology: Toxicology under Actions).
Others: Co-administration of Yondelis with potent inhibitors of the enzyme CYP3A4 should be avoided (see Interactions). 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. The concomitant use of trabectedin with alcohol must be avoided.
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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and 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.
Impairment of 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 Pharmacology: Toxicology under Actions) and 5 months after treatment for men.
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.
Use in 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 Pharmacology: Toxicology: Preclinical Safety Data under Actions) and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns.
If pregnancy occurs during treatment, genetic counseling should be considered. Genetic counseling is also recommended for patients wishing to have children after therapy.
Use In Pregnancy & Lactation
Use in 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 Pharmacology: Toxicology: Preclinical Safety Data under Actions) and be monitored carefully. If trabectedin is used at the end of pregnancy, potential adverse reactions should be monitored carefully in the newborns.
If pregnancy occurs during treatment, genetic counseling should be considered. Genetic counseling is also recommended for patients wishing to have children after therapy.
Use in lactation: Yondelis should not be administered to breastfeeding women.
It is not known whether trabectedin is excreted in human milk. The excretion of trabectedin in milk has not been studied in animals. Breastfeeding is contraindicated during treatment and 3 months thereafter.
Adverse Reactions
Unless otherwise specified, the following safety profile of Yondelis is based on the evaluation in clinical trials of 569 patients treated up to April 2007 with the recommended treatment regimen in several cancer types including soft tissue sarcoma, breast cancer, osteosarcoma, ovarian cancer, gastrointestinal stroma tumor (GIST), melanoma and renal carcinoma.
Approximately 91% of patients can be expected to have adverse reactions of any grade. Around 40% of patients are expected to have adverse reactions of grade 3 or 4 severity. The most common adverse reactions of any severity grade were nausea, fatigue, vomiting, anorexia, neutropenia and increases in AST/ALT.
Fatal adverse reactions have occurred in 1.9% of patients. They were often the result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal failure and rhabdomyolysis.
The following information displays the adverse reactions reported in ≥1% of patients 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 frequency.
Treatment Emergent Drug-Related Adverse Events Reported in ≥1% of Patients in Clinical Trials at the Recommended Regimen (1.5 mg/m2, 24-hr infusion every 3 weeks): Investigations: Increased blood creatinine* (31%), increased blood creatine phosphokinase* (26%), decreased blood albumin* (55%), decreased weight (6%).
Blood and Lymphatic System Disorders: Anaemia* (97%), leukopenia* (93%), neutropenia* (79%), thrombocytopenia* (49%), febrile neutropenia (2%).
Nervous System Disorders: Headache (11%), dysgeusia (4%), peripheral sensory neuropathy (2%), dizziness (2%), paraesthesia(2%).
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea (5%), cough (1%).
Gastrointestinal Disorders: Nausea (63%), vomiting (39%), constipation (16%), diarrhea (10%), stomatitis (6%), abdominal pain (5%), dyspepsia (3%), upper abdominal pain (2%).
Skin and Subcutaneous Tissue Disorders: Alopecia (3%).
Musculoskeletal and Connective Tissue Disorders: Myalgia (5%), arthralgia (2%), back pain (1%).
Metabolism and Nutrition Disorders: Anorexia (20%), dehydration (2%), decreased appetite (1%), hypokalemia (1%).
Infections and Infestations: Infection (3%).
Vascular Disorders: Flushing (2%), hypotension (2%).
General Disorders and Administration Site Conditions: Fatigue (55%), asthenia (11%), pyrexia (6%), edema (2%), peripheral edema (2%), injection site reaction (2%).
Hepatobiliary Disorders*: Increased ALT (95%), increased AST (94%), increased GGT (84%), increased blood alkaline phosphatase (60%), hyperbilirubinemia (24%).
Psychiatric Disorders: Insomnia (2%).
Note:*Based on laboratory measurements.
Most Frequent Adverse Reactions: Blood and Lymphatic Disorders: Neutropenia: Neutropenia occurred in 79% of patients. Grades 3 and 4 neutropenia occurred in 27% and 24% of patients, respectively. Neutropenia followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection.
Thrombocytopenia: Grades 3 and 4 thrombocytopenia occurred in 18% and 3% of patients, respectively. Bleeding events associated to thrombocytopenia occurred in <1% patients.
Anaemia: Anaemia occurred in 97% of patients although 52% of patients were anaemic at baseline. Grades 3 and 4 anaemia occurred in 13% and 4% of patients, respectively.
Hepatobiliary Disorders: AST/ALT Increases: Transient grade 3 increases of AST and ALT were observed in 38% and 44% of the patients and grade 4 elevations in 3% and 7% of the patients, respectively. 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 and <2% of cycles had recovery times longer than 25 days. Increased ALT and AST did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.
Hyperbilirubinemia: Grades 1-2 bilirubin increases were observed in 23% of the patients. Grade 3 hyperbilirubinemia occurred in 1% of patients. Bilirubin peaks approximately a week after onset and resolves approximately 2 weeks after onset.
Clinical manifestations of severe hepatic injury were uncommon with a <1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in <1% of patients.
Other Adverse Reactions: Nausea, Vomiting, Diarrhoea and Constipation: Nausea and vomiting were reported in 63% and 39% of patients, respectively. Grade 3-4 nausea and vomiting were reported in 6% and 7% of patients, respectively. Grade 3-4 diarrhoea and constipation were reported in <1% of patients.
Stomatitis: Grade 3-4 mucositis was reported in <1% of the patients.
Fatigue/Asthenia: Grade 3-4 fatigue/asthenia occurred in 9% and 1% of patients, respectively.
Anorexia: Grade 3-4 anorexia occurred in <1% of the patients.
Creatine Phosphokinase (CPK) Elevations and Rhabdomyolysis: CPK elevations of any grade were observed in 26% of patients. Grade 3 or 4 increases of CPK were observed in 4% of patients. CPK increases in association with rhabdomyolysis were reported in <1% of patients.
Dyspnoea: Grade 3-4 dyspnoea reported as trabectedin-related occurred in 2% of the patients.
Alopecia: Alopecia was reported in approximately 3% of all patients, of which the majority was grade 1 alopecia.
Drug Interactions
Effects of Other Substances on Trabectedin: Since trabectedin is metabolized mainly by CYP3A4, the concentrations of trabectedin in plasma are likely to be increased in patients who are co-administered with drugs that potently inhibit the activity of this isoenzyme (eg, oral ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant). If such combinations are needed, close monitoring of toxicities is required.
Results from the population pharmacokinetic analyses (n=831 subjects) indicated that the plasma clearance of trabectedin was 19% higher in patients who received any concomitant dexamethasone administration relative to those who did not. The co-administration with potent inducers of CPY3A4 (eg, rifampicin, phenorbarbital, St. John's wort) may also further increase the metabolic clearance of trabectedin.
Preclinical data have demonstrated that trabectedin is a substrate to P-glycoprotein (P-gp). Concomitant administration of inhibitors of P-gp eg, cyclosporine and verapamil, may alter trabectedin distribution or elimination. The clinical relevance of this interaction eg, central nervous system toxicity, has not been established and caution should be exercised when concomitantly administering trabectedin with inhibitors of P-gp.
Impact of Trabectedin on Co-Administered Drugs: In vitro, trabectedin does not induce or inhibit major cytochrome P-450 enzymes.
Incompatibilities: Yondelis must not be mixed or diluted with medicinal products except those mentioned in Instructions for Use, Handling and Disposal under Cautions for Usage.
Caution For Usage
Instructions for Use, Handling and Disposal: Preparation for IV Infusion: Yondelis reconstitution and dilution of reconstitution solution must be conducted under aseptic conditions in a manner consistent with recommended safe procedures for handling cytotoxic compounds. Each vial containing trabectedin 1 mg is reconstituted with sterile water for injections 20 mL. The solution obtained has a concentration of 0.05 mg/mL and is for single-use only.
Instructions for Reconstitution: A syringe is used to inject sterile water for injections 20 mL into the vial. Shake the vial until complete dissolution. The reconstituted solution results in a clear, colourless to brownish yellow solution, essentially free of visible particles.
This reconstituted solution contains trabectedin 0.05 mg/mL. It requires further dilution and is for single-use only.
Instructions for Dilution: The reconstituted solution should be diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion. The required volume should be calculated as follows: Volume (mL): [BSA (m2) x individual dose (mg/m2)]/0.05 mg/mL.
BSA=Body surface area.
The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 500 mL of normal saline 0.9% solution for infusion or dextrose 5% solution for infusion if administration is to be made through a central venous line.
If central venous access is not feasible and a peripheral venous line has to be used, the reconstituted solution should be added to an infusion bag containing ≥1000 mL of normal saline 0.9% solution for infusion or dextrose 5% solution for infusion.
Parenteral solutions should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After reconstitution and dilution, chemical and physical stability has been demonstrated for 30 hrs up to 25°C. The reconstituted solution should be diluted and used immediately. The total elapsed time between initial reconstitution and end of treatment should not be longer than 30 hrs.
Instructions for Handling and Disposal: Yondelis is a cytotoxic anticancer medicinal product and as with other potentially toxic compounds, caution should be exercised during handling. Procedures for proper handling and disposal of cytotoxic medicinal products must be followed. Yondelis should be handled and disposed of in a manner consistent with other anticancer drugs. Accidental contact with the skin, eyes or mucous membranes must be treated immediately with copious amounts of water.
Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic medicinal products.
No incompatibilities have been observed between Yondelis and polyvinyl chloride (PVC) and polyethylene (PE) bags and tubings, and titanium implantable vascular access systems.
Storage
Store in a refrigerator (2°-8°C).
Shelf-Life: After reconstitution, chemical and physical stability has been demonstrated for 30 hrs up to 25°C.
From a microbiological point of view, the reconstituted solution should be diluted and used immediately. If not diluted and used immediately, in-use storage times and conditions prior to use of the reconstituted product are the responsibility of the user, and would normally not be longer than 24 hrs at 2°-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
After dilution, chemical and physical stability has been demonstrated for 30 hrs up to 25°C. The total holding time between initial reconstitution and the end of treatment should not be longer than 30 hrs.
ATC Classification
L01CX01 - trabectedin ; Belongs to the class of other plant alkaloids and natural products. Used in the treatment of cancer.
Presentation/Packing
Powd for infusion (vial) (lyophilized, sterile, white to off-white powd) 1 mg.
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