Composition, form of production and packaging
Liofilizate for the preparation of a solution for infusions in the form of white or almost white powder.
trabeticin 1 mg
Excipients: sucrose (sucrose), potassium phosphate monosubstituted, phosphoric acid 0.1N, potassium hydroxide 0.1M (for pH correction).
Glass bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
Antitumor drug. Trabecectin is a tristetrahydroisoquinoline alkaloid of natural (marine) origin, first isolated from the Caribbean shell of Ecteinascidia turbinate. The drug has a complex mechanism of action, aimed at transcription. It suppresses the transcription of genes and interacts with the nucleotide repair system associated with transcription.
Trabecectin binds to a small groove of DNA, as a result of which the DNA helix curves toward the large groove. This triggers a cascade of processes that affect DNA transcription factors, proteins that bind to DNA, and DNA repair mechanisms, which ultimately leads to a disruption in the cell cycle.
Trabecectin has an antiproliferative effect in vitro and in vivo in a number of cultures of human tumor cells and in experimental tumors, including sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer and melanoma.
In in vitro and in vivo studies on xenotransplantation models, the additive or synergistic effect of trabectidine when combined with doxorubicin is shown.
Systemic exposure of Trabeticin after IV infusion at a constant rate is proportional to the administered dose up to a dose of 1.8 mg / m 2 inclusive. The pharmacokinetics of trabecdetin corresponds to a multi-compartment model of distribution.
Trabecectin has a large V d -> 5000 l, which is consistent with the extensive distribution in peripheral tissues.
Trabecectin binds to a large extent with blood plasma proteins; at plasma concentrations of 10 and 100 ng / ml, the free fraction is 2.23% and 2.72%, respectively.
With the introduction of 1 time in 3 weeks cumulation of the drug in the blood plasma was not detected.
Trabecectidine is actively metabolized. At clinically significant concentrations, oxidation takes place mainly with the CYP3A4 isoenzyme, but other enzymes of the cytochrome system can not be excluded from the metabolism of trabecadine. There was no significant glucuronidation of trabektidine.
T 1/2 is 175 hours.
After administration of radioactivity labeled trabektedin, the average amount of radioactivity in the feces (24 days) and in the urine (10 days) was 58% (17%) and 5.8% (1.73%) of the administered dose, respectively. In unchanged form with urine and feces, <1% of the administered dose of the drug is excreted. The clearance of trabektidine in whole blood is approximately 35 l / h, which is approximately half the blood flow through the human liver. Thus, the capture of trabecbudin in the liver can be considered moderate. The spread of the values вЂ‹вЂ‹of clearance of trabecadine in blood plasma reaches 28-49%.
Pharmacokinetics in special clinical cases
Population analysis of pharmacokinetics has shown that the clearance of trabectidine in the blood plasma does not depend on body weight (36-148 kg), body surface area (0.9-2.8 m 2 ), age (19-83 years) and sex of patients. The impact of race and ethnicity on this indicator has not been studied.
Kidney function, determined by QC, in the range of clinical participants (? 30.3 ml / min), did not significantly affect the pharmacokinetics of trabektidine. For patients with QC less than 30.3 ml / min there is no data. Low detection of radioactivity in the urine after a single injection of 14 C-trabektidine (<9% in all patients) suggests that impaired renal function has little effect on the excretion of trabektidine and its metabolites.
In patients with impaired hepatic function, the clearance of trabaktidine can decrease with a corresponding increase in the concentration of the drug in the blood plasma.
ovarian cancer, recurring after therapy based on platinum derivatives (Yondelis В® used in combination therapy with pegylated liposomal doxorubicin);
- common soft tissue sarcomas in patients not susceptible to anthracyclines and ifosfamide, or with contraindications to their use; effectiveness is shown mainly in patients with liposarcoma and leiomyosarcoma.
For the treatment of common soft tissue sarcoma, the recommended initial dose is 1.5 mg / m 2 body surface area in the form of a 24-hour IV infusion at intervals of 3 weeks.
For the treatment of recurrent ovarian cancer, Yondelis В® is prescribed in combination with pegylated liposomal doxorubicin (eg with Kelix) every 3 weeks. YondelisВ® is administered at a dose of 1.1 mg / m 2 as a 3-hour intravenous infusion after the administration of pegylated liposomal doxorubicin at a dose of 30 mg / m 2 as a 60-minute IV infusion.
All patients should undergo premedication of GCS, for example, dexamethasone 20 mg IV every 30 minutes before each infusion of the Yondelis В® drug to prevent vomiting, and also possible hepatoprotective action. If necessary, additional antiemetics may be used. The drug is recommended to enter through a central venous catheter.
Yondelis В® can be administered only at the following laboratory parameters:
- the absolute content of neutrophils (ASN)? 1500 / Ојl;
- the content of platelets? 100,000 / ОјL;
- the level of hemoglobin? 9 g / dL;
- the concentration of bilirubin not exceeding VGN;
- the activity of AF (not associated with damage to the osseous system), which does not exceed 2.5 times the IHT (if the activity of the AF is increased, possibly related to the lesion of the bone system, it is necessary to determine the activity of hepatic isoenzymes of 5-nucleotidase or GGT);
- ALT and ACT activity, which do not exceed 2.5 times the VGN;
- the content of albumin? 25 g / l;
- QA? 30 ml / min.
With combined therapy:
- at a concentration of serum creatinine? 1.5 mg / dl (? 132.6 Ојmol / L) or QC? 60 ml / min;
- CKK activity not exceeding 2.5 times VGN.
Repeated infusions of the Yondelis В® preparation can also be carried out only if the above criteria are met. Otherwise, the infusion is delayed for up to 3 weeks until the laboratory blood indices meet the above criteria, and the drug is administered at the same dose, in the absence of other non-hematological adverse events of grade 3-4 according to the classification of the National Cancer Institute of the United States.
If the toxicity persists for more than 3 weeks, treatment can be considered.
Correction of dose during treatment
During the first two 3-week cycles of activity, AP, CK, aminotransferases (ALT and ACT) and bilirubin concentration should be monitored weekly, and in subsequent cycles, at least 1 time between infusions.
The dose of the drug with the next infusion is reduced to 1.2 mg / m 2 with monotherapy and up to 0.9 mg / m in combination therapy with the appearance at any time between infusions of at least one of the following phenomena:
- neutropenia <500 / ОјL, persisting for more than 5 days or accompanied by a fever or infection;
- Thrombocytopenia <25 000 / ОјL;
- Increase in bilirubin concentration above VGN;
- Increase in activity of APF (not related to lesion of the bone system) more than 2.5 times higher than VGN;
- an increase in the activity of aminotransferases (ACT or ALT) is more than 2.5 times higher than ULN, not normalized by the 21st day of the cycle;
with combined therapy:
- an increase in ACT or ALT activity is more than 5 times higher than ULN, not normalized by the 21st day of the cycle. The dose of pegylated liposomal doxorubicin should also be reduced to 25 mg / m 2 ;
- Any undesirable phenomenon of 3 or 4 severity (for example, nausea, vomiting, weakness).
After dose reduction due to toxicity, its reverse increase in subsequent cycles is not recommended. If any of the toxic reactions reappears in subsequent cycles, and the treatment gives a favorable clinical effect, the dose may be further reduced to 1 mg / m 2 with monotherapy with Yondelis В® or up to 0.75 mg / m 2 when used with the Yondelis В® drug in the combination therapy. If an additional dose reduction is required, treatment can be considered. Colony-stimulating factors can be introduced to correct hematologic toxicity in subsequent cycles.
In elderly patients with different types of tumors, there were no significant differences in safety or efficacy indicators. Population analysis of pharmacokinetics indicates the absence of influence of the age of patients on clearance and V d of trabecdine. Therefore, dose adjustment according to age is usually not recommended.
In patients with impaired liver function, the risk of toxicity can be increased. The use of trabektidine in patients with impaired liver function has not been sufficiently studied. Clear recommendations on the initial dose of the drug for this category of patients are currently not available. In the treatment of such patients, care should be taken. A dosage adjustment is possible to reduce the risk of hepatotoxicity. Yondelis В® can not be used with an increased concentration of bilirubin.
Studies with patients with renal insufficiency ( CC <30 ml / min , with combined therapy - <60 ml / min ) have not been carried out, therefore Yondelis В® can not be used in these categories of patients. A mild to moderate impairment of kidney function is unlikely to affect the pharmacokinetics of trabecadine.
Recommendations for the preparation of solution
For infusion, Yondelis В® is dissolved and diluted using appropriate aseptic techniques and compliance with the rules for handling cytotoxic drugs. Add 20 ml of sterile water for injections into a vial of 1 mg of trabaktidine and shake until completely dissolved, to obtain a solution at a concentration of 0.05 mg / ml. The solution should be clear, colorless or brownish-yellow, with no visible particles.
Before the infusion, the resulting solution is diluted. To dilute the solution use 0.9 solution of sodium chloride or 5% solution of dextrose. Yondelis В® can not be mixed or diluted with other drugs.
For infusion through the central venous catheter, the required amount of the solution containing the required dose of the drug is taken from the vial with a syringe and inserted into an infusion bag / vial containing at least 500 ml of 0.9% sodium chloride solution or 5% dextrose solution.
If there is no possibility of infusion into the central vein and the need to introduce into the peripheral vein the required amount of solution is injected into the infusion bag / vial containing not less than 1000 ml of 0.9% sodium chloride solution or 5% dextrose solution.
After the introduction of the infusion solution of pegylated liposomal doxorubicin and before the administration of the Yondelis В® preparation, the IV system should be thoroughly washed with 5% aqueous dextrose solution. Pegylated liposomal doxorubicin should not be mixed with 0.9% sodium chloride solution.
Before administration, parenteral solutions are visually inspected for lack of particles and discoloration. After dissolution and dilution, the solution is chemically and physically stable for 30 hours at 25 В° C. After dissolution, the solution should be diluted immediately. The total time from dissolution to the end of administration to the patient should not exceed 30 hours.
Yondelis В® does not show incompatibility with polyvinyl chloride and polyethylene infusion bags and tubes, as well as with titanium intravascular catheters.
Most often (effects of any severity): neutropenia, nausea, vomiting, increased activity of AST and ALT, anemia, weakness, thrombocytopenia, anorexia, diarrhea.
Lethal outcome due to adverse events: 1.9% of patients with monotherapy, 0.9% - with combined therapy. Death usually came as a result of a combination of side effects, including pancytopenia and febrile neutropenia (in some cases with the development of sepsis), liver damage, renal or multiple organ failure and rhabdomyolysis.
The following are adverse reactions that have been evaluated as likely or possibly related to the use of the Yondelis В® drug and which have been observed in в‰Ґ1% of cases. Determination of the frequency of adverse reactions: very often (? 1/10), often (from <1/10 to? 1/100), infrequently (from <1/100 to? 1/1000). In parentheses, the incidence of adverse reactions (%) is indicated.
On the part of laboratory indicators: very often - an increase in the activity of serum CK (3-4 degrees - 4%), an increase in the concentration of creatinine, a decrease in the concentration of albumin in the blood serum; often - a decrease in body weight; 23-26% - increase in the level of CKK of any degree; less than 1% - an increase in the level of CK in combination with rhabdomyolysis.
From the hemopoietic system: very often - neutropenia, thrombocytopenia, anemia, leukopenia; often - febrile neutropenia.
Neutropenia is the most common manifestation of hematological toxicity. Neutropenia of grade 3 and 4 was observed in 19% and 8% cycles, respectively. Neutropenia was reversible and was rarely accompanied by a fever or infection. Thrombocytopenia of grade 3 and 4 was observed in 3% and <1% cycles, respectively.Thrombocytopenia-associated bleeding was <1% in patients treated with monotherapy. Anemia - 93% and 94% of patients with monotherapy and combination therapy, respectively. Anemia of grade 3 and 4 was observed in 3% and 1% cycles, respectively.
From the digestive system: very often - vomiting (3-4 degrees - 6.5%), nausea (3-4 degrees - 6%), constipation (3-4 degrees - <1%); often diarrhea (3-4 degrees - <1%), stomatitis (3-4 degrees - <1%), abdominal pain, indigestion, pain in the upper gastrointestinal tract.
On the part of the hepatobiliary system: very often - hyperbilirubinemia (grade 3 - 1%), increased ALT activity (3 degrees 38%, 4 degrees 3%), ACT (3 degrees 44%, 4 degrees 7% , GGT.
The transient increase in activity of ACT and ALT of the third degree was noted respectively in 12% and 20% of cycles, and 4 degrees - respectively in 1% and 2% of cycles. The median time to achieve the maximum activity of ACT and ALT was 5 days. In most cases this toxicity decreased to 1 degree or disappeared by 14-15 days, and only in <2% of cycles it took more than 25 days to normalize it. With the increase in the number of infusions, there was a tendency to decrease the activity of ACT and ALT. The bilirubin content increased to the maximum level approximately 7 days after the onset of its increase, and a week later the level of bilirubin was normalized. The frequency of jaundice, hepatomegaly and pain in the liver region did not exceed 1%. Mortality of patients due to liver damage did not exceed 1%.
From the nervous system: very often - headache; often peripheral sensory neuropathy, taste perversion, dizziness, paresthesia, insomnia.
From the cardiovascular system: often - lowering blood pressure, hot flushes.
On the part of the respiratory system: often - shortness of breath (3-4 degrees - 2%), cough. Dyspnoea of вЂ‹вЂ‹grade 3-4, regarded as associated with the use of trabektidine, was noted in 2% of patients.
From the skin and skin appendages: often - alopecia (observed in about 3% of patients with monotherapy).
From the musculoskeletal system: often - myalgia, arthralgia, back pain.
From the metabolism: very often - anorexia (3-4 degrees - <1%); often - dehydration, decreased appetite, hypokalemia.
Other: very often - weakness (3-4 degrees - 9%), increased fatigue (3-4 degrees - 1%); often - the attachment of secondary infections, fever, peripheral edema, reactions at the site of administration of the drug.
Post-marketing surveillance data: several cases of penetration of trabecadine into tissues have been reported with the development of necrosis and the need for surgical intervention.
Rare cases of hepatic insufficiency (including fatal cases) in patients with serious concomitant clinical conditions with treatment with trabecedin have been reported.Factors
risk, which probably contributed to the observed increase in toxicity of trabectidine in these cases, were: use of the drug in doses not appropriate, possible interaction with competitive substrates of the isoenzyme CYP3A4 or inhibitors of the isoenzyme CYP3A4, or lack of prophylaxis with dexamethasone.
In combination therapy with Yondelis В® and pegylated liposomal doxorubicin, clinically significant cases of rhabdomyolysis were observed in less than 1% of patients.
Rare cases of hypersensitivity reactions, with a very rare frequency of fatalities, were registered in the postmarketing period of observation, both with monotherapy with Yondelis В® and with combined therapy.
Penetration of trabecbudin in the tissue at the site of injection and tissue necrosis
Rare cases of penetration of trabecadine into tissues at the site of administration followed by tissue necrosis requiring surgical intervention were registered in the postmarketing period of observation.
In clinical studies and post-marketing reports of cases of septic shock patients both in mono- and combination therapy with Yondelis В® .
- active serious or uncontrolled infection;
- the period of lactation (breastfeeding);
- Hypersensitivity to the components of the drug.
With caution should be used drug in the human liver and / or kidney disease, as the level of CK, while suppression of bone marrow function.
PREGNANCY AND LACTATION
Do not use this drug during pregnancy and lactation (breast feeding).
The use of trabectedin in pregnancy can cause severe birth defects.
Men and women of childbearing age should use effective contraception during treatment and for 3 (women) or five (men) months after the end of treatment. Upon the occurrence of pregnancy, women should immediately notify your doctor.
APPLICATION FOR FUNCTIONS OF THE LIVER
Studies involving patients with renal failure (creatinine clearance <30 mL / min, with a combination therapy of <60 ml / min) was conducted, however YondelisВ® can not be used in these categories of patients. Mild to moderate impairment of renal function, it is not likely to affect the pharmacokinetics of trabectedin.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with impaired liver function the risk of toxicity may be increased. The use of trabectedin in patients with hepatic impairment has not been studied sufficiently. Clear recommendations on the initial dose of the drug for this patient no. In the treatment of such patients should be particularly careful. Possible dose adjustment to reduce the risk of hepatotoxicity. YondelisВ® can not be used at high concentrations of bilirubin.
APPLICATION FOR CHILDREN
Safety and efficacy of trabectedin in children is not currently installed. Therefore, Yondelis В® should not be used in children until further data will be received.
APPLICATION IN ELDERLY PATIENTS
In elderly patients with different types of tumors found no significant differences in safety or effectiveness indicators. Population pharmacokinetic analysis indicates the absence of the influence of patient age on the clearance and the V d trabectedin. Therefore dosage adjustment based on age, is generally not recommended.
Yondelis В® should be used under the supervision of a physician with experience in cancer chemotherapy.
Since the degree of hepatic insufficiency systemic exposure trabectedin probably enhanced, and may increase the risk of hepatotoxicity, then the patients with clinically significant liver disease, such as chronic active hepatitis and careful observation is required and when necessary dose adjustments. At elevated concentrations of bilirubin another infusion of trabectedin is impossible to carry out.
Reversible sharp increase in ACT and ALT activity was observed in patients treated with monotherapy and combination therapy with Yondelis В® . Patients with increased activity of ACT, ALT or alkaline phosphatase cycles between drug administration YondelisВ® may require dose reduction.
Before and during treatment should control the spacecraft. Trabectedin can not be used in patients with creatinine clearance <30 mL / min in monotherapy or in patients with creatinine clearance <60 mL / min in a combination therapy.
Prior to treatment, a weekly basis during the first two cycles and then 1 times for each next frame should be a full blood analysis including blood platelets and leukocytic formula. Yondelis В® should not be administered to patients with neutropenia less than 1500 / l, thrombocytopenia less than 100,000 / ml. In identifying severe neutropenia (less than 500 / ml) for 5 days or febrile infection recommended dose reduction.
When combination therapy is often observed leucopenia 3 or 4 degrees. The lower limit of the number of neutrophils norms observed, with a median of 15 days and recovered within a week.
All patients should be premedicated with corticosteroids, such as dexamethasone. Additional anti-emetics may be used if necessary.
Trabectedin can not be used in patients with CPK activity exceeding ULN more than 2.5 times.
Rhabdomyolysis is rarely observed, serious increase in CK activity were 4% and 2% in monotherapy and combination therapy, respectively, typically in the presence of myelotoxicity, severe liver dysfunction or renal failure. Therefore, at occurrence of any of these forms of toxicity, as well as muscle weakness or pain in the muscles, it is necessary to monitor the patient's condition. In the case of rhabdomyolysis should immediately start maintenance therapy, e.g., a liquid load and dialysis alkalization urine depending on the testimony. Use of the drug Yondelis В® stopped before complete resolution rhabdomyolysis. Caution should be exercised when applying trabectedin simultaneously with drugs able to induce rhabdomyolysis, such as statins.
It is strongly recommended infusion through a central venous catheter. When administered in a peripheral vein trabectedin is possible to develop potentially severe reactions at the injection site. It noted a few cases of trabectedin penetration in tissue necrosis with the development and the need for surgical intervention.
Specific antidote trabectedin when penetrating into the tissue does not exist.
In post-marketing follow-up of identified rare cases of hypersensitivity reactions (very rarely - fatal) as a monotherapy and in combination therapy.
Caution should be exercised when applying trabectedin simultaneously with drugs that provide hepatotoxic effect, as it increases the risk of hepatotoxicity.
During treatment trabectedin patients should avoid alcohol.
Trabectedin may have a genotoxic effect. Before treatment, the patient should be counseled about the feasibility of sperm preservation due to the possibility of infertility in the application of the drug Yondelis В® .
Use in Pediatrics
Safety and efficacy of trabectedin in children is not currently installed. Therefore, Yondelis В® should not be used in children until further data will be received.
Precautions when handling the drug
Yondelis В®- it is a cytotoxic anticancer drug and, as with other toxic substances when handling it is necessary to be cautious. It is necessary to observe the rules for handling and disposal of cytotoxic drugs.
In case of accidental contact of the drug to the skin, mucous membranes or eyes immediately wash the contact with water.
Unused medication waste and must be disposed of in accordance with local requirements for disposal of cytotoxic drugs.
Impact on the ability to drive vehicles and manage mechanisms
Some side effects of the drug, such as weakness / asthenia, may adversely affect driving ability and the performance of potentially hazardous activities that require high concentration and psychomotor speed reactions. Therefore, patients should refrain from driving vehicles and mechanisms during reception Yondelis preparationВ® .
Data on the effects of trabectedin overdose is very limited.
Symptoms: primary toxicity are expected gastrointestinal toxicity, bone marrow depression and liver toxicity.
Treatment: at present no specific antidote for trabectedin not. In the case of an overdose should monitor the patient's condition and implement symptomatic and supportive therapy, if necessary.
Since trabectedin metabolized mainly isoenzyme CYP3A4, simultaneous application of potential inhibitors of this isozyme, e.g., ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant may trabectedin increase the concentration in the blood. If necessary, the use of such combinations should be carefully monitored the development of toxicity.
Population pharmacokinetic analysis showed that the concentration of trabectedin is increased by 19% while the use of dexamethasone. Application isoenzyme inducers of CYP3A4, such as rifampin, phenobarbital, Hypericum perforatum preparations may further increase the clearance of trabectedin.
Preclinical studies have demonstrated that trabectedin is a substrate for P-glycoprotein (P-gp). The simultaneous use of inhibitors of P-gp, such as cyclosporin and verapamil, can alter the distribution and / or elimination of trabectedin. The clinical relevance of this interaction, e.g., for the development of toxicity to the central nervous system, has not been established. Caution should be exercised while the use of trabectidin and inhibitors of P-glycoprotein.
Trabectedin not activated and does not inhibit the major enzymes of cytochrome P450 in vitro.
Studies have shown comparable figures for plasma pharmacokinetics of pegylated liposomal doxorubicin dose of 30 mg / m 2 when applied at a dose of trabectedin 1.1 mg / m 2compared with monotherapy with pegylated liposomal doxorubicin.
Avoid joint use drug Yondelis В® with potent inhibitors isoenzyme CYP3A4. If this is not possible, it is necessary to conduct a thorough monitoring of toxicity and should consider reducing the dose of trabectedin.
With simultaneous use of trabectedin with phenytoin may decrease the absorption of phenytoin, which leads to aggravation of seizures. Not recommended simultaneous use of trabectedin with phenytoin.
Not recommended simultaneous use of trabectedin with live attenuated vaccines. The combined use of yellow fever vaccine is contraindicated and trabectedin.
During treatment trabectedin patients should avoid alcohol because of hepatotoxicity.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of reach of children at a temperature of from 2 В° to 8 В° C. Shelf life - 3 years.
After dissolving the chemical and physical stability of the preparation stored for 30 hours at a temperature not exceeding 25 В° C.
From a microbiological point of view, the solution should be diluted and used immediately. Otherwise, the time and conditions of storage of the solution remain at the user's discretion, but should normally not exceed 24 hours at a temperature of from 2 В° to 8 В° C (unless dissolution was carried out under controlled aseptic conditions and verified).