Yondelis® (Yondelis®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTrabecectinTrabecectin
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  • Yondelis®
    lyophilizate d / infusion 
    Johnson & Johnson, LLC     Russia
    • Dosage form: & nbspLyophilizate for solution for infusion.
    Composition:

    Each vial contains: active substance: Trabeticin 1 mg

    Excipients: sucrose (sucrose), potassium phosphate monosubstituted, phosphoric acid 0.1 N, potassium hydroxide 0.1 M (for pH correction)

    Description:White or almost white lyophilized powder.
    Pharmacotherapeutic group:Antitumor agent.
    ATX: & nbsp

    L.01.C.X   Alkaloids of plant origin and other preparations of natural origin

    L.01.C.X.01   Trabecectin

    Pharmacodynamics:
    Trabecectin is a tristetra-hydroisoquinoline alkaloid of natural (marine) origin, first isolated from the Caribbean shell of Ecteinascidia turbinata. 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
    to the violation of the cell cycle. Trabecectin has an antiproliferative effect in vitro in a number of cultures of human tumor cells and in vivo in experimental tumors, including sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer and melanoma.
    In studies in vitro and in vivo on xenotransplant models trabetedin showed an additive or synergistic effect when combined with doxorubicin.
    Pharmacokinetics:Systemic exposure of trabecdinedin after intravenous infusion at a constant rate is proportional to the administered dose up to a dose of 1.8 mg / m2 inclusive. Pharmacokinetics of trabecbetin corresponds to a multi-chamber model of distribution with a half-life of 175 hours. With the introduction of 1 time in 3 weeks of accumulation of the drug in the blood plasma was not detected.

    Distribution

    Trabecectin has a large volume of distribution (> 5000 liters), which is consistent with the extensive distribution of peripheral tissues.

    Trabecectin binds to a large extent with blood plasma proteins; at the total plasma concentrations of 10 and 100 ng / ml, the free fraction is 2.23% and 2.72%, respectively.

    Metabolism

    Trabecectidine is actively metabolized.At clinically significant concentrations, oxidation is carried out, mainly by isoenzyme CYP3A4, However, it is impossible to exclude the contribution of other isoenzymes of the cytochrome system to the metabolism of trabektidine.

    There was no significant glucuronidation of trabektidine.

    Excretion

    After the administration of radioactively labeled trabektidine, the average amount of radioactive

    in feces (24 days) and urine (10 days) were 58% (17%) and 5.8% (1.73%), respectively, of the administered dose. In unchanged form with urine and feces, <1% of the administered dose of the drug is excreted. The clearance of trabaktidine 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 ​​of clearance of trabecadine in blood plasma reaches 28 - 49%.

    Special categories of patients

    Population analysis of pharmacokinetics has shown that the clearance of trabectidine in blood plasma does not depend on body weight (36 - 148 kg), body surface area (0.9 - 2.8 m2), age (19 - 83 years) and sex of patients. The impact of race and ethnicity on this indicator has not been studied.

    Impaired renal function The renal function, as measured by creatinine clearance, in the range of participants in clinical trials (> 30.3 ml / min) did not significantly affect the pharmacokinetics of trabecadine. For patients with creatinine clearance less than 30.3 ml / min there is no data. Low detection of radioactivity in urine after a single administration 14C-trabektidine (<9% in all patients) suggests that renal dysfunction has little effect on the excretion of trabektidine and its metabolites.

    Impaired liver function In patients with impaired hepatic function, the clearance of trabecadine may decrease with a corresponding increase in the concentration of the drug in the blood plasma.

    Indications:
    Ovarian cancer recurring after therapy on the basis of platinum derivatives. Yondelis ® is used in combination with pegylated liposomal doxorubicin (hereinafter - combined therapy).
    Common soft tissue sarcomas in patients not susceptible to anthracyclines and ifosfamide, or with contraindications to their use. Efficacy is shown mainly in patients with liposarcoma and leiomyosarcoma.
    Contraindications:
    - hypersensitivity to any of the components of the drug;
    - active serious or uncontrolled infection;
    - pregnancy and the period of breastfeeding;
    Carefully:
    with violations of the liver and / or kidney function, with an increase in the level of creatine-phosphokinase, with oppression of bone marrow function.

    Dosing and Administration:

    Method of administration and dose For the treatment of common soft tissue sarcomas, the recommended initial dose is 1.5 mg / m2 the surface area of ​​the body in the form of a 24-hour intravenous infusion with an interval of 3 weeks.

    For the treatment of recurrent ovarian cancer, Yondelis® is prescribed in combination with pegylated liposomal doxorubicin (eg Kelix) every 3 weeks. Yondelis® is administered at a dose of 1.1 mg / m2 in the form of a 3-hour intravenous infusion after the administration of pegylated liposomal doxorubicin at a dose of 30 mg / m2 in the form of a 60-minute intravenous infusion.

    All patients should be premedicated with glucocorticosteroids, for example, dexamethasone 20 mg intravenously 30 minutes before each infusion of the drug Yondelis®, to prevent vomiting, and also possible hepatoprotective action. If necessary, additional anti-emetics may be used.The drug is recommended to enter through a central venous catheter.

    Yondelis ® can be administered only at the following laboratory parameters:

    - the absolute content of neutrophils (ASN) > 1500 / μL

    - the content of platelets > 100 000 / μL

    - hemoglobin level > 9 g / dL;

    - bilirubin concentration not exceeding the upper limit of the norm

    - activity of alkaline phosphatase (unrelated to the damage to the bone system), which does not exceed the upper limit of the norm by more than 2.5 times (with an increase in the activity of alkaline phosphatase, possibly associated with damage to the bone system, it is necessary to determine the activity of hepatic isoenzymes of 5-nucleotidase or gamma-glutamyl transpeptidase ) (GGT);

    - activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), not exceeding more than 2.5 times the upper limit of the norm;

    - albumin content > 25 g / l;

    - clearance of creatinine > 30 ml / min;

    With combined therapy:

    - at a concentration of serum creatinine <1.5 mg / dl (< 132.6 μmol / L) or creatinine clearance> 60 ml / min;

    - activity of creatine phosphokinase (CKF), which does not exceed the upper limit of the norm by more than 2.5 times;

    Repeated infusions of the drug Yondelis ® 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 of alkaline phosphatase, CK, aminotransferase (ALT and ACT) and the concentration of bilirubin 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 / m2 in monotherapy and up to 0.9 mg / m2 in the combination therapy at the appearance at any time between infusions of at least one of the following phenomena:

    - - neutropenia <500 / μL, persisting for more than 5 days or accompanied by fever or infection

    - - thrombocytopenia <25 000 / μL

    - - increase in bilirubin concentration above the upper limit of the norm

    increased activity of alkaline phosphatase (unrelated to lesion of the bone system), more than 2.5 above the upper limit of the norm

    - increased activity of aminotransferases (ACT or ALT) more than 2.5 times higher than the upper limit of the norm, not normalized to the 21 day of the cycle; With combined therapy:

    - - increased activity ACT or ALT more than 5 times higher than the upper limit of the norm, not normalized to the 21 day of the cycle. The dosage of pegylated liposomal doxorubicin should also be reduced to 25 mg / m2.

    - - 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 treatment gives a favorable clinical effect, the dose may be further reduced to 1 mg / m2 with monotherapy with Jondelis ® or up to 0.75 mg / m2 when using Yondelis® in combination therapy. If the dose is needed

    But to reduce still, it follows to consider possibility of cancellation of treatment. Colony-stimulating factors can be introduced to correct hematologic toxicity in subsequent cycles.

    Special categories of patients

    Children

    The safety and efficacy of trabecadine in children is not currently established. Therefore, Jondelis® should not be used in children until additional data are obtained.

    Elderly patients

    There were no significant differences in safety or efficacy in this category of patients with different types of tumors. Population analysis of pharmacokinetics testifies to the absence of influence of the age of patients on the clearance and the volume of distribution of trabektidine. Therefore, dose adjustment, based only on age, is usually not recommended. Patients with impaired liver function 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® should not be used with an increased concentration of bilirubin.

    Patients with impaired renal function Studies involving patients with renal insufficiency (creatinine clearance <30 ml / min, with combined therapy <60 ml / min) was not performed, therefore Yondelis ® 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® is dissolved and diluted using appropriate aseptic techniques and compliance with the rules for handling cytotoxic drugs. Add 20 ml of sterile water for injection into a bottle of 1 mg of trabaktidine and shake until completely dissolved, to obtain a solution with 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® can not be mixed or diluted with other drugs. For infusion through the central venous catheter, the required amount of 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 a 0.9% solution of sodium chloride or a 5% solution of dextrose.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 at least 1000 ml of a 0.9% solution of sodium chloride or a 5% solution of dextrose.

    After the introduction of the infusion solution of pegylated liposomal doxorubicin and the administration of the Yondelis® preparation, the intravenous system should be thoroughly washed with 5% aqueous dextrose. Pegylated liposomal doxorubicin can 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 ° C. After dissolution, the solution must be diluted immediately. The total time from dissolution to the end of administration to the patient should not exceed 30 hours.

    Yondelis® does not show incompatibility with polyvinyl chloride and polyethylene infusion bags and tubes, as well as with titanium intravascular catheters.

    Side effects:
    The most common adverse events of any severity were neutropenia, nausea, vomiting, increased activity of AST / ALT, anemia, weakness, thrombocytopenia, anorexia, diarrhea.
    Lethal outcome as a result of undesirable phenomena was recorded in 1.9% of patients with monotherapy and in 0.9% of patients with combined therapy. Death usually came as a result of a combination of adverse events, including pancytopenia and febrile neutropenia (in some cases with the development of sepsis), liver damage, renal or multi-organ failure and rhabdomyolysis. The following are undesirable phenomena that were regarded as likely or possibly associated with the use of the drug Yondelis® and which have been observed in more than> 1% of cases. The incidence of side effects was classified as very frequent (>1/10), frequent (from <1/10 to >1/100) and infrequent (from <1/100 to >1/1000). In brackets is indicated frequency occurrence of side effects (%).

    Changes in laboratory indicators: very often an increase in activity serum CK (3-4 degrees - 4%), an increase in the concentration of creatinine, decrease the concentration of albumin in the blood serum; often - a decrease in body weight. An increase in the activity of CK of any degree was observed in 23-26% of patients. The increase in activity of CK in combination with rhabdomyolysis had less than 1% of patients.

    On the part of the system hemopoiesis and lymphatic system: very often neutropenia, thrombocytopenia, anemia, leukopenia; often - febrile neutropenia. Neutropenia is the most frequent manifestation of hematologic 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 noted in 3% and <1% cycles, respectively. Thrombocytopenia-associated bleeding was <1% in patients treated with monotherapy. Anemia was detected in 93% and 94% of patients with monotherapy and combination therapy, respectively. Anemia of degrees 3 and 4 is registered in 3% and 1% cycles, respectively.

    From the gastrointestinal tract: 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.

    From 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%), alkaline phosphatase, gamma-glutamine transferase. Transient increase in activity ACT and grade 3 ALT were observed, respectively, in 12% and 20% of cycles, and 4 degrees - respectively, in 1% and 2% cycles. Deadline for the maximum activity 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 an increase in the number of infusions, there was a tendency to decrease in activity ACT and AJIT. Maximum concentration bilirubin was reached approximately 7 days after the onset of increasing its concentration, and a week later, the concentration 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 side of the peripheral and central nervous system: very often - headache; often peripheral sensory

    neuropathy, taste perversion, dizziness, paresthesia,

    insomnia.

    From the cardiovascular system: often - lowering blood pressure, "hot flashes" of blood.

    On the part of the respiratory system: often - shortness of breath (3-4 degrees - 2%), cough. Shortness of breath 3-4 degrees, regarded as associated with the use of trabektidine, had 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.

    Metabolic disorders: 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 data

    Observations: Registered

    several cases of penetration of trabecadine into tissues with the development of necrosis and the need for surgical intervention.

    Liver failure

    Rare cases of hepatic insufficiency (including fatal cases) in patients with serious concomitant clinical conditions in the treatment of trabecdine. Risk factors, which, probably, contributed to the observed increase in toxicity of trabectidine in these cases, were: use of the drug at doses,

    inconsistent with the recommended, possible interaction with competitive substrates isoenzyme CYP3A4 or isoenzyme inhibitors CYP3A4, or lack of prophylaxis with dexamethasone.

    Rhabdomyolysis

    When combined therapy with Yondelis® and pegylated liposomal doxorubicin less than 1% of patients experienced clinically significant cases of rhabdomyolysis.

    Allergic reactions Rare cases of hypersensitivity reactions, with a very rare frequency of fatalities, were registered in the postmarketing period

    observations with both monotherapy with Yondelis® 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 necrosis of tissues requiring surgical intervention were registered in post-marketing period observation.

    Septic shock

    Clinical and post-marketing studies reported cases of septic shock in patients with both mono- and combined therapy drug Yondelis®.

    Overdose:The data on the effects of the overdose of trabectidine are very limited. The main expected toxicity is gastrointestinal toxicity, bone marrow suppression and hepatotoxicity. At present, there is no specific antidote for trabektidine. In case of an overdose, the patient's condition should be monitored and, if necessary, symptomatic maintenance therapy should be performed.
    Interaction:
    Because the trabetedin is metabolized mainly by the isoenzyme CYP3A4, the simultaneous use of potential inhibitors of this isoenzyme, for example ketoconazole, fluconazole, ritonavir, clarithromycin, or aprepitant, may increase the concentration of trabecdate in the blood. If these combinations are to be used, development of toxicity. Population pharmacokinetic analysis
    showed that the concentration of trabaktidine increased by 19% with simultaneous use with dexamethasone. The use of inducers of the isoenzyme CYP3A4, for example, rifampicin,
    phenobarbital, preparations of St. John's wort perfumed, can further increase the clearance of trabecdine. Preclinical The research showed that trabetedin is a substrate of P-glycoprotein (P-gp). Simultaneous the use of P-gp inhibitors, for example cyclosporine and verapamil, can alter the distribution and / or induction trabektidine.
    The clinical significance of this interaction, for example, for the development of toxicity to the central nervous system, has not been established and caution should be exercised while simultaneously application of
    trabecadine and P-glycoprotein inhibitors.
    Trabecectin does not activate or inhibit the main enzymes of the cytochrome P450 system in vitro. The studies showed comparable figures for the plasma pharmacokinetics of 30 mg / m2 of pegylated liposomal doxorubicin when 1.1 mg / m of trabecadine was used compared to monotherapy with pegylated liposomal doxorubicin.
    Do not use Jondelis® with strong inhibitors
    isoenzyme CYP3A4. If this is not possible, then careful monitoring of toxicity should be carried out, and the possibility of reducing the dose of trabektidine should be considered.
    With the simultaneous use of trabectidine with phenytoin, the absorption of phenytoin may decrease, leading to an exacerbation of seizures. It is not recommended simultaneous application of trabectidine with phenytoin or living weakened vaccines.
    A joint the use of trabaktidine and the vaccine against yellow fever is contraindicated. When using trabektidine, alcohol should be avoided in view of hepatotoxicity.

    Special instructions:
    Yondelis® should be used under the supervision of a physician with experience in carrying out anti-tumor chemotherapy. Since in hepatic insufficiency the degree of systemic exposure to trabecotidine is likely to increase, and risk of hepatotoxicity may
    increase, then patients with clinically significant liver damage, such as active chronic hepatitis, require careful monitoring and, if necessary, dose adjustment. With increased concentration of bilirubin another infusion of trabecadine can not be carried out. A reversible acute increase in ACT and ALT activity was observed in patients receiving monotherapy and combined therapy with Yondelis®.Patients with increased activity of ACT, ALT, or alkaline phosphatase between the injections of Yondelis® may require a dose reduction.
    Before and during the treatment should monitor the clearance of creatinine. Trabecectin It should not be used in patients with creatinine clearance <30 ml / min in monotherapy or in patients with creatinine clearance <60 ml / min in combination therapy. Before the start of treatment, weekly for the first 2 cycles and then 1 time for each subsequent cycle, a complete blood test, including platelets and the leukocyte formula, should be performed. Yondelis® should not be given to patients with neutropenia less than 1500 / μL and thrombocytopenia less than 100,000 / μl. When detecting severe neutropenia (less than 500 / μl) for 5 days, accompanied by a fever or infection, a dose reduction is recommended. In combination therapy, leukopenia of grade 3 or 4 was very common. The lower limit of the norm of the number of neutrophils was observed with the median 15 days and was restored within a week. All patients should be premedicated
    glucocorticosteroids, for example, dexamethasone. If necessary, additional anti-emetics may be used. Trabecectin It should not be used in patients with CKK activity exceeding the upper limit of the norm by more than 2.5 times. Rhabdomyolysis was rare, a significant increase in CKK activity was 4% and 2% with monotherapy and combination therapy, respectively, usually in the presence of myelotoxicity, severe liver dysfunction or renal failure. Therefore, if any of these forms of toxicity occur, as well as muscle weakness or muscle pain, the patient's condition should be monitored. In the case of rhabdomyolysis, a supportive therapy,
    for example, fluid loading, alkalinization of urine and dialysis, depending on the indications. The use of Yondelis® is stopped until the rhabdomyolysis is completely resolved.
    Caution should be exercised when using trabektidine simultaneously with drugs that can cause rhabdomyolysis, for example, statins. Strongly recommended
    to carry out infusion through the central venous catheter. When introduced trabecdinedin at
    peripheral veins can develop potentially severe reactions at the injection site. There have been several cases of penetration of trabecadine into tissues with the development of necrosis andnecessity of surgical intervention. There is no specific antidote for the penetration of trabektidine into tissues. In the postmarketing period of observation, rare cases of hypersensitivity reactions (very rarely - with fatal outcomes) were detected both with monotherapy and with combined therapy. Caution should be exercised when using trabectidine simultaneously with drugs that have a hepatotoxic effect, as this increases the risk of hepatotoxicity. During the treatment with trabekthedin, alcohol should be avoided. The use of trabektidine during pregnancy can cause serious birth defects. Men's and women of reproductive age should effective methods of contraception during treatment and for 3 (women) or 5 (men) months after completion treatment. At the onset of pregnancy
    women should immediately notify the attending physician about this. Trabecectin can have genotoxic effect. Before starting treatment should consult a patient about the appropriateness of preservation of sperm due to the possibility of infertility in the use of the drug Yondelis®.Yondelis® is a cytotoxic antitumor drug and, as with other toxic substances, care must be taken when handling it. Follow the rules of handling and disposal for cytotoxic drugs. In case of accidental contact with the skin, mucous membranes or eyes, immediately wash the contact area with plenty of water.
    Unused product and waste should be disposed of in accordance with from local
    requirements for the disposal of cytotoxic drugs.

    Effect on the ability to drive transp. cf. and fur:Some of the side effects of the drug, such as weakness / asthenia, can adversely affect the ability to drive and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. Therefore, you should refrain from driving and handling vehicles while taking Yondelis®.
    Form release / dosage:Lyophilizate for the preparation of solution for iphyuzi.
    Packaging:
    Lyophilizate for the preparation of a solution for iifusium, containing 1 mg of trabektidine, in glass bottles,sealed with a cork made of bromobutyl rubber and an aluminum lid.
    1 bottle with instructions for use in a cardboard pack.
    Storage conditions:
    Store at a temperature of 2 to 8 ° C. Keep out of the reach of children.
    After dissolution, the chemical and physical stability of the preparation is maintained for 30 hours at a temperature not exceeding 25 ° C.
    From a microbiological point of view, the solution should be diluted and used immediately. Otherwise, the term and storage conditions for the solution remain at the discretion of the user, but should not normally exceed 24 hours when stored at 2 ° C to 8 ° C (unless dissolution has been carried out under controlled and tested aseptic conditions).
    Shelf life:
    3 years. Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-008960/08
    Date of registration:17.11.2008
    The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia
    Manufacturer: & nbsp
    Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia
    Information update date: & nbsp01.10.2015
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