Trabecectin (Trabectedinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antitumor agents of vegetable origin

Included in the formulation
  • Yondelis®
    lyophilizate d / infusion 
    Johnson & Johnson, LLC     Russia
    • АТХ:

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

    L.01.C.X.01   Trabecectin

    Pharmacodynamics:

    Antineoplastic alkaloid of natural (marine) origin, isolated from the Caribbean shell Ecteinascidia turbinate. Suppresses the transcription of genes and interacts with the nucleotide repair system associated with transcription. Has 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.

    Pharmacokinetics:

    Trabecectin largely binds to blood plasma proteins. It 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. Half-life is 175 hours. In unchanged form with urine and feces, <1% of the administered dose of the drug is excreted.

    Indications:

    Ovarian cancer recurring after therapy on the basis of platinum derivatives (trabetedin It is 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.

    ICD-10

    II.C45-C49.C49   Malignant neoplasm of other types of connective and soft tissue

    II.C51-C58.C56   Malignant neoplasm of ovary

    Contraindications:
    • Active serious or uncontrolled infection.
    • Pregnancy.
    • Lactation period (breastfeeding).
    • Hypersensitivity to the components of the drug.
    Carefully:

    The drug should be used for violations of the liver and / or kidney function, with an increase in the level of creatine phosphokinase, with inhibition of bone marrow function.

    Pregnancy and lactation:

    Contraindicated use of the drug during pregnancy and lactation (breastfeeding).

    The use of trabektidine in pregnancy can cause serious birth defects.

    Recommendations for FDA - category X.

    Dosing and Administration:

    For the treatment of common soft tissue sarcoma, 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 trabetedin prescribe in combination with pegylated liposomal doxorubicin every 3 weeks. Trabecectin 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.

    Side effects:

    Most often (effects of any severity): neutropenia, nausea, vomiting, increased activity of AST and ALT, anemia, weakness, thrombocytopenia, anorexia, diarrhea.

    Lethal outcome as a result of undesirable phenomena: 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 trabecditin and which have been observed in ≥ 1% of cases.Determination of the incidence of adverse reactions: very often (≥ 1/10), often (<1/10 to ≥ 1/100), infrequently (<1/100 to ≥ 1/1000). In parentheses, the incidence of adverse reactions (%) is indicated.

    From the side of laboratory indicators: very often - an increase in the activity of serum creatine phosphokinase (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 creatine phosphokinase of any degree; less than 1% - increase in the level of creatine phosphokinase in combination with rhabdomyolysis.

    From the side hematopoiesis 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 side 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.

    From the side hepatobiliary system: hyperbilirubinemia (3 degrees - 1%), increased ALT activity (3 degrees 38%, 4 degrees 3%), ACT (3 degrees 44%, 4 degrees 7%), alkaline phosphatase, gamma-glutamyltransferase.

    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 side nervous system: very often - headache; often peripheral sensory neuropathy, taste perversion, dizziness, paresthesia, insomnia.

    From the side of cardio-vascular system: often - a decrease in blood pressure, hot flushes.

    From the side respiratory system: often - shortness of breath (3-4 degrees - 2%), cough. Dyspnoea of ​​grade 3-4, regarded as associated with the use of trabektidine, was noted in 2% of patients.

    From the side skin and skin appendages: often - alopecia (observed in about 3% of patients with monotherapy).

    From the side musculoskeletal system: often - myalgia, arthralgia, back pain.

    From the side 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 the tissue with the development of necrosis and the need for surgical intervention have been reported.

    Liver failure.

    Rare cases of hepatic insufficiency (including fatal cases) in patients with serious concomitant clinical conditions with treatment with trabecedin have been reported. The risk factors that probably contributed to the observed increase in toxicity of trabectidine in these cases were: the use of the drug in doses inappropriate, the possible interaction with competitive substrates of the isoenzyme CYP3A4 or inhibitors of the isoenzyme CYP3A4, or lack of prophylaxis with dexamethasone.

    Rhabdomyolysis.

    In combination therapy with trabetedin and pegylated liposomal doxorubicin, clinically significant cases of rhabdomyolysis were observed in less than 1% of patients.

    Allergic reactions.

    Rare cases of hypersensitivity reactions, with a very rare frequency of fatalities, were registered in the postmarketing period of observation, both with monotherapy with trabektidine 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 the post-marketing period of observation.

    Septic shock.

    Clinical and postmarketing studies reported cases of septic shock in patients with both mono- and combined therapy with trabetedin.

    Overdose:

    The data on the effects of the overdose of trabectidine are very limited.

    Symptoms: the main expected toxicity are gastrointestinal toxicity, bone marrow suppression and hepatotoxicity.

    Treatment: currently there is no specific antidote for trabaktidine. In case of an overdose, the patient's condition should be monitored and, if necessary, symptomatic and supportive therapy should be provided.

    Interaction:

    Because the trabetedin is metabolized mainly by the CYP3A4 isoenzyme, the simultaneous use of potential inhibitors of this isoenzyme, for example, ketoconazole, fluconazole, ritonavir, clarithromycin or aprepitant, can increase the concentration of trabectidine in the blood.If these combinations are necessary, the development of toxicity should be closely monitored.

    Population pharmacokinetic analysis showed that the concentration of trabecbudin 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, can further increase the clearance of trabektidine.

    Pre-clinical studies have shown that trabetedin is a substrate of P-glycoprotein (P-gp). The simultaneous use of P-gp inhibitors, for example, cyclosporine and verapamil, can alter the distribution and / or excretion of trabektidine. The clinical significance of this interaction, for example, for the development of toxicity against the central nervous system, has not been established. Caution should be exercised with the simultaneous use of trabectidine and P-glycoprotein inhibitors.

    Trabecectin does not activate or inhibit the main enzymes of the cytochrome P450 system in vitro.

    Studies have shown comparable indicators of plasma pharmacokinetics of pegylated liposomal doxorubicin in a dose of 30 mg / m2 when using trabaktidine in a dose of 1.1 mg / m2 compared with monotherapy with pegylated liposomal doxorubicin.

    It should be avoided the combined use of trabectidine with strong inhibitors of the isoenzyme CYP3A4. If this is not possible, careful toxicity monitoring should be carried out, and the possibility of reducing the dose of trabektidine should be considered.

    With the simultaneous use of trabectidine with phenytoin, a reduction in the absorption of phenytoin is possible, which leads to aggravation of seizures. It is not recommended simultaneous use of trabectidine with phenytoin.

    It is not recommended simultaneous use of trabectidine with live attenuated vaccines. The combined use of trabaktidine and the vaccine against yellow fever is contraindicated.

    During treatment with rabbitadine, patients should avoid drinking alcohol because of hepatotoxicity.

    Special instructions:

    Trabecectin should be used under the supervision of a doctor who has experience in carrying out anti-tumor chemotherapy.

    Since with hepatic insufficiency, the degree of systemic exposure to trabaktidine is likely to increase, and the risk of hepatotoxicity may increase,then for patients with clinically significant liver damage, for example, active chronic hepatitis, careful monitoring and, if necessary, dose adjustment are required. With an 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 trablectedin. Patients with increased activity of ACT, ALT or alkaline phosphatase between cycles of administration of trabecbudin may require a dose reduction.

    Before and during the treatment should monitor the clearance of creatinine. Trabecectin Do not use 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. Trabecectin should not be administered to patients with neutropenia less than 1500 / μL, 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.

    With combined therapy, leukopenia of grade 3 or 4 was very often noted. The lower limit of the norm of the number of neutrophils was observed with a median of 15 days and was restored within a week.

    All patients should be premedicated with glucocorticosteroids, for example, dexamethasone. If necessary, additional antiemetics may be used.

    Trabecectin should not be used in patients with creatine phosphokinase activity exceeding the upper limit of the norm by more than 2.5 times.

    Rhabdomyolysis was rare, a serious increase in activity creatine phosphokinase had 4% and 2% with monotherapy and combination therapy, respectively, usually in the presence of myelotoxicity, severe impairment of liver function 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, supportive therapy should be started immediately, for example, fluid loading, alkalinization of urine and dialysis, depending on the indications. The use of trabectidine is stopped until the complete resolution of rhabdomyolysis.Caution should be exercised when using trabektidine simultaneously with drugs that can cause rhabdomyolysis, for example, statins.

    It is strongly recommended that infusion is performed through the central venous catheter. With the introduction of trabecdate into peripheral veins, potentially severe reactions at the site of injection are possible. There have been several cases of penetration of trabecadine into tissues with the development of necrosis and the need for 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 treatment with trabektidine, patients should avoid drinking alcohol.

    Trabecectin may have a genotoxic effect. Before the beginning of treatment it is necessary to consult the patient about the expediency of preserving the spermbecause of the possibility of developing infertility with the use of trabektidine.

    Use in Pediatrics

    The safety and efficacy of trabecadine in children is not currently established. therefore trabetedin Do not use in children until additional data are obtained.

    Precautions for handling the drug.

    Trabecectin 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.

    The unused preparation and waste should be disposed of in accordance with local requirements for the disposal of cytotoxic drugs.

    Impact on the ability to drive vehicles and manage mechanisms.

    Some of the side effects of the drug, such as weakness, asthenia, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.Therefore, patients should refrain from controlling vehicles and mechanisms during the administration of trabektidine.

    Instructions
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