Yondelis

General characteristics. Structure:

Active agent: трабектедин 1 mg.

Excipients: a sukroza (sucrose), potassium phosphate monosubstituted, phosphoric acid 0,1 N, potassium hydroxide of 0,1 M (for correction рН) 

Pharmacological properties:

Pharmacodynamics. Trabektedin represents the tristetrahydroisoquinolinic alkaloid of a natural (sea) origin for the first time emitted from the Caribbean tunicate of Ecteinascidia turbinata. Drug possesses the difficult mechanism of action directed to a transcription. It suppresses a transcription of genes and interacts with system of the reparation of nucleotides connected with a transcription.

Trabektedin contacts a small groove of DNA therefore the spiral of DNA is bent towards a big groove. It starts the cascade of the processes influencing the factors of a transcription of DNA, proteins contacting DNA and DNA repair mechanisms that, finally, leads to disturbance of a cellular cycle. Trabektedin has anti-proliferative effect of in vitro in a number of cultures of cells of tumors of the person and in vivo in experimental tumors, including sarcoma, a breast cancer, not small-celled cancer of a lung, ovarian cancer and a melanoma. In the researches in vitro and in vivo on ksenotransplantatny models трабектедин showed the additive or synergy effect at combined use with doxorubicine.

Pharmacokinetics. System exposure of a trabektedin after intravenous infusion with a constant speed is proportional to the entered dose up to a dose of 1,8 mg/sq.m inclusive. The pharmacokinetics of a trabektedin corresponds to a multichamber distribution model with an elimination half-life of 175 hours. At introduction of 1 times to 3 weeks of accumulation of drug in a blood plasma it is not revealed.

Distribution. Trabektedin has the large volume of distribution (> 5000 l) that will be coordinated with extensive distribution on peripheral fabrics. Trabektedin substantially contacts proteins of a blood plasma; at the general concentration in a blood plasma of 10 and 100 ng/ml the free fraction makes respectively 2,23% and 2,72%.

Metabolism. Trabektedin is actively metabolized. At clinically significant concentration there is an oxidation which is carried out generally by CYP3A4 isoenzyme however it is impossible to exclude also a contribution of other isoenzymes of system of cytochrome to metabolism of a trabektedin. The essential glyukuronirovaniye of a trabektedin was not observed.

Removal. After introduction the average number of radioactivity in Calais (24 days) is radioactive a marked trabektedin and to urine (10 days) respectively 58% (17%) and 5,8% (1,73%) of the entered dose made. In not changed view with urine and a stake it is removed <1% of the entered drug dose. The clearance of a trabektedin is equal in whole blood to about 35 l/hour that makes about a half of a blood-groove through a liver of the person. Thus, capture of a trabektedin in a liver can be considered as moderate. The dispersion of values of clearance of a trabektedin in a blood plasma reaches 28–49%.

Special categories of patients. The population analysis of pharmacokinetics showed that the clearance of a trabektedin in a blood plasma does not depend on the body weight (36–148 kg), the body surface area (0,9–2,8 sq.m), age (19–83 years) and a sex of patients. Influence of race and an ethnic origin on this indicator was not studied.

Disturbance of functions of kidneys. The function of kidneys determined by clearance of creatinine in the range which was available for participants of clinical trials (≥30,3 ml/min.) significantly did not influence pharmacokinetics of a trabektedin. For patients with clearance of creatinine less than 30,3 ml/min. there are no data. Low detection of radioactivity in urine after single introduction of a 14C-trabektedin (<9% are at all patients) allows to assume that disturbance of functions of kidneys poorly influences removal of a trabektedin and its metabolites.

Disturbance of functions of a liver. At patients with disturbance of functions of a liver the clearance of a trabektedin can decrease with the corresponding increase in concentration of drug in a blood plasma.

Indications to use:

The ovarian cancer recuring after therapy on the basis of platinum derivatives. Yondelis is applied in a combination with pegylated liposomal doxorubicine (further in the text – a combination therapy). Widespread sarcomas of soft tissues at patients, insensitive to anthracyclines and an ifosfamid, or with contraindications to their use. Efficiency is shown generally at patients with a liposarcoma and leiomyosarcoma.

Route of administration and doses:

For therapy of widespread sarcomas of soft tissues the recommended initial dose makes 1,5 mg/sq.m of surface area of a body in the form of 24-hour intravenous infusion at an interval of 3 weeks.

For therapy of recurrent ovarian cancer Yondelis is appointed in a combination with pegylated liposomal doxorubicine (for example, drug of Keliks) each 3 weeks. Yondelis is entered in a dose of 1,1 mg/sq.m in the form of 3-hour intravenous infusion after administration of pegylated liposomal doxorubicine in a dose of 30 mg/sq.m in the form of 60-minute intravenous infusion.

All patients should carry out premedication by glucocorticosteroids, for example, dexamethasone of 20 mg intravenously in 30 minutes prior to each infusion of drug Yondelis, for the purpose of prevention of vomiting, and also possible hepatoprotective action. If necessary additional antiemetics can be applied. The drug is recommended to be administered through the central venous catheter.

Yondelis it is possible to enter only at the following laboratory indicators:

− absolute maintenance of neutrophils (AMN) 1500/mkl;

− maintenance of thrombocytes ≥100 000/мкл;

− level of hemoglobin of ≥9 g/dl;

− the concentration of bilirubin which is not exceeding the upper bound of norm

− activities of an alkaline phosphatase (bone system, untied with defeat) which is not exceeding more than by 2,5 times the upper bound of norm (at increase in activity of an alkaline phosphatase, perhaps, the bone system connected with defeat, it is necessary to define activity of hepatic isoenzymes 5 nucleotidases or gamma glutamiltranspeptidaza) (GGT);

− activities of alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant) which are not exceeding more than by 2,5 times the upper bound of norm;

− content of albumine of ≥25 g/l;

− clearance of creatinine of ≥30 ml/min.

At a combination therapy:

− at concentration of serumal creatinine of ≤1,5 mg/dl (≤132,6 µmol/l) or clearance of creatinine of ≥60 ml/min.;

− activities of a kreatinfosfokinaza (KFK) which is not exceeding more than by 2,5 times the upper bound of norm.

Repeated infusions of drug Yondelis can also be carried out only at respect for above-mentioned criteria. Otherwise infusion is postponed for a period of up to 3 weeks until achievement of compliance of laboratory indicators of blood to above-mentioned criteria, at the same time the drug is administered in the same dose, in case of lack of other not hematologic undesirable phenomena by 3-4 degrees according to classification of National institute of cancer of the USA.

If toxicity remains more than 3 weeks, then it is necessary to consider the possibility of cancellation of treatment.

Dose adjustment during treatment.

During the first two 3 weeks cycles of activity of an alkaline phosphatase, KFK, aminotransferases (ALT and nuclear heating plant) and concentration of bilirubin should be controlled weekly, and in the subsequent cycles – at least, 1 time between infusions.

The drug dose at the following infusion is reduced to 1,2 mg/sq.m in monotherapy and to 0,9 mg/sq.m in a combination therapy at emergence between infusions at least one the investigating phenomena at any time:

− a neutropenia <500/mkl, remaining more than 5 days or followed by fever or an infection;

− thrombocytopenia <25 000/mkl;

− increase in concentration of bilirubin is higher than the upper bound of norm;

− increase in activity of an alkaline phosphatase (bone system, untied with defeat), is more than 2,5 times higher than the upper bound of norm;

− increase in activity of aminotransferases (nuclear heating plant or ALT) is more than 2,5 times higher than the upper bound of norm, not normalized by 21 days of a cycle.

At a combination therapy:

− the increase in activity of nuclear heating plant or ALT of norm more than 5 times higher than the upper bound which was not normalized by 21 days of a cycle. The dosage of pegylated liposomal doxorubicine also has to be lowered to 25 mg/sq.m;

− any undesirable phenomenon 3 or 4 severity (for example, nausea, vomiting, weakness).

After a dose decline because of toxicity its return increase in the subsequent cycles is not recommended. If any of toxic reactions appears in the subsequent cycles again, and treatment gives favorable clinical effect, then the dose can be lowered further to 1 mg/sq.m at monotherapy by drug Yondelis or to 0,75 mg/sq.m at use Yondelis in a combination therapy. If the dose needs to be lowered still, then it is necessary to consider the possibility of cancellation of treatment. Colony stimulating factors can be entered for correction of hematologic toxicity in the subsequent cycles.

Special categories of patients.

Children. Safety and efficiency of a trabektedin at children is not established now. Therefore Yondelis it is not necessary to apply at children, additional data will not be obtained yet.

Elderly patients. Significant differences of indicators of safety or efficiency at this category of patients with different types of tumors are not revealed. The population analysis of pharmacokinetics confirms lack of influence of age of patients on clearance and volume of distribution of a trabektedin. Therefore dose adjustment, proceeding only from age, usually is not recommended.

Patients with disturbance of functions of a liver. At patients with disturbance of functions of a liver the risk of toxicity can be increased. Use of a trabektedin for patients with disturbance of functions of a liver sufficiently was not studied. There are no accurate recommendations of an initial dose of drug for this category of patients now. At treatment of such patients it is necessary to show extra care. Dose adjustment for the purpose of reduction of risk of a hepatotoxic is possible. Yondelis it is impossible to apply at the increased concentration of bilirubin.

Patients with disturbance of functions of kidneys. Researches with participation of patients with a renal failure (clearance of creatinine <30 ml/min., at a combination therapy <60 ml/min.) were not carried out therefore to apply Yondelisnelzya at these categories of patients. The weak or moderately expressed disturbance of functions of kidneys, most likely, does not influence pharmacokinetics of a trabektedin.

Recommendations about solution preparation. For performing infusion Yondelis dissolve and dilute with use of sootvetstvuyushchikhmetod of an asepsis and observance of rules of the treatment of cytotoxic drugs. With 1 mg of a trabektedin add 20 ml of sterile water for injections to a bottle and stir up before full dissolution, receiving solution with concentration of 0,05 mg/ml. Solution has to be transparent, colourless or brownish-yellow, without visible particles.

Before infusion the received solution is diluted.

For dilution of solution use 0,9% solution of sodium of chloride or 5% dextrose solution. Yondelis it is impossible to mix or dilute with other drugs.

For infusion through the central venous catheter the necessary amount of the solution containing a necessary dose of drug is selected from a bottle the syringe and brought in the infusional bag / bottle containing not less than 500 ml of 0,9% of solution of sodium of chloride or 5% of solution of a dextrose.

In the absence of a possibility of infusion in the central vein and need of introduction to a peripheral vein the necessary amount of solution is entered into the infusional bag / bottle containing not less than 1000 ml of 0,9% of solution of sodium of chloride or 5% of solution of a dextrose.

After administration of infusion solution of pegylated liposomal doxorubicine and before administration of the drug Yondelis® the system for intravenous administration has to be washed carefully out by 5% aqueous solution of a dextrose. Pegylated liposomal doxorubicine cannot be mixed from 0,9% chloride sodium solution.

Before introduction parenteral solutions visually check regarding lack of particles and discoloration. After dissolution and dilution solution chemically is also physically stable within 30 hours at 25 °C. After dissolution solution has to be divorced immediately. The general time from dissolution before the end of introduction to the patient should not exceed 30 hours. Yondelis does not show incompatibility with polyvinylchloride and polyethylene of infusional bags and tubes, and also with titanium of intravascular catheters.

Features of use:

Yondelis it is necessary to apply under observation of the doctor having experience of carrying out antineoplastic chemotherapy.

As at a liver failure extent of system influence of a trabektedin probably amplifies, and the risk of a hepatotoxic can increase, for patients with clinically significant damage of a liver, for example, with active chronic hepatitis, careful observation and if necessary dose adjustment is required. At the increased concentration of bilirubin the next infusion of a trabektedin cannot be carried out.

Reversible acute increase in activity of nuclear heating plant and ALT was observed at the patients receiving monotherapy and a combination therapy drug Yondelis. Yondelis can be required by patients with a superactivity of nuclear heating plant, ALT or an alkaline phosphatase between cycles of administration of drug a dose decline.

Before the beginning and during treatment it is necessary to control clearance of creatinine. Trabektedin it is impossible to apply at patients with clearance of creatinine <30 ml/min. in monotherapy or at patients with clearance of creatinine <60 ml/min. in a combination therapy.

Prior to treatment, weekly during the first 2 cycles and then 1 time during each following cycle it is necessary to carry out an integrated analysis of blood, including thrombocytes and a leukocytic formula. Yondelis patients should not appoint with a neutropenia less 1500/mkl and thrombocytopenia less 100000/mkl. At identification of the heavy neutropenia (less 500/mkl) within 5 days which is followed by fever or an infection reduction of a dose is recommended.

In a combination therapy the leukopenia 3 or 4 degrees was very often noted. The lower bound of norm of number of neutrophils was observed with a median of 15 days and recovered within a week. All patients should carry out premedication by glucocorticosteroids, for example, dexamethasone. If necessary additional antiemetics can be applied.

Trabektedin it is impossible to apply at patients with activity of KFK, exceeding the upper bound of norm more than by 2,5 times.

Rabdomioliz was marked out seldom, 4% and 2% at monotherapy and a combination therapy had serious increase in activity of KFK respectively, usually in the presence of a miyelotoksichnost, a heavy abnormal liver function or a renal failure. Therefore at emergence of any of these forms of toxicity, and also muscular weakness or muscle pains, it is necessary to control a condition of the patient. In case of a rabdomioliz it is necessary to begin immediately a maintenance therapy, for example, loading with liquid, alkalinization of urine and dialysis depending on indications. Drug use Yondelis is stopped to full permission of a rabdomioliz.

It is necessary to show care at use of a trabektedin along with the drugs capable to cause рабдомиолиз, for example, statines.

It is strongly recommended to carry out infusion through the central venous catheter. At introduction of a trabektedin to peripheral veins potentially heavy reactions in the place of an injection can develop. Several cases of penetration of a trabektedin into fabrics with development of a necrosis and need of surgical intervention were noted. The specific antidote at penetration of a trabektedin into fabrics does not exist.

In the post-marketing period of observation exceptional cases of reactions of hypersensitivity were revealed (very seldom – from deadly an outcome) both at monotherapy, and at a combination therapy.

It is necessary to show care at use of a trabektedin along with the drugs having a hepatotoxic action as at the same time the risk of a hepatotoxic increases. During treatment trabektediny it is necessary to avoid alcohol intake. Use of a trabektedin during pregnancy can cause serious inborn defects.

Men and women of reproductive age have to use effective methods of contraception during treatment and during 3 (women) or 5 (men) of months after the end of treatment. At approach of pregnancy of the woman have to inform on it the attending physician immediately.

Trabektedin can have genotoksichesky effect. Before an initiation of treatment it is necessary to consult the patient about expediency of preservation of sperm because of a possibility of development of infertility at drug use Yondelis.

Yondelis is a cytotoxic antineoplastic drug and, as well as in a case with other toxic substances, at the treatment of him it is necessary to show care. It is necessary to follow rules of the address and utilization for cytostatic drugs.

At accidental hit of drug on skin, mucous membranes or in eyes it is necessary to wash out immediately the place of contact by a large amount of water.

Unused drug and waste should be utilized according to local requirements to utilization of cytotoxic medicines.

Influence on driving of the car and work with mechanisms. Some side effects of drug, such as weakness/adynamy, can negatively influence ability of driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. Therefore it is necessary to refrain from control of vehicles and mechanisms during administration of drug of Yondelis®.

Side effects:

The neutropenia, nausea, vomiting, increase in activity AST/ALT, anemia, weakness, thrombocytopenia, anorexia, diarrhea were the most widespread undesirable phenomena of any severity.

The lethal outcome as a result of the undesirable phenomena is recorded at 1,9% of patients at monotherapy and at 0,9% of patients at a combination therapy. Death usually was caused by a combination of the adverse phenomena, including a pancytopenia and a febrile neutropenia (in certain cases with development of sepsis), damage of a liver, renal or multiorgan failure and рабдомиолиз.

The undesirable phenomena which were regarded as possibly or perhaps connected using drug Yondelis and which were observed more than in ≥1% of cases are listed below. Frequency of emergence of by-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 the frequency of emergence of by-effects (%) is specified.

Changes of laboratory indicators: very often – increase in activity of serumal KFK (3-4 degrees – 4%), increase in concentration of creatinine, reduction of concentration of albumine in blood serum; often – a body degrowth. Increase in activity of KFK of any degree was observed at 23–26% of patients. In combination with rabdomiolizy less than 1% of patients had increase in activity of KFK.

From system of a hemopoiesis and lymphatic system:

- very often – a neutropenia, thrombocytopenia, anemia, a leukopenia;

- often – a febrile neutropenia.

Neutropenia – the most frequent manifestation of hematologic toxicity. The neutropenia 3 and 4 degrees was observed respectively in 19% and 8% of cycles. The neutropenia was reversible and seldom was followed by fever or an infection. Thrombocytopenia 3 and 4 degrees was noted in 3% and <1% of cycles, respectively. Had the bleeding connected with thrombocytopenia <1% of patients at treatment in the monotherapy mode. Anemia is revealed at 93% and 94% of patients at monotherapy and a combination therapy, respectively. Anemia 3 and 4 degrees is registered in 3% and 1% of cycles, respectively.

From digestive tract:

- very often – vomiting (3-4 degrees – 6,5%), nausea (3 - 4 degrees – 6%), a lock (3-4 degrees – <1%);

- often – diarrhea (3-4 degrees – <1%), stomatitis (3-4 degrees – <1%), an abdominal pain, dyspepsia, pain in an upper part of a GIT.

From gepatobiliarny system:

- very often – a hyperbilirubinemia (3 degrees – 1%), increase in activity of ALT (3 degrees – 38%, 4 degrees – 3%), nuclear heating plant (3 degrees – 44%, 4 degrees – 7%), an alkaline phosphatase, gamma glutaminetransferase.

Passing increase in activity of nuclear heating plant and ALT 3 degrees was noted, respectively, in 12% and 20% of cycles, and 4 degrees – respectively, in 1% and 2% of cycles. The median of term of achievement of the maximum activity of nuclear heating plant and ALT made 5 days. In most cases this toxicity decreased to 1 degree or disappeared by 14–15 day, and only in <2% of cycles its normalization required more than 25 days. With increase in number of infusions the tendency to reduction of activity of nuclear heating plant and ALT was observed. The maximum concentration of bilirubin was reached approximately in 7 days after the beginning of increase in its concentration, and in a week after that concentration of bilirubin was normalized. Frequency of jaundice, a hepatomegalia and pain in a liver did not exceed 1%. Mortality of patients because of damage of a liver did not exceed 1%.

From peripheral and central nervous system:

- very often – a headache;

- often – peripheral touch neuropathy, a food faddism, dizziness, paresthesia, sleeplessness.

From cardiovascular system:

- often – a lowering of arterial pressure, blood "inflows".

From a respiratory organs:

- often – an asthma (3-4 degrees – 2%), cough. As connected using a trabektedin, 2% of patients had the asthma 3-4 degrees regarded.

From skin and skin appendages:

- often – an alopecia (it was observed approximately at 3% of patients at monotherapy).

From a musculoskeletal system:

- often – a mialgiya, an arthralgia, a back pain.

Metabolic disturbances:

- very often - anorexia (3-4 degrees – <1%);

- often – dehydration, a loss of appetite, a hypopotassemia.

Others:

- very often – weakness (3-4 degrees – 9%), increased fatigue (3-4 degrees – 1%);

- often – accession of consecutive infections, fervescence, peripheral hypostases, reactions in a drug injection site.

Data of post-marketing observation: several cases of penetration of a trabektedin into fabrics with development of a necrosis and need of surgical intervention are registered.

Liver failure. Exceptional cases of developing of a liver failure (including cases from the death) at patients with the serious accompanying clinical states were registered at treatment trabektediny. Risk factors which probably promoted the increase in toxicity of a trabektedin observed in these cases were: use of drug in the doses inappropriate recommended, possible interaction with competitive substrates of an isoenzyme CYP3A4 or inhibitors of an isoenzyme CYP3A4, or lack of prevention by dexamethasone.

Rabdomioliz. At a combination therapy the drug Yondelis® and a pegylated liposomalnymdoksorubitsin less than at 1% of patients observed clinically significant cases of emergence of a rabdomioliz.

Allergic reactions. Exceptional cases of emergence of reactions of hypersensitivity, with very rare frequency of deaths, were registered in the post-marketing period of observation both at monotherapy by the drug Yondelis®, and at a combination therapy.

Penetration of a tradektedin into fabrics in an injection site and a necrosis of fabrics. Exceptional cases of penetration of a trabektedin into fabrics in an injection site with the subsequent necrosis of fabrics demanding surgical intervention were registered in the post-marketing period of observation.

Septic shock. During the clinical and post-market researches it was reported about cases of emergence of septic shock, at patients both at mono - and at a combination therapy by the drug Yondelis®.

Interaction with other medicines:

As трабектедин it is metabolized generally by CYP3A4 isoenzyme, simultaneous use of potential inhibitors of this isoenzyme, for example, of a ketokonazol, a flukonazola, a ritonavira, a klaritromitsin or an aprepitant, can increase concentration of a trabektedin in blood. In need of use of such combinations it is necessary to control toxicity development carefully.

The population pharmacokinetic analysis showed that concentration of a trabektedin increases by 19% at simultaneous use with dexamethasone. Use of inductors of an isoenzyme of CYP3A4, for example, of rifampicin, phenobarbital, drugs of the St. John's Wort which is made a hole can increase clearance of a trabektedin even more.

Preclinical trials showed what трабектедин is substrate of a P-glycoprotein (Pgp). Simultaneous use of P-gp inhibitors, for example, of cyclosporine and verapamil, can change distribution and/or removal of a trabektedin. The clinical importance of this interaction, for example, for development of toxicity concerning TsNS, it is not established and is necessary to show care at simultaneous use of a trabektedin and P-inhibitors of a glycoprotein.

Trabektedin does not activate and does not inhibit the main enzymes of system of in vitro P450 cytochrome. Researches showed comparable indicators of plasma pharmacokinetics of 30 mg/sq.m of pegylated liposomal doxorubicine at use of 1,1 mg/sq.m of a trabektedin in comparison with monotherapy by pegylated liposomal doxorubicine.

It is necessary to avoid combined use of the drug Yondelis® with strong inhibitors of an isoenzyme CYP3A4. If it is not possible, then it is necessary to carry out careful monitoring of toxicity, and also the possibility of reduction of a dose of a trabektedin has to be considered.

At simultaneous use of a trabektedin with Phenytoinum the absorption of Phenytoinum leading to an exacerbation of spasms can decrease. Simultaneous use of a trabektedin with Phenytoinum or live attenuated vaccines is not recommended. Combined use of a trabektedin and vaccine against yellow fever contraindicated. At use of a trabektedin it is necessary to avoid use of alcohol in a type of a hepatotoxic.

Contraindications:

− hypersensitivity to any of drug components;

− active serious or uncontrollable infection;

− pregnancy and period of feeding by a breast.

With care: at abnormal liver functions and/or kidneys, at increase in level creatine - phosphokinases, at oppression of function of marrow.

Overdose:

The overdoses of a trabektedin given about effects are very limited. The main expected toxicity is gastrointestinal toxicity, oppression of marrow and a hepatotoxic. There is no specific antidote for a trabektedin now. In case of overdose it is necessary to control a condition of the patient and, if necessary, to carry out a symptomatic maintenance therapy.

Storage conditions:

To store at a temperature from 2 to 8 ºC. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

The lyophilisate for preparation of solution for infusions containing 1 mg of a trabektedin in the bottles from glass corked by a stopper from brombutilovy rubber and an aluminum cover. On 1 bottle together with the application instruction in a cardboard pack.