Yondelis

Chemotherapeutic monopreparation of natural origin, hindering the process of growth and development of a number of neoplasms. The active ingredient is trabektidine (tristetrahydroisoquinoline alkaloid extracted from the marine aquatic organism of ascidia).

Additional ingredients: cane sugar, potassium dihydroorthophosphate, 0.1H phosphoric acid solution, 0.1M potassium hydroxide solution.

Indications Yondelis

Recurrence of malignant neoplasm of ovaries after chemotherapy with carboplatin or cisplatin. Yondelis is prescribed in combination with doxil.

Liposarcoma and soft tissue leiomyosarcoma with intolerance to Ifos and preparations of the anthracycline group or in case of their ineffectiveness. 

[1], [2], [3]

Release form

Lyophilized powder for making a solution for intravenous infusions, packaged in vials of glass, containing 1 mg of active ingredient.

Pharmacodynamics

Trabecectin depresses the process of transfer of the oncogenetic code from deoxyribonuclease to ribonuclease in the cells of tumors, which, as a result, disrupts the circular process of development of cancer cells. This leads to a normalization of the neoplastic modification of the cells and a slowing of the growth of the neoplasm. 

In vitro and in vivo tests suggest that Trabectedin inhibits the growth of cancer cells of some human neoplasms, including sarcomas, melanomas, lung carcinomas, malignant tumors of the breast and ovaries.

Application in combination with doxil significantly improves the effectiveness of drugs. 

[4], [5], [6], [7]

Pharmacokinetics

The duration of a noticeable action of a portion of trabaktidine injected by the continuous infusion method is commensurate with the administered amount of the drug (up to 1.8 mg / m²). Pharmacokinetic parameters correspond to a multicameral model of distribution with a half-life of 175 hours. Application once every three weeks does not cause it to accumulate in the blood plasma.

Yondelis is characterized by a significant volume of distribution (more than 5000 liters), which corresponds to a large area of distribution in peripheral tissues. The drug binds well to albumin; at a density in the blood plasma of 10 and 100 ng / ml, the protein unbound with the proteins is 2.23% and 2.72%, respectively.

The process of metabolism is intense. At clinically significant plasma density, the active ingredient is oxidized, mainly due to the isoenzyme CYP3A4, it is possible that the remaining enzymes of the P450 family are involved in its metabolism. The active reaction of the second phase of metabolism of trabektidine is not traced.

Excretion of the drug occurs mainly through the intestine, ten times less excreted by the kidneys, in an unchanged form - less than 1%. The coefficient of purification in whole blood is approximately 35 liters per hour (1/2 of the hepatic blood flow) - hence, the liver captures a moderate amount of the drug. The rate of purification of blood plasma from 28 to 49%. It is not due to the weight of the patient, the surface area of the body, its age and sex.

The results of clinical studies show that renal dysfunction has almost no effect on the excretion of this drug and the products of its metabolism.

The presence of liver dysfunction can reduce the rate of excretion of trabektidine with a corresponding increase in its density in the blood plasma.

[8], [9], [10], [11], [12]

Dosing and administration

Preparation of the formulation

The powder in the vial is filled with 20 ml of water for injection and, shaking, dissolve the contents. The concentration of the resulting homogeneous mixture is 50 g / ml, it should not be cloudy, colorless or with a yellowish brown tinge, without sediment. After this it is necessary to dilute the mixture.

If the mixture is poured into the central vein (using a venous catheter), it is further diluted as follows: fill the syringe with the required capacity of the resulting mixture and puncture the rubber stopper of the dropper bottle and inject the mixture into it. For additional dilution Yondelis use saline or isotonic solution of d-glucose 5% with a capacity of at least 0.5 liters (other solutions can not dilute this drug).

In case of impossibility of infusion into the central vein - the mixture is poured into the peripheral. In this case, a dilution of not less than 1 liter of saline or an isotonic solution of 5% glucose is used.

If complex therapy with doxil is carried out, then before the procedure described, the dropper system should be thoroughly rinsed with an isotonic solution of 5% d-glucose, since doxyl residues should not be mixed with saline.

Before placing the dropper, the prepared mixtures are carefully inspected to ensure that there is no sediment and discoloration. The finished mixture can be stored for 30 hours at an air temperature of 25 ° C (however, it is better to use it immediately). After more than 30 hours, the mixture must be disposed of.

Yondelis is fully compatible with the polymeric materials of the system for intravenous infusions, as well as with titanium venous catheters.

Dosing of Yondelis

Connective tissue sarcoma - every three weeks, intravenously administered for 24 hours, a dosage of 1.5 mg per 1 m 2 of body surface area.

Malignant ovarian tumor with relapses - Yondelis is used together with doxilum with an interval of three weeks. The drug is injected intravenously at a dosage of 1.1 mg / m² for three hours after the infusion of doxil (30 mg / m2 for an hour).

All patients to prevent the development of liver failure is a preliminary intravenous glucocorticosteroids for half an hour before each infusion Yondelis, you can additionally designate antiemetics. Dosage appoints the attending physician individually.

Chemotherapy Jondelis is carried out only with the proper results of the tests:

• the absolute number of neutrophils (AFN) is not less than 1.5 × 10 3 cells / μl;
• the number of platelets is not less than 100 × 10 cells / μl;
• the hemoglobin value is not less than 90 g / l;
• the content of direct bilirubin is not more than 5.1 mkmol / l;
• the activity index of phosphatases does not exceed the maximum value of the norm by 2.5 times, (with a greater deviation of this parameter, the attending physician may prescribe additional tests);
• the activity index of aminotransferases does not exceed 2.5 times the maximum value of the norm;
• the albumin value is not less than 25 g / l;

Complex treatment is carried out at a blood cleansing rate from creatinine of at least 60 ml / min and an activity index of creatine kinase, which does not exceed a maximum of 2.5 times.

Repeat the infusion of this medication is necessary, adhering to the above conditions. Otherwise, chemotherapy is delayed up to three weeks, until the results of the analyzes stabilize within the required limits. Dosage infusions are the same, provided there is no undesirable action of Yondelis on other systems of the organism III-IVst. Severity (according to the classification of the National Cancer Institute of the United States).

If the intoxication does not pass more than three weeks, then the probability of taking the drug should be analyzed.

Correction of dosing during chemotherapy

In the course of two initial three-week courses of the drug, the activity of phosphatases, creatine kinase, aminotransferases and bilirubin density should be monitored every week, and in the following courses, at least once in the interval between infusions.

If any of the following effects appear in any interval between infusions, the dosage of Yondelis next time is reduced to 1.2 mg / m² - for monotherapy and 0.9 mg / m² - for a complex:

• agranulocytosis less than 0.5 × 10 10 cells / μl, remaining longer than five days or complicated by temperature increase or infection;
• decrease in the number of platelets less than 25 × 10³ cells / μl;
• the bilirubin density is higher than the maximum norm;
• the activity index of phosphatases exceeding the maximum maximum by more than 2.5 times (differentiate with deviations in pathological changes in the skeletal system);
• the activity index of aminotransferases exceeding the maximum of the norm is more than 2.5 times, and not recovered after three weeks;

With complex treatment (dosoxyl dosage is reduced to 25 mg / m²):

• the activity index of aminotransferases exceeding the maximum of the norm is more than 5 times, and not recovered in three weeks;
• any undesirable manifestation of III-IVst. Gravity (eg, insomnia, anorexia, myalgia).

Increase the previously lowered due to intoxication dose in the following courses of the drug is not recommended. In cases of drug intoxication with its simultaneous favorable clinical effect, the dosage is further reduced (monotherapy - up to 1 mg / m², complex treatment - up to 0.75 mg / m²).

If there is a need for an additional dose reduction, the likelihood of discontinuing the drug should be considered.

To eliminate the toxic effect on blood composition, subsequent courses of the drug include colony-stimulating factors.

In elderly patients with neoplasms of different localization and oncogenesis, there are no significant differences in safety or efficacy indexes. The fact that patients belong to different age groups does not influence pharmacokinetics and does not require a change in dosage.

Treatment Yondelis of persons with liver dysfunction was not thoroughly investigated. Precise prescriptions for the initial dosage of Yondelis for this group of patients are not yet available, however, in their treatment it is necessary to adjust the dosage to eliminate the risk of hepatotoxicity.

Yondelis is not recommended for patients with kidney dysfunction and in childhood, because its impact on these categories has not been studied.

[15]

Use Yondelis during pregnancy

Pregnant and lactating women should be contraindicated. This drug can contribute to the emergence of congenital pathologies.

Persons of fertile age in the treatment of Yondelis should use contraceptives during and after treatment (female patients - three months, male - 5 months).

Pregnant women, the patient is obliged to immediately notify the attending physician.

Contraindications

Sensitization to the ingredients of Yondelis, an intensive infectious process.

With caution in cases of hepatic and / or renal dysfunction, an increase in the creatine kinase index, bone marrow dysfunction.

[13], [14]

Side effects Yondelis

Very likely - agranulocytosis, nausea, vomiting, increased activity of aspartate aminotransferase and alanine aminotransferase, anemia, weakness, decreased platelet count, complete lack of appetite, diarrhea.

Occasionally, the development of side effects led to the death of patients - with monotherapy by Yondelis (1.9% of cases), with complex therapy (0.9%). Lethal outcome usually comes from a combination of undesirable effects of the drug, incl. A sharp decrease in erythrocytes, leukocytes, platelets, febrile agranulocytosis (sometimes with septicemia), hepatic, renal or multi-organ dysfunction and muscle necrosis.

Next comes a list of side effects attributed to the probable in connection with the use of this drug and observed at least 1% of cases.

To compare the frequency of side effects:

• a high probability (very often) - at least 0.1%,
• often (often) - at least 0.01 to 0.1%,
• infrequently - at least 0,001% to 0,01%.

Deviations from the norm of laboratory test indices: a large percentage of cases of increased activity of serum creatinine phosphokinase (III-IV, 4%), increased creatinine density, decreased albumin density; very often - weight loss; in about a quarter of cases, the level of creatine kinase increases in different degrees, less than 1% of them - in combination with muscle necrosis.

Deviations from the norm of the functions of the hematopoiesis: a high probability of agranulocytosis, a decrease in the number of platelets, erythrocytes, leukocytes, anemia; often - febrile agranulocytosis.

Agranulocytosis most often manifests hematologic intoxication, this symptom of III and IV century. Was traced in 19% and 8% of the Yondelis courses, respectively. Agranulocytosis was reversible, with little or no fever and / or endemia.

The decrease in the number of platelets was traced in 3% and less than 1% of the courses, respectively. Manifestations of hemorrhage, which have arisen because of this, were less than in 1% of patients with therapy only by Yondelis.

Reduction of hemoglobin - with therapy only Yondelis and in a complex in 93% and 94% of patients, respectively. This symptom of III and IV st. Was traced in 3% and 1% of courses, respectively.

Deviations from the norm of the functions of the digestive organs: a high likelihood of nausea (III-IV st. - 6%), vomiting (III-IV st. - 6.5%), constipation (III-IV st. - less than 1%); often - diarrhea (III-IV st. - less than 1%), stomatitis (III-IV st. - less than 1%), abdominal and epigastric pain, indigestion.

Abnormal hepatobiliary system functions: a high probability of raising the level of bilirubin (III v - 1%.), Increased alanine aminotransferase activity (III v - 38%, IV v - 3%..), Aspartate aminotransferase (III st.- 44%, IV 7%), deviation from the norm of alkaline phosphatase and gamma-glutamyltransferase.

The bilirubin index rose to a maximum in about a week, another week was enough to normalize it. Part of the undesirable consequences in the form of jaundice, increased liver and pain in her area, as well as part of the deceased due to violations of the patients' hepatic activity, did not exceed 1%.

Temporal increase in the intensity of alanine aminotransferase and aspartate aminotransferase III st. Was found in 12% and 20% of courses, and IV in 1% and 2% in courses, respectively. The half-period of reaching the highest index was five days. In most cases, the activity index of these enzymes decreased approximately to two weeks to Ist. Or up to the norm, in less than 2% of the cycles - the normalization process slightly exceeded three weeks. An increase in the number of infusions in the patient contributed to a trend towards the normalization of enzyme activity.

Deviations from the norm of the functions of the nervous system: a greater likelihood of a headache; often - sensory polyneuropathy, parrerexia, dizziness, paresthesia, insomnia.

Deviations from the norm of the functions of the cardiovascular system: a high probability of hypotension, tides of blood.

Deviations from the norm of the functions of the respiratory system: a high probability of dyspnea (III-IV st. - 2%), cough.

Deviations from the norm of skin functions: high probability of hair loss (with monotherapy - 3%).

Deviations from the norm of the functions of the musculoskeletal system: frequent pain in the lower back, as well as joint and muscular.

Deviations from the norm of metabolic functions: a high probability of lack of appetite (III-IV st. - less than 1%); often dehydration, a decrease in the content of potassium in the blood.

Other side effects: a high likelihood of weakness (III-IV st. - 9%), increased fatigue (III-IV st. - 1%); often - the addition of secondary infections, fever, peripheral edema, local reactions to the administration of trabektidine.

According to the results of post-registration studies, there were few episodes of the drug getting into the tissue with their necroticization and the need for surgical removal of these tissue sites.

Occasionally, there was a manifestation of acute liver dysfunction (including lethal cases) in patients on the background of a severe accompanying clinic with infusions of trabecadine.

Risk factors, possibly contributing to the marked increase in toxic properties of trabectidine noted in these situations:

• dosage of the drug did not meet the recommended;
• the reaction with competitive biomes of the CYP3A4 isoenzyme or its inhibitors is likely;
• There was no prophylactic therapy (dexamethasone).

Overdose

Information on the effects of doses of Yondelis, exceeding recommended, meager. The main symptoms that are expected from this are toxic effects on the digestive tract and liver, as well as bone marrow suppression.

Because to date, a specific antidote for this drug is not detected, in cases of exceeding the recommended dose, it is necessary to regularly monitor the patient's well-being and, if necessary, provide symptomatic assistance.

[16], [17]

Interactions with other drugs

Assignment together with drugs inactivating the isoform of cytochrome 450 CYP3A4 (the main catalyst of the Yondelis metabolism process) can slow the excretion of the active substance of the drug and increase its concentration in the blood. If the simultaneous use of Yondelis with aprepitant, fluconazole, ritonavir, ketoconazole and clarithromycin, etc. Is caused by necessity, then it is necessary to regularly monitor the manifestations of toxicity.

Studies of pharmacokinetics suggest that the accumulation of trabaktidine increases in the case of combined use with dexamethasone (by 19%).

Co-administration with rifampicin, phenobarbital, preparations containing St. John's Wort, inducing the isoform of cytochrome 450 CYP3A4, increases the rate of purification of trabektidine.

The administration, together with drugs that oppress the protein of multiple drug resistance, for example cyclosporine, affects the distribution and / or excretion of trabektidine (therefore, these combinations must be used with caution).

 The active ingredient of Jondelis under laboratory conditions showed no activating or retarding properties with respect to the basic isoforms of cytochrome P450.

During the study, the pharmacokinetic parameters of blood plasma using Doxil (30 mg / m²) concurrently with Yondelis (1.1 mg / m²) were similar to those in Doxil monotherapy.

Co-administration with phenytoin is not indicated, since it can lead to increased seizures.

Joint use with live attenuated vaccines is not shown.

During treatment, you should not drink alcohol, tk. Hepatic intoxication is increased. 

[18], [19]

Storage conditions

Keep in accordance with the temperature regime of 2-8 ° C. Keep away from children. 

Shelf life

Not more than 3 years.