Yondelis

A chemotherapeutic monodrug of natural origin that prevents the growth and development of a number of neoplasms. The active component is trabectedin (tristetrahydroisoquinoline alkaloid extracted from the marine hydrobiont ascidian).

Additional ingredients: cane sugar, potassium dihydrogen orthophosphate, 0.1N phosphoric acid solution, 0.1M potassium hydroxide solution.

Indications Yondelis

Recurrence of ovarian malignancy after chemotherapy with carboplatin or cisplatin. Yondelis is administered in combination with Doxil.

Liposarcoma and leiomyosarcoma of soft tissues in case of intolerance to Ifos and anthracycline drugs or in case of their ineffectiveness.

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Release form

Lyophilized powder for the preparation of a solution for intravenous infusions, packaged in glass vials containing 1 mg of the active substance.

Pharmacodynamics

Trabectedin inhibits the process of transferring the oncogenetic code from deoxyribonuclease to ribonuclease in neoplasm cells, which, as a result, disrupts the circular process of cancer cell development. This leads to normalization of neoplastic cell modification and slowing down of neoplasm growth.

In vitro and in vivo studies indicate that Trabectedin inhibits the proliferation of certain human cancer cells, including sarcoma, melanoma, lung carcinoma, breast cancer and ovarian cancer.

Use in combination with Doxil significantly increases the effectiveness of the drugs.

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Pharmacokinetics

The duration of noticeable action of a continuous infusion dose of trabectedin is comparable to the administered amount of the drug (up to 1.8 mg/m²). Pharmacokinetic parameters correspond to a multi-compartment distribution model with a half-life of 175 hours. Administration once every three weeks does not cause its accumulation in blood plasma.

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

The metabolism process is intensive. At clinically significant plasma density, the active ingredient is oxidized mainly by the CYP3A4 isoenzyme; the involvement of other enzymes of the P450 family in its metabolism cannot be ruled out. No active reaction of the second phase of trabectedin metabolism is observed.

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

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

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

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Dosing and administration

Preparation of the composition

Add 20 ml of water for injection to the powder in the vial and dissolve the contents by shaking. The concentration of the resulting homogeneous mixture is 50 g/ml, it should not be cloudy, colorless or have a yellowish-brown tint, and have no sediment. After this, the mixture must be diluted.

If the mixture is injected into a central vein (using a venous catheter), it is additionally diluted as follows: fill a syringe with the required volume of the mixture obtained and, having pierced the rubber stopper of the dropper bottle, inject the mixture into it. For additional dilution of Yondelis, use a saline solution or an isotonic 5% d-glucose solution with a capacity of at least 0.5 l (this drug cannot be diluted with other solutions).

If it is impossible to infuse into the central vein, the mixture is infused into the peripheral vein. In this case, at least 1 liter of saline or 5% isotonic d-glucose solution is used for dilution.

If complex therapy with Doxil is carried out, then before the described procedure the IV system must be thoroughly flushed with 5% isotonic d-glucose solution, since Doxil residues should not mix with the saline solution.

Before using the IV drip, carefully inspect the prepared mixtures to ensure there is no sediment or color change. The prepared 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 is subject to disposal.

Yondelis is fully compatible with polymeric materials of intravenous infusion systems, as well as with titanium of venous catheters.

Yondelis Dosage

Connective tissue sarcoma – every three weeks, 1.5 mg per 1 m² of body surface area is injected intravenously for 24 hours.

Malignant ovarian tumor with relapses - Yondelis is used together with Doxil with an interval of three weeks. The drug is infused 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 are given a preliminary intravenous glucocorticosteroid injection half an hour before each Yondelis infusion to prevent liver failure; antiemetics may be added. Dosages are prescribed by the attending physician individually.

Chemotherapy with Yondelis is carried out only with the appropriate test results:

• absolute neutrophil count (ANC) not less than 1.5×10³cells/μl;
• platelet count not less than 100×10³cells/μl;
• hemoglobin level not less than 90 g/l;
• direct bilirubin content is no more than 5.1 μmol/l;
• the phosphatase activity indicator does not exceed the maximum normal value by 2.5 times (if this indicator deviates more, the attending physician may prescribe additional tests);
• the aminotransferase activity index does not exceed the maximum normal value by 2.5 times;
• albumin level not less than 25 g/l;

Complex treatment is carried out when the creatinine clearance rate in the blood is at least 60 ml/min and the creatine phosphokinase activity level does not exceed the maximum norm by 2.5 times.

Repeated infusions of this drug must be done in accordance with the above conditions. Otherwise, chemotherapy is postponed for up to three weeks until the test results stabilize within the required limits. The dosages of infusions are the same, provided that there are no adverse effects of Yondelis on other body systems of grade III-IV severity (according to the classification of the US National Cancer Institute).

If the intoxication does not go away for more than three weeks, then the possibility of discontinuing the drug should be analyzed.

Dosage adjustments during chemotherapy

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

If even one of the following effects occurs during any interval between infusions, the dosage of Yondelis is reduced the next time to 1.2 mg/m² for monotherapy and 0.9 mg/m² for combination therapy:

• agranulocytosis less than 0.5×10³cells/µl, persisting for more than five days or complicated by fever or infection;
• decrease in the platelet count to less than 25×10³cells/μl;
• bilirubin density is higher than the maximum normal value;
• phosphatase activity level exceeding the maximum norm by more than 2.5 times (differentiate with deviations in pathological changes in the skeletal system);
• an aminotransferase activity level that exceeds the maximum normal value by more than 2.5 times and has not returned to normal within three weeks;

In complex treatment (the dosage of Doxil is reduced to 25 mg/m²):

• an aminotransferase activity level that is more than 5 times higher than the maximum normal value and has not returned to normal within three weeks;
• any undesirable manifestation of grade III-IV severity (for example, insomnia, anorexia, myalgia).

It is not recommended to increase the dosage previously reduced due to intoxication in subsequent courses of the drug. In cases of intoxication with the drug 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).

In cases where there is a need for further reduction in dosage, the possibility of discontinuing the drug should be considered.

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

In elderly patients with neoplasms of different localization and oncogenesis, no significant differences in safety or efficacy indices are found. The patients' belonging to different age groups does not affect the pharmacokinetic parameters and does not require changes in dosage.

Treatment of patients with liver dysfunction with Yondelis has not been thoroughly studied. There are no precise initial dosage recommendations for Yondelis in this group of patients, but the dosage should be adjusted to eliminate the risk of hepatotoxicity.

Yondelis is not recommended for patients with renal dysfunction and in childhood, since its effect on these categories has not been studied.

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Use Yondelis during pregnancy

Pregnant and lactating women are contraindicated to use, as this medicine may contribute to the development of congenital pathologies.

Persons of childbearing age who are treated with Yondelis must use contraceptives during and after treatment (female patients – three months, male patients – five months).

If a patient becomes pregnant, she must immediately notify her attending physician.

Contraindications

Sensitization to the ingredients of Yondelis, intense infectious process.

With caution in cases of liver and/or kidney dysfunction, increased creatine kinase levels, bone marrow dysfunction.

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Side effects Yondelis

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

Occasionally, the development of side effects led to the death of patients - with monotherapy with Yondelis (1.9% of cases), with complex therapy (0.9%). The fatal outcome usually occurred from a combination of undesirable effects of the drug, including a sharp decrease in red blood cells, white blood cells, platelets, febrile agranulocytosis (sometimes with septicemia), liver, kidney or multiorgan dysfunction and muscle necrosis.

The following is a list of side effects that are considered likely to occur with the use of this drug and that occur in at least 1% of cases.

To compare the frequency of side effects:

• high probability (very often) – not less than 0.1%,
• often (not infrequently) – not less than 0.01 to 0.1%,
• infrequently – not less than 0.001% to 0.01%.

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

Abnormalities in the functions of the hematopoietic organs: high probability of agranulocytosis, decreased number of platelets, erythrocytes, leukocytes, anemia; often febrile agranulocytosis.

Agranulocytosis is most often a manifestation of hematological intoxication; this symptom of stage III and IV was observed in 19% and 8% of Yondelis courses, respectively. Agranulocytosis was reversible and was practically not accompanied by fever and/or endemia.

A decrease in platelet count was observed in 3% and less than 1% of courses, respectively. Manifestations of hemorrhage resulting from this were observed in less than 1% of patients with therapy with Yondelis alone.

A decrease in hemoglobin – with therapy with Yondelis alone and in combination in 93% and 94% of patients, respectively. This symptom of stage III and IV was observed in 3% and 1% of courses, respectively.

Abnormalities in the functions of the digestive organs: high probability of nausea (III-IV stage - 6%), vomiting (III-IV stage - 6.5%), constipation (III-IV stage - less than 1%); often - diarrhea (III-IV stage - less than 1%), stomatitis (III-IV stage - less than 1%), abdominal and epigastric pain, indigestion.

Abnormalities in the functions of the hepatobiliary system: high probability of increased bilirubin levels (stage III – 1%), increased activity of alanine aminotransferase (stage III – 38%, stage IV – 3%), aspartate aminotransferase (stage III – 44%, stage IV – 7%), abnormalities in alkaline phosphatase and gamma-glutamyltransferase.

The bilirubin level increased to its maximum within about a week, another week was enough for it to return to normal. The share of undesirable consequences in the form of jaundice, enlargement of the liver and pain in its area, as well as the share of patients who died due to liver dysfunction, did not exceed 1%.

Temporary increase in the intensity of alanine aminotransferase and aspartate aminotransferase stage III was detected in 12% and 20% of courses, and stage IV - in 1% and 2% of courses, respectively. The half-life of achieving the highest indicator was five days. In most cases, the activity of these enzymes decreased to stage I or to normal in about two weeks, in less than 2% of cycles - the normalization process slightly exceeded three weeks. An increase in the number of infusions in the patient contributed to the tendency to normalize enzyme activity.

Deviations from the norm of nervous system functions: high probability of headache; often – sensory polyneuropathy, parorexia, dizziness, paresthesia, insomnia.

Deviations from the norm of cardiovascular functions: high probability of hypotension and hot flashes.

Deviations from the norm of respiratory system functions: high probability of shortness of breath (III-IV stage – 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 muscle pain.

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

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

According to the results of post-registration studies, there were a few cases of the drug entering tissues with their necrosis and the need for surgical removal of these tissue areas.

Rarely, acute liver dysfunction (including fatal cases) has been observed in patients with severe accompanying clinical symptoms during trabectedin infusions.

Risk factors that may have contributed to the increased toxicity of trabectedin observed in these situations include:

• the dosages of the drug did not correspond to the recommended ones;
• possible reaction with competitive biomes of the CYP3A4 isoenzyme or its inhibitors;
• no prophylactic therapy (dexamethasone) was administered.

Overdose

There is little information on the effects of higher than recommended doses of Yondelis. The main symptoms to be expected are gastrointestinal and liver toxicity and bone marrow suppression.

Since a specific antidote for this drug has not yet been identified, in cases where the recommended dose is exceeded, the patient’s well-being should be regularly monitored and symptomatic care provided if necessary.

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Interactions with other drugs

Administration together with drugs that inactivate the cytochrome 450 isoform CYP3A4 (the main catalyst of the metabolism process of Yondelis) can slow down the elimination 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 necessary, then it is necessary to regularly monitor for toxicity.

Pharmacokinetic studies indicate that the accumulation of trabectedin increases when co-administered with dexamethasone (by 19%).

Concomitant use with rifampicin, phenobarbital, and St. John's wort-containing drugs that induce the cytochrome 450 CYP3A4 isoform increases the clearance rate of trabectedin.

Co-administration with drugs that inhibit multidrug resistance protein, such as cyclosporine, affects the distribution and/or excretion of trabectedin (therefore, such combinations should be used with caution).

The active ingredient of Yondelis did not exhibit activating or inhibiting properties in laboratory conditions in relation to the main isoforms of cytochrome P450.

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

Concomitant use with phenytoin is not indicated as it may lead to increased seizures.

Concomitant use with live attenuated vaccines is not indicated.

During treatment, you should not drink alcohol, as it increases liver intoxication.

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Storage conditions

Store at a temperature of 2-8ºС. Keep out of reach of children.

Shelf life

No more than 3 years.