Trabectedin-Promomed (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

L01CX01 (Trabectedin)

Active Substance

Trabectedin (Rec.INN registered by WHO)

Dosage Form

Trabectedin-Promomed

Lyophilisate for the preparation of infusion solution 1 mg

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of a concentrate for the preparation of an infusion solution

– vials – cardboard packs – By prescription
– vials (10 pcs.) – cardboard packs – By prescription
– vials (5 pcs.) – cardboard packs – By prescription

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; plant alkaloids and other natural substances; other plant alkaloids and natural substances

Pharmacological Action

Antineoplastic agent. It is a tetrahydroisoquinoline alkaloid of natural (marine) origin, first isolated from the Caribbean tunicate Ecteinascidia turbinata. It has a complex mechanism of action aimed at transcription. It suppresses gene transcription and interacts with the nucleotide excision repair system associated with transcription.

Trabectedin binds to the minor groove of DNA, causing the DNA helix to bend towards the major groove. This triggers a cascade of processes affecting DNA transcription factors, DNA-binding proteins, and DNA repair mechanisms, which ultimately leads to disruption of the cell cycle. Trabectedin has an antiproliferative effect in vitro and in vivo in a number of human tumor cell cultures and in experimental tumors, including sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer, and melanoma.

Pharmacokinetics

The level of systemic exposure to trabectedin after administration by 24-hour intravenous infusion at a constant rate is proportional to the administered dose up to and including a dose of 1.8 mg/m². The pharmacokinetics of trabectedin corresponds to a multi-compartment distribution model with a T_1/2 in the terminal elimination phase of 180 hours. When administered once every 3 weeks, no accumulation of the active substance in the blood plasma was detected.

Trabectedin has a large V_d (> 5000 L), which is consistent with wide distribution to peripheral tissues.

Trabectedin is largely bound to plasma proteins; at plasma concentrations of 10 and 100 ng/mL, the free fraction is 2.23% and 2.72%, respectively.

Trabectedin is actively metabolized. At clinically significant concentrations, it is metabolized by oxidation primarily involving the CYP3A4 isoenzyme, although the role of other enzymes of this system in the metabolism of trabectedin cannot be ruled out.

< 1% is excreted unchanged in urine and feces. The clearance of trabectedin in whole blood is approximately 35 L/hour, which is approximately half the blood flow through the human liver. The values of trabectedin clearance in plasma range from 28% to 51%.

Population pharmacokinetic analysis showed that the clearance of trabectedin in plasma does not depend on the age (19-83 years) and sex of the patients. The influence of race and ethnic origin on this indicator has not been studied.

It is assumed that impaired renal function has little effect on the excretion of trabectedin and its metabolites.

In patients with impaired liver function, a decrease in trabectedin clearance with a corresponding increase in the concentration of the drug in the blood plasma is possible.

Indications

Treatment of advanced soft tissue sarcoma in patients who are insensitive to anthracyclines and ifosfamide, or who have contraindications to their use. Efficacy has been demonstrated primarily for liposarcoma and leiomyosarcoma.

ICD codes

Dosage Regimen

It is administered as a 24-hour intravenous infusion, preferably through a central venous catheter.

All patients should receive premedication with corticosteroids; if necessary, additional antiemetics can be used.

The recommended initial dose is 1.5 mg/m² at 3-week intervals.

Trabectedin can only be administered with the following laboratory parameters: absolute neutrophil count > 1500/µL; platelet count > 100,000/µL; hemoglobin level > 9 g/dL; bilirubin level not exceeding the upper limit of normal (ULN); alkaline phosphatase (ALP) level not exceeding 2.5 times the ULN (if the ALP level is elevated, possibly associated with bone involvement, the level of hepatic isoenzymes 5′-nucleotidase or gamma-glutamyltransferase should be determined); with ALT and AST levels not exceeding 2.5 times the ULN; albumin content > 25 g/L; creatinine clearance (CrCl) > 30 mL/min; creatine phosphokinase (CPK) level not exceeding 2.5 times the ULN.

Repeat infusions can also only be carried out if the above criteria are met. Otherwise, the infusion is postponed for up to 3 weeks until the blood laboratory parameters meet the above criteria, and the drug is administered at the same dose, provided there are no other non-hematological adverse events of grade 3-4.

If toxicity persists for more than 3 weeks, discontinuation of treatment should be considered.

During the first two 3-week cycles, levels of ALP, bilirubin, CPK, ALT, and AST should be monitored weekly, and in subsequent cycles – at least once between infusions.

At the next infusion, the dose is reduced to 1.2 mg/m² if at any time between infusions at least one of the following phenomena occurs: neutropenia < 500/µL, lasting more than 5 days or accompanied by fever or infection; thrombocytopenia < 25,000/µL; increase in bilirubin level above ULN and/or ALP more than 2.5 times above ULN; increase in AST or ALT levels more than 2.5 times above ULN, not normalized by day 21 of the cycle; any adverse event of grade 3 or 4 severity (e.g., nausea, vomiting, weakness).

After a dose reduction due to toxicity, its re-increase in subsequent cycles is not recommended. If any of the toxic reactions reappears in subsequent cycles, and the treatment has a favorable clinical effect, the dose may be further reduced to 1 mg/m². If a further dose reduction is required, discontinuation of treatment should be considered.

Adverse Reactions

Most frequently nausea, weakness, vomiting, anorexia, neutropenia, increased AST/ALT levels.

Death as a result of adverse reactions was observed in 1.9% of patients and usually occurred as a result of a combination of adverse reactions, including pancytopenia and febrile neutropenia; in some cases, sepsis, liver damage, renal failure, and rhabdomyolysis were observed.

From the hematopoietic and lymphatic system: anemia, leukopenia, neutropenia, thrombocytopenia, febrile neutropenia.

From the digestive system: nausea, vomiting, anorexia, constipation, diarrhea, stomatitis, abdominal pain, increased ALT, AST, ALP activity, hyperbilirubinemia, jaundice, hepatomegaly, liver pain. Mortality due to liver damage did not exceed 1%.

From the central and peripheral nervous system: headache, taste perversion, peripheral sensory neuropathy/paresthesia, dizziness, insomnia.

From the cardiovascular system: decreased blood pressure, flushing.

From the respiratory system: dyspnea, cough.

Dermatological reactions: alopecia.

From the musculoskeletal system: myalgia, arthralgia, back pain, increased CPK level, increased CPK level in combination with rhabdomyolysis.

From metabolism: increased blood albumin level, dehydration, hypokalemia, peripheral edema, weight loss.

Other: weakness, increased fatigue, increased body temperature, secondary infections, reactions at the injection site, increased blood creatinine level.

Contraindications

Active severe or uncontrolled infection, pregnancy, lactation (breastfeeding), hypersensitivity to trabectedin.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Use in Hepatic Impairment

Should be used with caution in patients with impaired liver function.

In patients with impaired liver function, the risk of toxicity may be increased. The use of trabectedin in patients with impaired liver function has not been sufficiently studied. There are currently no clear recommendations on the initial dose for this category of patients. Particular caution should be exercised when treating such patients. Dose adjustment may be possible to reduce the risk of hepatotoxicity. Trabectedin is not used in cases of elevated bilirubin levels.

Use in Renal Impairment

No studies have been conducted in patients with severe renal failure (CrCl <30 mL/min), so use in this category of patients is contraindicated. Should be used with caution in patients with impaired renal function. Mild or moderate renal impairment is unlikely to affect the pharmacokinetics of trabectedin.

Pediatric Use

The safety and efficacy of trabectedin in children have not been established to date, so use in pediatrics is contraindicated.

Geriatric Use

No specific studies have been conducted in elderly patients. Population pharmacokinetic analysis indicates no effect of patient age on the clearance and V_d of trabectedin. Therefore, dose adjustment based on age alone is usually not required.

Special Precautions

Should be used with caution in patients with impaired liver and/or kidney function, with elevated CPK levels, and with bone marrow suppression.

In patients with impaired liver function, the risk of toxicity may be increased. The use of trabectedin in patients with impaired liver function has not been sufficiently studied. There are currently no clear recommendations on the initial dose for this category of patients. Particular caution should be exercised when treating such patients. Dose adjustment may be possible to reduce the risk of hepatotoxicity. Trabectedin is not used in cases of elevated bilirubin levels.

No studies have been conducted in patients with severe renal failure (CrCl <30 mL/min), so use in this category of patients is contraindicated. Mild or moderate renal impairment is unlikely to affect the pharmacokinetics of trabectedin.

The safety and efficacy of trabectedin in children have not been established to date, so use in pediatrics is contraindicated.

No specific studies have been conducted in elderly patients. Population pharmacokinetic analysis indicates no effect of patient age on the clearance and V_d of trabectedin. Therefore, dose adjustment based on age alone is usually not required.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.