Trabectedin ever pharma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRABECTEDIN EVER PHARMA (TRABECTEDIN EVERPHARMA)

Composition:

Active substance: trabectedin;

1 vial contains 0.25 mg or 1 mg of trabectedin;

Excipients: citric acid anhydrous, L-arginine, phosphoric acid diluted, phosphoric acid concentrated, sodium hydroxide.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: powder/mass of white to almost white color.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. ATC code L01CX01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Trabectedin binds to the minor groove of DNA, resulting in bending of the DNA helix towards the major groove. This triggers a cascade of processes affecting several DNA transcription factors, DNA-binding proteins, and DNA repair mechanisms, leading to disruption of the cell cycle.

Pharmacodynamic effects

Trabectedin exerts anti-proliferative effects in vitro and in vivo in certain human tumor cell cultures and experimental tumors, including sarcoma, breast cancer, non-small cell lung cancer, ovarian cancer, and melanoma.

Electrocardiogram (ECG) studies

In placebo-controlled QT/QTc interval studies, trabectedin did not cause QTc interval prolongation in patients with advanced solid tumors.

Pharmacokinetics.

Distribution

Systemic exposure to trabectedin after intravenous infusion administered at a constant rate is proportional to the dose administered up to 1.8 mg/m². The pharmacokinetics of trabectedin follow a multi-compartment distribution model.

After intravenous administration, trabectedin demonstrates a large volume of distribution, due to extensive binding to peripheral tissues and plasma proteins (94% to 98% of trabectedin in plasma is protein-bound). The steady-state volume of distribution of trabectedin in humans exceeds 5000 L.

Metabolism

The CYP3A4 isoenzyme of the cytochrome P450 system is the primary isoenzyme responsible for the oxidative metabolism of trabectedin at clinically relevant concentrations. The contribution of other cytochrome P450 enzymes to trabectedin metabolism cannot be excluded. Trabectedin does not induce or inhibit major cytochrome P450 enzymes.

Elimination

A small amount (<1%) of unchanged trabectedin is excreted in the urine in humans. The terminal elimination half-life is long (population estimate of terminal elimination phase: 180 hours). After administration of radiolabeled trabectedin to cancer patients, the mean (SD) cumulative excretion of total radioactivity was 58% (17%) in feces and 5.8% (1.73%) in urine of the administered dose. Based on the population estimate of trabectedin plasma clearance (30.9 L/h) and the blood-to-plasma ratio (0.89), the whole blood clearance of trabectedin is approximately 35 L/h. This value is about half of the hepatic blood flow in humans. Therefore, the blood clearance can be considered moderate. The inter-individual variability in plasma clearance of trabectedin was 49%, and intra-individual variability was 28%.

Population pharmacokinetic analysis showed that concomitant administration of trabectedin and pegylated liposomal doxorubicin (PLD) reduced trabectedin plasma clearance by 31%; the pharmacokinetics of PLD were not altered when administered concomitantly with trabectedin.

Special patient populations

Population pharmacokinetic analysis demonstrated that trabectedin plasma clearance is independent of age (19–83 years), patient sex, total body weight (36–148 kg), or body surface area (0.9–2.8 m²). Population pharmacokinetic analysis showed that plasma concentrations of trabectedin observed in Japanese patients at a dose of 1.2 mg/m² were equivalent to those observed in non-Japanese Western patients at a dose of 1.5 mg/m².

Renal impairment

Renal function, assessed by creatinine clearance, had no clinically significant effect on the pharmacokinetics of trabectedin within the range of values (≥30 mL/min) observed in patients enrolled in clinical studies.

There are no data available for patients with creatinine clearance <30.3 mL/min. The low urinary excretion (<9% in all studied patients) of radioactivity after a single dose of 14C-labeled trabectedin suggests that impaired renal function has minimal impact on the elimination of trabectedin or its metabolites.

Hepatic impairment

The effect of impaired liver function on the pharmacokinetics of trabectedin was evaluated in 15 oncology patients receiving doses of 0.58 to 1.3 mg/m² administered as a 3-hour infusion. The geometric mean dose-normalized exposure (AUC) of trabectedin increased by 97% (90% CI: 20–222%) in 6 patients with moderate hepatic impairment (elevated serum bilirubin levels of 1.5 to 3 × ULN and elevated aminotransferase levels [AST or ALT] <8 × ULN) after a single dose of trabectedin 0.58 mg/m² (n=3) or 0.9 mg/m² (n=3), compared to 9 patients with normal liver function who received a single dose of 1.3 mg/m² (see sections "Special precautions for use" and "Dosage and administration").

Clinical characteristics.
Indications.

Treatment of adult patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or when such treatment is contraindicated. Efficacy has been demonstrated primarily in patients with liposarcoma and leiomyosarcoma.

Treatment of patients with platinum-sensitive relapsed ovarian cancer in combination with pegylated liposomal doxorubicin (PLD).

Contraindications.

• Hypersensitivity to trabectedin or to any of the excipients.
• Active serious or uncontrolled infection.
• Breastfeeding period (see section "Pregnancy and breastfeeding").
• Concomitant administration with yellow fever vaccine (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on trabectedin

Drug interaction studies have been conducted only in adults. Since trabectedin is primarily metabolized by CYP3A4, concomitant use of inhibitors of this enzyme may increase trabectedin plasma concentrations. Similarly, concomitant use of strong inducers of this enzyme may increase the metabolic clearance of trabectedin. Two phase 1 in vivo drug interaction studies confirmed trends of increased and decreased trabectedin exposure when co-administered with ketoconazole and rifampicin, respectively.

When ketoconazole was administered concomitantly with trabectedin, an increase in trabectedin plasma exposure (approximately 21% and 66% increase in Cmax and AUC, respectively) was observed, but no new safety concerns were identified. Patients receiving trabectedin in combination with strong CYP3A4 inhibitors (e.g., oral ketoconazole, fluconazole, ritonavir, clarithromycin, or aprepitant) require careful monitoring for toxic effects, and such combinations should be avoided if possible. If such combinations are necessary, appropriate dose adjustments should be considered in case of toxic effects (see sections "Special precautions for use" and "Dosage and administration").

Concomitant administration of rifampicin with trabectedin resulted in reduced trabectedin plasma exposure (approximately 22% and 31% decrease in Cmax and AUC, respectively). Therefore, if possible, concomitant use of trabectedin with strong CYP3A4 inducers (e.g., rifampicin, phenobarbital, St. John's wort) should be avoided (see section "Special precautions for use").

Alcohol consumption should be avoided during trabectedin treatment due to the hepatotoxic potential of the drug (see section "Special precautions for use").

Preclinical studies have shown that trabectedin is a substrate of P-glycoprotein. Concomitant administration of P-glycoprotein inhibitors, such as cyclosporine and verapamil, may alter the distribution and/or elimination of trabectedin. The clinical significance of this interaction, for example, regarding the development of central nervous system (CNS) toxicity, has not been established. Caution should be exercised in such cases.

Special precautions for use.

Hepatic impairment

Patients must meet specific liver function criteria prior to initiating treatment with Trabectedin Ever Pharma. Since hepatic impairment results in approximately a doubling of systemic exposure to trabectedin (see section "Pharmacokinetics"), and thus may increase the risk of toxic effects, patients with clinically significant liver diseases such as active chronic hepatitis should be closely monitored, and the dose of the medicinal product should be adjusted if necessary. Trabectedin treatment is contraindicated in patients with elevated bilirubin levels (see section "Posology and method of administration").

Renal impairment

Creatinine clearance should be monitored before and during treatment. Trabectedin Ever Pharma, either as monotherapy or in combination therapy, must not be administered to patients with creatinine clearance < 30 mL/min and < 60 mL/min, respectively (see section "Posology and method of administration").

Neutropenia, thrombocytopenia

Grade 3 or 4 neutropenia and thrombocytopenia have been frequently reported with trabectedin use. A complete blood count with differential white blood cell count and platelet count should be performed prior to initiation of treatment, weekly during the first two cycles, and then once between cycles (see section "Posology and method of administration"). Patients who develop fever must seek immediate medical attention. In such cases, prompt supportive therapy should be initiated.

Trabectedin Ever Pharma should not be administered to patients with baseline neutrophil counts below 1,500 cells/mm³ or platelet counts below 100,000 cells/mm³. In cases of severe neutropenia (less than 500 cells/mm³) lasting more than 5 days or accompanied by fever or infection, dose reduction is recommended (see section "Posology and method of administration").

Nausea and vomiting

All patients should receive antiemetic premedication with corticosteroids, such as dexamethasone (see section "Posology and method of administration").

Rhabdomyolysis and marked increase in creatine phosphokinase (CPK) levels (>5 × ULN)

Trabectedin must not be administered to patients with creatine phosphokinase levels exceeding 2.5 times the upper limit of normal (ULN) (see section "Posology and method of administration"). Rhabdomyolysis has been infrequently reported, usually in the presence of myelotoxicity, severe hepatic impairment, and/or renal or multiorgan failure. Therefore, serum creatine phosphokinase levels should be monitored if any of these toxicities develop, as well as in the presence of muscle weakness or muscle pain. In the event of rhabdomyolysis, immediate supportive measures such as parenteral hydration, urine alkalinization, and dialysis, as indicated, should be initiated. Treatment with Trabectedin Ever Pharma should be discontinued until complete recovery.

Caution should be exercised when administering trabectedin concomitantly with agents known to induce rhabdomyolysis (e.g., statins), as this may increase the risk of rhabdomyolysis.

Changes in liver function parameters

Reversible acute elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have been observed in most patients. Trabectedin Ever Pharma must not be administered to patients with elevated bilirubin levels. Dose adjustments may be required in patients with elevated AST, ALT, and alkaline phosphatase levels between cycles (see section "Posology and method of administration").

Infusion site reactions

Infusion should be administered exclusively via a central venous catheter (see section "Posology and method of administration"). Administration of trabectedin into peripheral veins may lead to potentially severe infusion site reactions.

Extravasation of trabectedin may result in tissue necrosis requiring surgical intervention. There is no specific antidote for tissue infiltration of trabectedin. Management of extravasation should follow national standard practices.

Hypersensitivity reactions

Very rare cases of fatal hypersensitivity reactions associated with trabectedin, either as monotherapy or in combination with pegylated liposomal doxorubicin (PLD), have been reported.

Cardiac dysfunction

Patients should be monitored for cardiac adverse effects or myocardial dysfunction.

Comprehensive cardiac evaluation, including assessment of left ventricular ejection fraction (LVEF) by echocardiography or radionuclide ventriculography (MUGA), should be performed prior to initiating trabectedin treatment and every 2–3 months thereafter until discontinuation of therapy.

Patients with LVEF below the lower limit of normal (LVEF < LLN), prior cumulative anthracycline dose > 300 mg/m², age > 65 years, or history of cardiovascular disease (particularly those taking cardiac medications) may have an increased risk of cardiac dysfunction when treated with trabectedin, either as monotherapy or in combination with doxorubicin.

Trabectedin should be discontinued in patients experiencing grade 3 or 4 cardiac adverse events indicative of cardiomyopathy, or in patients with LVEF below LLN (defined as an absolute decrease in LVEF of ≥ 15% or < LLN with an absolute decrease of ≥ 5%) (see section "Posology and method of administration").

Capillary leak syndrome (CLS)

Cases of capillary leak syndrome (CLS), including fatal cases, have been reported with trabectedin use. In the event of symptoms suggestive of possible CLS, such as unexplained edema with or without arterial hypotension, serum albumin levels should be reassessed. A rapid decline in serum albumin levels may indicate CLS. If CLS is confirmed after exclusion of other causes, trabectedin should be discontinued and treatment for CLS initiated according to clinical guidelines (see sections "Posology and method of administration" and "Undesirable effects").

Other

Concomitant use of Trabectedin Ever Pharma with strong inhibitors of the CYP3A4 enzyme should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). If coadministration is unavoidable, careful monitoring for toxicity and dose reduction of trabectedin, if necessary, should be implemented.

Caution should be exercised when administering trabectedin concomitantly with hepatotoxic agents, as this may increase the risk of hepatotoxicity.
Concomitant use of trabectedin and phenytoin may reduce phenytoin absorption, leading to increased seizure risk. The combination of trabectedin with phenytoin or live attenuated vaccines is not recommended. Concomitant administration of trabectedin with the yellow fever vaccine is contraindicated (see section "Contraindications"). Alcohol consumption should be avoided during treatment with trabectedin (see section "Interaction with other medicinal products and other forms of interaction").

Women of childbearing potential must use effective contraception during treatment and for 3 months after completion of therapy and must inform their physician immediately if pregnancy occurs. Men of reproductive potential should also use reliable contraception during treatment and for 5 months after therapy discontinuation (see section "Use in pregnancy or breastfeeding").

See also the prescribing information for PLD regarding warnings and precautions.

This medicinal product contains less than 1 mmol (23 mg) of sodium per vial, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There is insufficient clinical data on the use of this medicinal product during pregnancy. However, based on its known mechanism of action, trabectedin use during pregnancy may cause severe congenital malformations. Trabectedin crosses the placenta when administered to pregnant rats. Trabectedin must not be used during pregnancy. If pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus and closely monitored. When trabectedin is used near the end of pregnancy, newborns should be carefully monitored for possible adverse reactions.

Women of reproductive potential

Women of reproductive potential should use effective contraception during treatment and for 3 months after completion of therapy and must inform their physician immediately if pregnancy occurs.

If pregnancy occurs during treatment, genetic counseling should be considered.

Breastfeeding

It is unknown whether trabectedin is excreted in human breast milk. Excretion of trabectedin into animal milk has not been studied. Breastfeeding is contraindicated during treatment and for 3 months after its completion (see section "Contraindications").

Fertility

Men of reproductive potential should use effective contraception during treatment and for 5 months after discontinuation of therapy (see section "Special precautions for use").

Trabectedin may cause genotoxic effects. Patients should be counseled before treatment initiation regarding the advisability of oocyte or sperm cryopreservation due to the potential for irreversible infertility following treatment with Trabectedin Ever Pharma. Genetic counseling is also recommended for patients who wish to have children after treatment.

Ability to influence reaction speed while driving or operating machinery.

No studies have been conducted on the effect of trabectedin on the ability to drive or operate machinery. However, weakness and/or asthenia have been reported with trabectedin use. Patients experiencing these symptoms should not drive or operate machinery.

Method of administration and dosage.

Trabectedin Ever Pharma must be administered under the supervision of a physician experienced in chemotherapy. This medicinal product should be administered only by qualified oncologists or other healthcare professionals who have received specific training in the use of cytotoxic agents.

Dosing

For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m² body surface area administered as a 24-hour intravenous infusion every three weeks.

For the treatment of ovarian cancer, Trabectedin Ever Pharma should be administered every three weeks as a 3-hour intravenous infusion at a dose of 1.1 mg/m² immediately after administration of pegylated liposomal doxorubicin (PLD) at a dose of 30 mg/m². To reduce the risk of infusion reactions following PLD, the initial dose should be infused at a rate not exceeding 1 mg/min. If no infusion reactions occur, subsequent PLD infusions may be administered over 1 hour (see also the Package Leaflet for PLD).

All patients should receive premedication with corticosteroids, for example, 20 mg of dexamethasone intravenously 30 minutes before each PLD infusion (combination therapy) or Trabectedin Ever Pharma (monotherapy), not only for antiemetic purposes but also due to the hepatoprotective effect of dexamethasone. Additional antiemetic agents may be used if necessary.

Treatment with Trabectedin Ever Pharma may be initiated only if the following conditions are met:

• absolute neutrophil count ≥ 1500/mm³;
• platelet count ≥ 100,000/mm³;
• bilirubin level not exceeding the upper limit of normal (ULN);
• alkaline phosphatase level not exceeding 2.5 times the ULN (if elevation may be of bone origin, liver isoenzyme levels of 5'-nucleotidase or γ-glutamyltransferase should be analyzed);
• albumin level ≥ 25 g/L;
• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels not exceeding ULN by more than 2.5 times;
• creatinine clearance ≥ 30 mL/min (monotherapy), serum creatinine level ≤ 1.5 mg/dL (≤ 132.6 µmol/L), or creatinine clearance ≥ 60 mL/min (combination therapy);
• creatine phosphokinase (CPK) level not exceeding 2.5 times the ULN;
• hemoglobin level ≥ 9 g/dL.

The same criteria must be met prior to each subsequent cycle. Otherwise, treatment should be delayed for up to 3 weeks until all parameters meet these criteria. Bilirubin, alkaline phosphatase, aminotransferases, and creatine phosphokinase levels should be monitored weekly during the first two cycles and at least once between treatment cycles.

The same dose should be used in all treatment cycles in the absence of grade 3–4 toxicity and provided the above criteria are met before each subsequent cycle.

Dose adjustment during treatment

Prior to each subsequent treatment cycle, laboratory parameters should be checked for compliance with the above-mentioned criteria. If any of the following events occur at any time between infusions, the dose should be reduced by one level at the next infusion according to Table 1 below:

• neutropenia < 500 cells/mm³ lasting more than 5 days or accompanied by fever or infection;
• thrombocytopenia < 25,000 cells/mm³;
• increased bilirubin level above ULN and/or alkaline phosphatase above 2.5 times ULN;
• increased aminotransferase levels (AST or ALT) > 2.5 times (monotherapy) or > 5 times (combination therapy) above ULN that has not normalized by day 21 of the cycle;
• any adverse reaction of grade 3 or 4 severity (e.g., nausea, vomiting, fatigue).

If the dose has been reduced due to toxicity, dose escalation in subsequent cycles is not recommended.

If any toxic reaction recurs in subsequent cycles in a patient showing a positive response to treatment, the dose may be further reduced (see Table 1).

Colony-stimulating factors may be used in subsequent cycles for the management of hematological toxicity according to local standard practice.

Table 1

Dose adjustment table for trabectedin (as monotherapy for the treatment of soft tissue sarcoma) or in combination with PLD (for the treatment of ovarian cancer)

	Soft tissue sarcoma	Ovarian cancer
	Trabectedin	Trabectedin	PLD
Initial dose	1.5 mg/m²	1.1 mg/m²	30 mg/m²
First dose reduction	1.2 mg/m²	0.9 mg/m²	25 mg/m²
Second dose reduction	1 mg/m²	0.75 mg/m²	20 mg/m²

For detailed information on dose adjustment of PLD, see the PLD medicinal product instructions for use.

If further dose reduction is required, consideration should be given to discontinuation of treatment.

Duration of treatment

In clinical studies, there were no defined limitations regarding the number of treatment cycles.
Treatment was continued as long as clinical benefit was observed. Trabectedin was administered for 6 or more cycles in 29.5% and 52% of patients as monotherapy and in combination therapy, respectively. The number of treatment cycles reached up to 38 and 21 cycles in monotherapy and combination regimens, respectively. No cumulative toxicity was observed in patients who underwent multiple cycles of treatment.

Special patient categories
Elderly patients

No specific studies were conducted in elderly patients. Overall, 20% of 1164 patients in the integrated safety analysis of clinical studies of trabectedin monotherapy were aged 65 years or older. Of the 333 patients with ovarian cancer who received trabectedin in combination with PLD, 24% were aged 65 years or older and 6% were aged 75 years or older. No significant differences in safety profiles were observed in this patient group. This suggests no impact of patient age on the clearance and volume of distribution of trabectedin. Therefore, dose adjustment based solely on age is generally not recommended.

Patients with hepatic impairment

Extreme caution should be exercised. Dose adjustment may be required in patients with impaired liver function, as systemic exposure to trabectedin may increase and the risk of hepatotoxicity may be elevated.

Trabectedin Ever Pharma must not be administered to patients with elevated baseline bilirubin levels. Liver function tests should be monitored during treatment with Trabectedin Ever Pharma, as dose adjustment may be indicated (see Table 1 and section "Special instructions for use").

Patients with renal impairment

Studies in patients with renal impairment (creatinine clearance < 30 ml/min [monotherapy], < 60 ml/min [combination therapy]) have not been conducted; therefore, Trabectedin Ever Pharma must not be used in this patient population (see section "Special instructions for use"). Based on the pharmacokinetic characteristics of trabectedin, dose adjustment is not required in patients with mild to moderate renal impairment (see section "Pharmacokinetics").

Method of administration

It is strongly recommended that the drug be administered only through a central venous catheter (see section "Special instructions for use").

Preparation for intravenous administration

For intravenous infusion, Trabectedin Ever Pharma must be reconstituted and diluted. Appropriate aseptic techniques should be used for preparation of the infusion solution (see "Reconstitution instructions" and "Dilution instructions").

When used in combination with PLD, the intravenous infusion system should be flushed with 50 mg/ml (5%) glucose infusion solution after administration of PLD and before administration of Trabectedin Ever Pharma. The use of any solvent other than 50 mg/ml (5%) glucose infusion solution may lead to precipitation of PLD (see also the instructions for use of pegylated liposomal doxorubicin).

Reconstitution instructions

Trabectedin Ever Pharma 0.25 mg

Reconstitute the vial containing 0.25 mg of trabectedin with 5 ml of water for injections. The resulting solution has a concentration of 0.05 mg/ml and is intended for single use only.

Using a syringe, add 5 ml of sterile water for injections to the vial. Shake the vial until the contents are completely dissolved. The reconstituted solution should be clear, colorless or slightly yellowish, and practically free from visible particles. The resulting solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is intended for single use only.

Trabectedin Ever Pharma 1 mg

Reconstitute the vial containing 1 mg of trabectedin with 20 ml of water for injections. The resulting solution has a concentration of 0.05 mg/ml and is intended for single use only.

Using a syringe, add 20 ml of sterile water for injections to the vial. Shake the vial until the contents are completely dissolved. The reconstituted solution should be clear, colorless or slightly yellowish, and practically free from visible particles.

The resulting solution contains 0.05 mg/ml of trabectedin. It requires further dilution and is intended for single use only.

From a microbiological standpoint, the reconstituted solution should be diluted and used immediately. If not used immediately, the duration and conditions of storage during use of the reconstituted product are the responsibility of the user and should generally not exceed 24 hours at 2°C to 8°C, unless reconstitution was performed under controlled and validated aseptic conditions.

Dilution instructions

Use 9 mg/ml (0.9%) sodium chloride infusion solution or 50 mg/ml (5%) glucose infusion solution for dilution.

Calculate the volume of solution using the formula:

volume (ml) = BSA (m²) × individual dose (mg/m²)

0.05 mg/ml

BSA = body surface area.

For infusions via central venous catheter, withdraw the appropriate amount of reconstituted solution from the vial and transfer it into an infusion bag containing ≥ 50 ml of diluent (9 mg/ml [0.9%] sodium chloride infusion solution or 50 mg/ml [5%] glucose infusion solution), so that the final concentration of trabectedin in the infusion solution is ≤ 0.030 mg/ml.

If central venous infusion is not feasible and peripheral venous administration is required, transfer the reconstituted solution into an infusion bag containing ≥ 1000 ml of diluent (9 mg/ml [0.9%] sodium chloride infusion solution or 50 mg/ml [5%] glucose infusion solution).

Parenteral solutions should be visually inspected for particulate matter prior to administration. The solution should be used immediately after preparation.

Handling and disposal instructions

Trabectedin Ever Pharma is a cytotoxic antineoplastic medicinal product, and caution should be exercised when handling it. Procedures for proper handling and disposal of cytotoxic agents should be followed. Personnel should be trained in the correct methods of reconstitution and dilution of the medicinal product and should use protective equipment, including mask, gloves, and goggles. Pregnant women must not handle this product.

In case of accidental contact with skin, mucous membranes, or eyes, the affected area should be immediately flushed with copious amounts of water.

Trabectedin Ever Pharma shows no incompatibility with Type I glass vials, polyvinyl chloride and polyethylene infusion bags and tubing, polyisoprene reservoirs, and titanium implanted vascular access systems.

Unused medicinal product and waste material must be disposed of in accordance with local requirements for disposal of cytotoxic medicinal products.

Children

Trabectedin Ever Pharma must not be used in children.

Overdose

Data on trabectedin overdose are limited. The main expected types of toxicity are gastrointestinal toxicity, bone marrow suppression, and hepatotoxicity. There is currently no specific antidote for trabectedin. In case of overdose, patients should be closely monitored and symptomatic and supportive therapy should be administered as necessary.

Adverse reactions

General safety profile

Adverse reactions of any grade are expected to occur in the majority of patients receiving treatment with Trabectedin Ever Pharma (in 91% with monotherapy and in 99.4% with combination therapy). Serious adverse reactions of grade 3 and 4 are expected to occur in less than one-third of patients (10% [monotherapy] and 25% [combination therapy]). The most common adverse reactions of any grade were neutropenia, nausea, vomiting, increased AST/ALT levels, anemia, fatigue, thrombocytopenia, anorexia, and diarrhea.

Fatal adverse reactions occurred in 1.9% of patients receiving trabectedin as monotherapy and in 0.6% of patients receiving trabectedin as part of combination therapy. Death often resulted from a combination of adverse reactions, including pancytopenia, febrile neutropenia (some including sepsis), hepatic injury, renal or multiorgan failure, and rhabdomyolysis.

List of adverse reactions in tabular form

The safety profile of trabectedin described below is based on data from adverse reactions reported in clinical trials, post-marketing safety studies, and spontaneous reports.

Table 2 below lists adverse reactions reported in patients with soft tissue sarcoma and ovarian cancer who received treatment according to the recommended regimen for each indication. Both adverse reaction reports and laboratory parameters were used to determine frequencies.

Adverse reactions are listed by system organ class and frequency. Frequencies were defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

Table 2

System organ class	Very common	Common	Uncommon	Rare
Infections and infestations	Neutropenic infection	Sepsis	Sepsis shock
Blood and lymphatic system disorders	Neutropenia Thrombocytopenia Anemia Leukopenia	Febrile neutropenia
Immune system disorders		Hypersensitivity
Metabolism and nutrition disorders	Decreased appetite	Dehydration Hypokalemia
Psychiatric disorders		Insomnia
Nervous system disorders	Headache	Dizziness Dysgeusia Peripheral sensory neuropathy Syncope*
Cardiac disorders		Palpitations* Left ventricular dysfunction*
Vascular disorders		Arterial hypotension Flushing	Capillary leak syndrome
Respiratory, thoracic and mediastinal disorders	Dyspnea Cough	Pulmonary embolism*	Pulmonary edema
Gastrointestinal disorders	Abdominal pain Nausea Vomiting Constipation Diarrhea Stomatitis	Dyspepsia
Hepatobiliary disorders	Increased alanine aminotransferase Increased aspartate aminotransferase Increased blood alkaline phosphatase Increased bilirubin	Increased gamma-glutamyl transferase		Hepatic failure
Skin and subcutaneous tissue disorders	Palmar-plantar erythrodysesthesia syndrome*	Rash Alopecia Skin hyperpigmentation*
Musculoskeletal and connective tissue disorders	Back pain Increased blood creatine phosphokinase	Arthralgia Myalgia	Rhabdomyolysis
General disorders and administration site conditions	Increased fatigue Pyrexia Edema Mucosal inflammation*	Injection site reactions	Extravasation Soft tissue necrosis
Investigations	Increased blood creatinine Decreased blood albumin	Decreased body weight

*Adverse reactions only in patients with ovarian cancer, including data from the ET743 OVA 301 study, a randomized Phase III trial involving 672 patients who received either trabectedin (1.1 mg/m²) and pegylated liposomal doxorubicin (PLD) (30 mg/m²) every 3 weeks, or PLD (50 mg/m²) every 4 weeks; and from study ET743-OVC-3006, which included 576 patients who received either PLD (30 mg/m²) followed by trabectedin (1.1 mg/m²) every 3 weeks, or PLD (50 mg/m²) every 4 weeks.

In the ET743 OVA 301 study, in the trabectedin + PLD group, non-Caucasian patients (predominantly of Asian origin) experienced a higher incidence of Grade 3 or 4 adverse reactions compared to Caucasian patients (96% vs. 87%), as well as serious adverse reactions (all grades, 44% vs. 23%). The differences were primarily observed in neutropenia (93% vs. 66%), anemia (37% vs. 14%), and thrombocytopenia (41% vs. 19%). However, the frequency of clinical complications related to hematological toxicity, such as severe infections or bleeding, or those leading to fatal outcomes or treatment discontinuation, was similar in both subgroups.

Description of selected adverse reactions

Most common adverse reactions

Blood and lymphatic system disorders

Neutropenia

Neutropenia is the most common hematological toxicity. It has a predictable pattern, occurs rapidly, is reversible, and rarely associated with fever or infection. The nadir of neutrophil count occurs on average on Day 15 and returns to baseline within one week. Monitoring of neutrophil levels in each cycle among patients receiving monotherapy revealed Grade 3 neutropenia in 19% of cycles and Grade 4 neutropenia in 8% of cycles. Within this patient group, febrile neutropenia occurred in 2% of patients and in <1% of cycles.

Thrombocytopenia

Bleeding events associated with thrombocytopenia were observed in <1% of patients receiving trabectedin as monotherapy. Monitoring of platelet levels in each cycle among these patients showed Grade 3 thrombocytopenia in approximately 3% of cycles and Grade 4 thrombocytopenia in <1% of cycles.

Anemia

Anemia developed in 93% (monotherapy) and 94% (combination therapy) of patients, respectively. The percentage of patients with anemia prior to treatment initiation was 46% and 35%, respectively. Analysis of erythrocyte levels in each cycle among patients receiving trabectedin as monotherapy revealed Grade 3 anemia in approximately 3% of cycles and Grade 4 anemia in 1% of cycles.

Hepatobiliary disorders

Elevated ALT/AST levels

The median time to peak AST and ALT levels was 5 days. In most cases, AST/ALT levels decreased to Grade 1 toxicity or normalized by Day 14–15 (see section "Special warnings and precautions for use"). Cycle analysis among patients receiving trabectedin as monotherapy showed Grade 3 elevations in AST and ALT in 12% and 20% of cycles, respectively.

Grade 4 elevations in AST and ALT were observed in 1% and 2% of cycles, respectively. In most cases, transaminase levels decreased to Grade 1 or baseline levels within 15 days, and normalization required more than 25 days in only <2% of cycles. Elevations in ALT and AST levels were not cumulative, but a trend toward milder increases over time was observed.

Hyperbilirubinemia

Maximum bilirubin elevation occurred approximately one week after the onset of bilirubin increase and normalized within two weeks from the onset.

Liver function test abnormalities predictive of severe toxicity (according to Hy's Law), and clinical manifestations of severe liver injury including jaundice, hepatomegaly, and liver area pain, were infrequent and did not exceed 1% of cases.
Mortality due to liver injury did not exceed 1% for either treatment regimen.

Other adverse reactions

Hepatic failure

Rare cases of hepatic failure (including fatal cases) have been reported with trabectedin treatment in patients with significant comorbid conditions during clinical trials and in the post-marketing period. Potential risk factors for increased trabectedin toxicity in these cases included incorrect dosing according to recommendations, potential interaction with CYP3A4 due to the presence of multiple competing CYP3A4 substrates or CYP3A4 inhibitors, or lack of dexamethasone premedication.

Capillary leak syndrome (CLS)

Cases of CLS have been reported in association with trabectedin use (including fatal cases) (see section "Special warnings and precautions for use").

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in a refrigerator at 2–8°C. Keep out of the reach of children.

Incompatibilities.

Trabectedin Ever Pharma must not be mixed or diluted with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

1. 0.25 mg powder in a clear glass vial stoppered with a butyl rubber stopper with fluoropolymer coating and sealed with an aluminum cap with a light blue plastic disc; 1 vial per cardboard box.
2. 1 mg powder in a clear glass vial stoppered with a butyl rubber stopper with fluoropolymer coating and sealed with an aluminum cap with a pink plastic disc; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

EVER Pharma Jena GmbH.

Manufacturer's address and place of business.

Otto-Schott-Strasse 15, Sued, Jena, Thuringia, 07745, Germany.