Thiotepa-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THIOTEPA-VISTA

Composition:

Active substance: thiotepa;

1 vial contains 100 mg of thiotepa.

Pharmaceutical form.

Powder for concentrate for solution for infusion.

Main physicochemical properties: white lyophilisate.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Antineoplastic agents. Alkylating agents. Ethylenimines. Thiotepa. ATC code L01A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Thiotepa is a polyfunctional cytotoxic agent chemically and pharmacologically related to nitrogen mustard. Radiomimetic activity of thiotepa is believed to occur through the release of ethylenimine radicals, which, as in radiation therapy, disrupt DNA bonds, for example by alkylating guanine at N-7, breaking the bond between the purine base and sugar, and releasing alkylated guanine. Clinical safety and efficacy.

Treatment provides cytoreduction and disease reversal. Thiotepa has dose-limiting toxicity. In allogeneic hematopoietic stem cell transplantation (HSCT), therapy must be sufficiently immunosuppressive and myeloablative to overcome graft rejection. Due to its high myeloablative characteristics, thiotepa enhances immunosuppression and myeloablation in the recipient, thereby promoting engraftment; this compensates for the loss of the "graft-versus-host" disease effect associated with the "graft-versus-leukemia" effect. As an alkylating agent, thiotepa provides the most profound suppression of tumor cell growth in vitro with the smallest increase in drug concentration. Due to the absence of extramedullary toxicity, even with dose escalation above myelotoxic dose limits, thiotepa has been used for decades in combination with other chemotherapeutic agents for autologous and allogeneic hematopoietic stem cell transplantation.

Pharmacokinetics.

Absorption.

Thiotepa is poorly absorbed from the gastrointestinal tract: acid instability prevents oral administration of thiotepa.

Distribution.

Thiotepa is a highly lipophilic compound. After intravenous administration, the plasma concentration of the active substance follows a two-compartment model with a rapid distribution phase. The volume of distribution of thiotepa is large, ranging from 40.8 L/m² to 75 L/m², indicating distribution throughout total body water. The apparent volume of distribution of thiotepa is independent of the administered dose. The fraction unbound to plasma proteins is 70–90%. Minimal binding of thiotepa to gamma-globulin has been reported, and minimal binding to albumin (10–30%).

After intravenous administration, drug exposure in cerebrospinal fluid is nearly equivalent to plasma exposure; the mean ratio of the area under the concentration-time curve (AUC) in cerebrospinal fluid to plasma for thiotepa is 0.93. Concentrations of TEPA, the first identified active metabolite of thiotepa, in cerebrospinal fluid and plasma exceed those of the parent compound.

Biotransformation.

Thiotepa undergoes rapid and extensive hepatic metabolism; metabolites can be detected in urine within 1 hour after infusion. The metabolites are active alkylating agents, but their role in the antitumor activity of thiotepa remains unclear. Thiotepa undergoes oxidative desulfurization via the cytochrome P450 isoenzyme families CYP2B and CYP3A to form the primary and active metabolite TEPA (triethylenephosphoramide). The total excreted amount of thiotepa and its identified metabolites accounts for 54–100% of total alkylating activity, suggesting the presence of other alkylating metabolites. During the conversion of gamma-glutamyl-L-cysteinylglycine conjugates to N-acetylcysteine conjugates, gamma-glutamyl-L-cysteinylglycine, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not detected in urine and, if formed, are likely excreted in bile or rapidly converted into thiotepamercurate as intermediate metabolites.

Elimination.

Total clearance of thiotepa ranged from 11.4 to 23.2 L/h/m². The elimination half-life varies from 1.5 to 4.1 hours. Identified metabolites TEPA, monochlorothiotepa, and thiotepa-mercapturate are excreted in urine. Urinary excretion of thiotepa and TEPA is complete within 6 and 8 hours, respectively. Mean urinary excretion of thiotepa and its metabolites is 0.5% for unchanged drug and monochlorothiotepa, and 11% for TEPA and thiotepa-mercapturate.

Linearity/non-linearity.

There is no clear evidence of saturation mechanisms in metabolic clearance at high doses of thiotepa.

Special populations.

Pediatric population.

The pharmacokinetics of high-dose thiotepa in children aged 2 to 12 years does not differ from that in children receiving a dose of 75 mg/m² or in adults receiving similar doses.

Renal impairment.

The effect of renal impairment on thiotepa elimination has not been evaluated. Hepatic impairment.

The effect of hepatic impairment on the metabolism and elimination of thiotepa has not been evaluated.

Clinical characteristics.

Indications.

In combination with other chemotherapeutic agents as part of combination therapy:

• As preparative treatment in hematological diseases in adults and children prior to allogeneic and autologous hematopoietic stem cell transplantation (HSCT), with or without total body irradiation;
• For the treatment of solid tumors in adults and children in combination with high-dose chemotherapy supported by hematopoietic stem cell transplantation.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Pregnancy and breastfeeding period.
• Concomitant use with yellow fever vaccine and with live viral and bacterial vaccines.

Safety precautions.

Disposal of unused medicinal product or expired product.

The medicinal product THIOTEPA-VISTA is intended for single use only. Environmental release of the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. Disposal should be carried out using a designated "waste collection system," if available. Any unused medicinal products or waste materials must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Specific interactions with thiotepa.

Live vaccines must not be administered to patients receiving immunosuppressive chemotherapeutic agents, and at least three months should elapse between discontinuation of therapy and vaccination.

Thiotepa is metabolized by CYP2B6 and CYP3A4. Concomitant use with CYP2B6 inhibitors (e.g., clopidogrel and ticlopidine) or CYP3A4 inhibitors (e.g., azole antifungals, macrolides such as erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase plasma concentrations of thiotepa and potentially reduce concentrations of the active metabolite TEPA. Concomitant use of cytochrome P450 inducers (such as rifampicin, carbamazepine, phenobarbital) may enhance thiotepa metabolism, leading to increased plasma concentrations of the active metabolite. Therefore, careful monitoring of patients is required when thiotepa is used concomitantly with these medicinal products. Thiotepa is a weak inhibitor of CYP2B6 and may therefore potentially increase plasma concentrations of substances metabolized by CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz, and cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide into its active form, 4-hydroxycyclophosphamide (4-OHCP). Therefore, concomitant administration of thiotepa may lead to reduced concentrations of active 4-OHCP. Clinical monitoring is therefore recommended when thiotepa is used concomitantly with these medicinal products.

Contraindicated concomitant use.

Yellow fever vaccine: risk of fatal generalized vaccine-induced disease.

In general, live vaccines must not be administered to patients receiving immunosuppressive chemotherapy, and at least three months should elapse between discontinuation of therapy and vaccination.

Concomitant use not recommended.

Live attenuated vaccines (except for yellow fever): risk of systemic disease, possibly fatal. This risk is increased in patients who already have immunosuppression due to their underlying disease. Inactivated viral vaccines (e.g., polio) should be used instead, if possible.

Phenytoin. Risk of seizure exacerbation due to reduced gastrointestinal absorption of phenytoin caused by cytotoxic medicinal products, or risk of increased toxicity and loss of efficacy of the cytotoxic agent due to enhanced hepatic metabolism of phenytoin.

Concomitant use to be taken into consideration.

Cyclosporine, tacrolimus. Excessive immunosuppression with risk of lymphoproliferative disorders. Alkylating chemotherapeutic agents, including thiotepa, inhibit plasma pseudocholinesterase by 35–70%. The effect of succinylcholine may be prolonged by 5–15 minutes.

Cyclophosphamide. Thiotepa must not be administered simultaneously with cyclophosphamide if both agents are included in the same treatment regimen. Thiotepa should be administered only after completion of any cyclophosphamide infusion.

Other myelosuppressive or myelotoxic agents. Concomitant use of thiotepa with other myelosuppressive or myelotoxic agents (e.g., cyclophosphamide, melphalan, busulfan, fludarabine, treosulfan) may enhance the risk of hematological adverse reactions due to overlapping toxicity profiles of these medicinal products.

Interaction common to all cytotoxic medicinal products.

Due to the increased risk of thrombosis in malignant tumors, anticoagulant therapy is frequently used. High intra-individual variability in coagulation status in malignant diseases and the potential interaction between oral anticoagulants and anticancer chemotherapy require more frequent monitoring of the international normalized ratio (INR).

Special precautions for use.

Treatment with thiotepa at recommended doses results in profound myelosuppression occurring in all patients. Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. During treatment and until recovery, regular monitoring of complete blood counts, including differential white blood cell count and platelet count, is required. Platelet and red blood cell support, as well as the use of growth factors such as granulocyte colony-stimulating factor, should be administered as clinically indicated. Daily monitoring of white blood cell and platelet counts is recommended during thiotepa treatment and for at least 30 days following transplantation.

Prophylactic or empirical use of anti-infective agents (antibacterial, antifungal, antiviral) should be considered to prevent and treat infections during the neutropenic period.

The use of thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is primarily metabolized in the liver, caution should be exercised when administering the drug to patients with pre-existing liver dysfunction, especially those with severe hepatic insufficiency. Regular monitoring of serum transaminases, alkaline phosphatase, and bilirubin is recommended after transplantation in such patients to detect hepatotoxicity early.

Patients who have received prior radiation therapy, three or more cycles of chemotherapy, or previous stem cell transplantation may have an increased risk of developing veno-occlusive liver disease.

Thiotepa should be administered with caution in patients with a history of cardiac disease, and regular monitoring of cardiac function throughout the treatment period is recommended.

The drug should be used cautiously in patients with a history of renal disease, and periodic monitoring of renal function during thiotepa therapy is advised.

Thiotepa may cause pulmonary toxicity, which may add to the existing effects of other cytotoxic agents (e.g., busulfan, fludarabine, cyclophosphamide). Prior cranial irradiation or craniospinal irradiation may lead to serious toxic reactions (e.g., encephalopathy).

Patients should be informed of the potential increased risk of developing secondary malignant neoplasms when receiving thiotepa.

Concomitant use with live attenuated vaccines (except yellow fever vaccine), phenytoin, and fosphenytoin is not recommended.

The drug must not be administered simultaneously with cyclophosphamide if both agents are part of the same treatment regimen. Thiotepa must be administered after completion of any cyclophosphamide infusion.

Careful monitoring is required when thiotepa is used concomitantly with CYP2B6 or CYP3A4 inhibitors.

Like most alkylating agents, thiotepa may impair male or female fertility. Male patients should undergo sperm cryopreservation prior to starting therapy and must not father a child during treatment and for one year after treatment discontinuation.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception in men and women.

Women of childbearing potential must use effective contraception during treatment. A pregnancy test should be performed prior to initiating therapy. Male patients must not father a child during treatment and for one year after treatment discontinuation.

Pregnancy.

There are no data on the use of THIOTEPA-VISTA during pregnancy. Preclinical studies have shown that thiotepa, like most alkylating agents, causes embryolethality and teratogenicity. This medicinal product is contraindicated during pregnancy.

Breastfeeding period.

It is unknown whether thiotepa is excreted in human breast milk. Due to its pharmacological properties and potential toxicity to newborns, breastfeeding is contraindicated during thiotepa treatment.

Fertility.

Like most alkylating agents, thiotepa may have a negative impact on male and female fertility. Male patients should undergo sperm cryopreservation prior to starting therapy.

Ability to affect reaction speed when driving or operating machinery.

THIOTEPA-VISTA affects the ability to drive and operate machinery. Adverse reactions such as dizziness, headache, and blurred vision may influence these functions.

Administration and Dosage.

Prior to hematopoietic stem cell transplantation, administration of the medicinal product must be supervised by a physician experienced in this field.

Dosage.

The medicinal product THIOTEPA-VISTA is administered in combination with other chemotherapeutic agents to patients with hematological disorders or solid tumors prior to HSCT.

The dosage of THIOTEPA-VISTA for adult and pediatric patients is determined according to the type of HSCT (autologous or allogeneic) and the underlying disease.

Adults.

AUTOLGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT).

Hematological Disorders.

The recommended dose for hematological disorders ranges from 125 mg/m²/day (3.38 mg/kg/day) to 300 mg/m²/day (8.10 mg/kg/day) as a single daily infusion administered for 2 to 4 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the treatment period.

LYMPHOMA.

The recommended dose ranges from 125 mg/m²/day (3.38 mg/kg/day) to 300 mg/m²/day (8.10 mg/kg/day) as a single daily infusion administered for 2 to 4 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 900 mg/m² (24.32 mg/kg) throughout the treatment period.

CENTRAL NERVOUS SYSTEM (CNS) LYMPHOMA.

The recommended dose is 185 mg/m²/day (5 mg/kg/day) as a single daily infusion administered over 2 consecutive days prior to autologous HSCT, without exceeding the total maximum cumulative dose of 370 mg/m² (10 mg/kg) throughout the treatment period.

MULTIPLE MYELOMA.

The recommended dose ranges from 150 mg/m²/day (4.05 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered over 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the treatment period.

Solid Tumors.

The recommended dose for solid tumors ranges from 120 mg/m²/day (3.24 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day), divided into one or two daily infusions administered for 2 to 5 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the treatment period.

BREAST CANCER.

The recommended dose ranges from 120 mg/m²/day (3.24 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered for 3 to 5 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 800 mg/m² (21.62 mg/kg) throughout the treatment period.

CNS TUMORS.

The recommended dose ranges from 125 mg/m²/day (3.38 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day), divided into 1 or 2 daily infusions administered for 3 to 4 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the treatment period.

OVARIAN CANCER.

The recommended dose is 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered over 2 consecutive days prior to autologous HSCT, without exceeding the total maximum cumulative dose of 500 mg/m² (13.51 mg/kg) throughout the treatment period.

GERMINAL CELL TUMORS.

The recommended dose ranges from 150 mg/m²/day (4.05 mg/kg/day) to 250 mg/m²/day (6.76 mg/kg/day) as a single daily infusion administered over 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 750 mg/m² (20.27 mg/kg) throughout the treatment period.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT). Hematological Disorders.

The recommended dose for hematological disorders is from 185 mg/m²/day (5 mg/kg/day) to 481 mg/m²/day (13 mg/kg/day), divided into 1 or 2 daily infusions administered for 1 to 3 consecutive days prior to allogeneic HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 555 mg/m² (15 mg/kg) throughout the treatment period.

LYMPHOMA.

The recommended dose for lymphoma is 370 mg/m²/day (10 mg/kg/day), divided into 2 daily infusions prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 370 mg/m² (10 mg/kg) throughout the treatment period.

MULTIPLE MYELOMA.

The recommended dose is 185 mg/m²/day (5 mg/kg/day) as a single daily infusion prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 185 mg/m² (5 mg/kg) throughout the treatment period.

LEUKEMIA.

The recommended dose ranges from 185 mg/m²/day (5 mg/kg/day) to 481 mg/m²/day (13 mg/kg/day), divided into one or two daily infusions administered for 1 to 2 consecutive days prior to allogeneic HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 555 mg/m² (15 mg/kg) throughout the treatment period.

THALASSEMIA.

The recommended dose is 370 mg/m²/day (10 mg/kg/day), divided into 2 daily infusions administered prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 370 mg/m² (10 mg/kg) throughout the treatment period.

Pediatric Patients.

AUTOLGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT).

Solid Tumors.

The recommended dose for solid tumors ranges from 150 mg/m²/day (6 mg/kg/day) to 350 mg/m²/day (14 mg/kg/day) as a single daily infusion administered for 2 to 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 1050 mg/m² (42 mg/kg) throughout the treatment period.

CNS TUMORS.

The recommended dose ranges from 250 mg/m²/day (10 mg/kg/day) to 350 mg/m²/day (14 mg/kg/day) as a single daily infusion administered over 3 consecutive days prior to autologous HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 1050 mg/m² (42 mg/kg) throughout the treatment period.

ALLOGENEIC HSCT.

Hematological Disorders.

The recommended dose for hematological disorders is from 125 mg/m²/day (5 mg/kg/day) to 250 mg/m²/day (10 mg/kg/day), divided into 1 or 2 daily infusions administered for 1 to 3 consecutive days prior to allogeneic HSCT, depending on combination with other chemotherapeutic agents, without exceeding the total maximum cumulative dose of 375 mg/m² (15 mg/kg) throughout the treatment period.

LEUKEMIA.

The recommended dose is 250 mg/m²/day (10 mg/kg/day), divided into 2 daily infusions administered prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the treatment period.

THALASSEMIA.

The recommended dose ranges from 200 mg/m²/day (8 mg/kg/day) to 250 mg/m²/day (10 mg/kg/day), divided into 2 daily infusions administered prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the treatment period.

REFRACTORY CYTOPENIA.

The recommended dose is 125 mg/m²/day (5 mg/kg/day) as a single daily infusion administered over 3 consecutive days prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 375 mg/m² (15 mg/kg) throughout the treatment period.

GENETIC DISORDERS.

The recommended dose is 125 mg/m²/day (5 mg/kg/day) as a single daily infusion administered over 2 consecutive days prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the treatment period.

SICKLE CELL ANEMIA.

The recommended dose is 250 mg/m²/day (10 mg/kg/day), divided into 2 daily infusions administered prior to allogeneic HSCT, without exceeding the total maximum cumulative dose of 250 mg/m² (10 mg/kg) throughout the treatment period.

Special Patient Populations.

Renal Impairment.

Studies in patients with renal impairment have not been conducted. Since thiopeta and its metabolites are poorly excreted in urine, dosage adjustment is not required in patients with mild or moderate renal impairment. However, caution is recommended when administering the medicinal product.

Hepatic Impairment.

Studies in patients with hepatic impairment have not been conducted. Since thiopeta is primarily metabolized in the liver, caution should be exercised when administering THIOTEPA-VISTA to patients with existing hepatic dysfunction, especially those with severe hepatic impairment. Dose adjustment is not recommended for transient changes in liver function tests.

Elderly Patients.

The use of thiopeta in elderly patients has not been specifically studied. However, in clinical trials, patients aged 65 years and older received the same cumulative dose as other patients. Dose adjustment was not considered necessary.

Administration.

The medicinal product THIOTEPA-VISTA must be administered by trained healthcare personnel as a 2–4-hour intravenous infusion via a central venous catheter. Each 100 mg vial of thiopeta should be reconstituted with 10 mL of sterile water for injection. The total volume of reconstituted vials should be further diluted in 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection prior to administration (1000 mL if the dose exceeds 500 mg). In pediatric patients, if the dose is less than 250 mg, an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection may be used to achieve the final thiopeta concentration. Instructions for dilution and further dilution prior to administration are provided below.

Precautions to be taken before handling or administering the medicinal product. Local reactions may occur following accidental exposure of the medicinal product THIOTEPA-VISTA to the skin. Therefore, gloves are recommended when preparing the infusion solution. If the solution of THIOTEPA-VISTA accidentally contacts the skin, the skin must be immediately and thoroughly washed with soap and water. If the solution accidentally contacts mucous membranes, they must be thoroughly rinsed with water (see below).

Preparation of THIOTEPA-VISTA.

Proper handling and disposal procedures for cytotoxic drugs must be observed. All preparation procedures must strictly follow aseptic techniques, preferably using a biological safety cabinet with vertical laminar airflow.

As with other cytotoxic agents, care must be taken during handling and preparation of THIOTEPA-VISTA solutions to avoid accidental contact with skin or mucous membranes. Local reactions may occur following accidental exposure to the solution of THIOTEPA-VISTA. Gloves are recommended when preparing the infusion solution. If the solution contacts the skin, the skin must be immediately and thoroughly washed with soap and water. If the solution of THIOTEPA-VISTA accidentally contacts mucous membranes, they must be thoroughly rinsed with water.

Reconstitution of THIOTEPA-VISTA 100 mg.

The medicinal product THIOTEPA-VISTA must be reconstituted with 10 mL of sterile water for injection. Using a syringe with a needle under aseptic conditions, draw 10 mL of sterile water for injection. Inject the contents of the syringe into the vial through the rubber stopper. Remove the syringe and needle and mix manually by repeated inversion. Only clear, particle-free solutions should be used. Reconstituted solutions may occasionally exhibit opalescence; such solutions are still suitable for administration.

Further dilution in an infusion bag/bottle.

The prepared solution is hypotonic and must be further diluted prior to administration with 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection (1000 mL if the dose exceeds 500 mg) or an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution to achieve a final concentration of THIOTEPA-VISTA between 0.5 and 1 mg/mL.

Administration.

Prior to administration, the infusion solution of THIOTEPA-VISTA must be visually inspected for the presence of particulate matter. Solutions containing precipitate must be discarded.

The catheter line must be flushed with approximately 5 mL of sodium chloride 9 mg/mL (0.9%) solution for injection before and after each infusion.

The infusion solution must be administered to patients using an infusion set equipped with an in-line 0.2 µm filter. Filtration does not affect the efficacy of the solution.

Children.

The medicinal product is indicated for use in pediatric patients (see section "Administration and Dosage").

Overdose.

Symptoms. There is no clinical experience with overdose of THIOTEPA-VISTA. The most significant expected adverse reactions in case of overdose are myeloablation and pancytopenia.

Treatment. There is no antidote for THIOTEPA-VISTA. Monitoring of the patient's hematological parameters and appropriate supportive measures are recommended.

Adverse reactions.

Summary of safety profile.

Serious toxic effects related to the hematological, hepatic, and respiratory systems were considered expected consequences of treatment and the transplantation process. These include infections and graft-versus-host disease, which, although not directly related, were the main causes of morbidity and mortality, especially in allogeneic HSCT.

The most frequently reported adverse reactions were: infections, cytopenia, acute graft-versus-host disease and chronic graft-versus-host disease, gastrointestinal disorders, hemorrhagic cystitis, and mucositis. Leukoencephalopathy.

Cases of leukoencephalopathy have been observed following administration of the medicinal product THIOTEPA-VISTA in adult and pediatric patients who had previously received multiple chemotherapy regimens, including methotrexate and radiation therapy. Some cases were fatal.

List of adverse reactions is presented in the tables below.

Adults.

Adverse reactions, at least possibly related to treatment with thiotepa, reported in adult patients as individual cases, are listed below by system organ class and frequency. Within each frequency group, adverse reactions are listed in order of decreasing severity. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Pediatric patients.

Adverse reactions that are at least possibly related to the use of the medicinal product THIOTEPA-VISTA, reported in pediatric patients as single cases, are listed below by system organ classes and frequency. Within each group, the frequency of adverse reactions is presented in order of decreasing severity. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions.

Reporting of adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 24 months.

After reconstitution.

Chemical and physical stability during use after dissolution has been demonstrated for 8 hours.

Store at 2–8 °C.

After dilution.

Chemical and physical stability during use after dilution has been demonstrated for 24 hours when stored at 2–8 °C and for 4 hours when stored at 25 °C.

From a microbiological standpoint, the medicinal product should be used immediately after dilution. If not used immediately, responsibility for storage conditions and duration prior to use lies with the physician and should not exceed the above-mentioned timeframes, provided dilution was performed under controlled, aseptic conditions.

Storage conditions.

Store in the original packaging at 2–8 °C. Do not freeze. Keep out of reach and sight of children.

Incompatibilities.

Thiotepa is unstable in acidic environments.

The medicinal product must not be mixed with other medicinal products except those specified in the section "Method of administration and dosage."

Packaging.

100 mg of powder in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

HCW Pharma Services GmbH

Manufacturer's address and location of operations.

Strassburger Strasse 77, Urloffen, Appenweier, Baden-Wuerttemberg, 77767, Germany