Thiotepa for injection
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THIOTEPA FOR INJECTION
Composition:
Active substance: thiotepa;
1 vial contains 100 mg of thiotepa.
Medicinal form. Lyophilized powder for solution for injection.
Main physico-chemical properties: prior to reconstitution: white lyophilized powder.
After reconstitution: clear or slightly opalescent solution, free from visible particulate matter.
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. The radiomimetic effect of thiotepa is believed to occur through the release of ethylenimine radicals, which, similar to radiation therapy, disrupt DNA bonds—for example, by alkylating guanine at the N-7 position, breaking the bond between the purine base and the sugar, and releasing alkylated guanine.
Clinical Safety and Efficacy
Treatment results in 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 at doses exceeding myelotoxic thresholds, thiotepa has been used for decades in combination with other chemotherapeutic agents in both 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, plasma concentrations of the active substance follow a two-compartment model with a rapid distribution phase. The volume of distribution of thiotepa is substantial, ranging from 40.8 to 75 L/m², indicating distribution throughout the 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, along with minimal binding to albumin (10–30%).
After intravenous administration, drug exposure in cerebrospinal fluid is nearly equivalent to plasma exposure; the mean AUC ratio of cerebrospinal fluid to plasma for thiotepa is 0.93. The concentration of triethylenephosphoramide (TEPA), the first identified active metabolite of thiotepa, in cerebrospinal fluid and plasma exceeds that of the parent compound.
Biotransformation
Thiotepa undergoes rapid and extensive hepatic metabolism, with metabolites detectable in urine within one 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. The total excreted amount of thiotepa and its identified metabolites accounts for 54–100% of total alkylating activity, suggesting the presence of additional alkylating metabolites. During the conversion of gamma-glutamyl-L-cysteinylglycine conjugates into 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 via bile or rapidly converted into intermediate metabolites such as thiotepea-mercapturate.
Elimination
Total clearance of thiotepa ranged from 11.4 to 23.2 L/h/m². Elimination half-life varied from 1.5 to 4.1 hours. Identified metabolites—TEPA, monoepoxybutane (monochlorothiopane), and thiotepea-mercapturate—are excreted in urine. Elimination of thiotepa and TEPA in urine is nearly complete within 6 and 8 hours, respectively. The mean urinary excretion of thiotepa and its metabolites is 0.5% for unchanged drug and monochlorothiopane, and 11% for TEPA and thiotepea-mercapturate.
Linearity / Non-linearity
There is no clear evidence of saturation mechanisms in metabolic clearance at high doses of thiotepa.
Special Populations
Children
The pharmacokinetics of high-dose thiotepa in children aged 2 to 12 years do not differ from those in children receiving 75 mg/m² or in adults receiving equivalent doses.
Hepatic Impairment
The effect of hepatic impairment on thiotepa exposure is unknown.
Renal Impairment
The effect of renal impairment on thiotepa exposure is unknown.
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 HSCT.
Contraindications
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Pregnancy and breastfeeding (see section "Use in pregnancy or breastfeeding").
Concomitant use with yellow fever vaccine and with live viral and bacterial vaccines (see section "Interaction with other medicinal products and other forms of interaction").
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. At least 3 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 antifungal agents, 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 increase 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. Since CYP2B6 catalyzes the metabolic conversion of cyclophosphamide into its active form 4-hydroxycyclophosphamide (4-OHCP), concomitant use of thiotepa may lead to reduced concentrations of active 4-OHCP. Therefore, clinical monitoring is 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 3 months should elapse between discontinuation of therapy and vaccination.
Concomitant use not recommended
Live attenuated vaccines (other than 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 medicinal product due to enhanced hepatic metabolism of phenytoin.
Concomitant use to be considered
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.
Thiotepa must not be administered concomitantly with cyclophosphamide if both medicinal products are included in the same treatment regimen. Thiotepa should be administered after completion of any cyclophosphamide infusion.
Concomitant use of thiotepa and 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 diseases, anticoagulant therapy is frequently used. High intra-individual variability in coagulation status in malignant diseases and potential interactions between oral anticoagulants and anticancer chemotherapy require increased frequency of 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. Blood counts, including differential leukocyte count and platelet count, must be monitored during treatment and until recovery. Platelet and red blood cell support, as well as the use of growth factors such as granulocyte colony-stimulating factor, should be employed as medically 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 for prevention and treatment of infections during the neutropenic period.
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, particularly those with severe hepatic impairment. Regular monitoring of serum transaminases, alkaline phosphatase, and bilirubin is recommended after transplantation to enable early detection of hepatotoxicity.
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 (see section "Adverse reactions").
Thiotepa should be administered with caution in patients with a history of cardiac disease; 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 recommended.
Thiotepa may cause pulmonary toxicity, which may add to the existing effects of other cytotoxic agents (e.g., busulfan, fludarabine, cyclophosphamide). Prior cranial or craniospinal irradiation may lead to serious toxic reactions (e.g., encephalopathy).
Patients should be informed about the potential increased risk of secondary malignancies associated with thiotepa use.
Concomitant administration with live attenuated vaccines (except for yellow fever vaccine), phenytoin, and fosphenytoin is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
The drug must not be administered simultaneously with cyclophosphamide if both agents are part of the same treatment regimen. Thiotepa should be administered only after completion of any cyclophosphamide infusion (see section "Interaction with other medicinal products and other forms of interaction").
Careful monitoring of patients is required when thiotepa is used concomitantly with CYP2B6 or CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").
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 discontinuation of therapy.
Use during pregnancy or breastfeeding
Women of childbearing potential / contraception in men and women
Women of childbearing potential must use effective contraception during treatment, and a pregnancy test should be performed prior to initiation of therapy. Male patients must not father a child during treatment and for one year after discontinuation of therapy.
Pregnancy
There are no data on the use of thiotepa during pregnancy. Preclinical studies have shown that thiotepa, like most alkylating agents, causes embryolethality and teratogenicity. This medicinal product is contraindicated during pregnancy.
Breastfeeding
It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and potential toxicity to newborns, breastfeeding is contraindicated during thiotepa therapy.
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 affects the ability to drive a vehicle or operate machinery. Adverse reactions such as dizziness, headache, and blurred vision may impair these functions.
Method of 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 for injection is administered in combination with other chemotherapeutic agents to patients with hematological disorders or solid tumors prior to HSCT.
Dosage for adult and pediatric patients is determined according to the type of HSCT (autologous or allogeneic) and the underlying disease.
Adults
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION
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 the 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 the 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 for 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 for 3 consecutive days prior to autologous HSCT, depending on the 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 the 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 the 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 the 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 for 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 for 3 consecutive days prior to autologous HSCT, depending on the 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 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 the 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 the 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
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION
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 the 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 for 3 consecutive days prior to autologous HSCT, depending on the 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 the 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 for 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 for 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 Populations
Renal Impairment
Studies in patients with renal impairment have not been conducted. Since thiotepa 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 (see sections "Pharmacological Properties" and "Special Instructions").
Hepatic Impairment
Studies in patients with hepatic impairment have not been conducted. Since thiotepa is primarily metabolized in the liver, caution should be exercised when administering the medicinal product to patients with existing hepatic dysfunction, especially those with severe hepatic impairment. Dose adjustment is not recommended for transient changes in liver function tests (see section "Special Instructions").
Elderly Patients
The use of thiotepa 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.
Method of Administration
Thiotepa for injection must be administered by qualified medical personnel as a 2–4 hour intravenous infusion via a central venous catheter. Each vial containing 100 mg of thiotepa 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 before 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 concentration of thiotepa. 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 if thiotepa for injection solution accidentally comes into contact with the skin. Therefore, gloves are recommended when preparing the infusion solution. If the thiotepa for injection solution accidentally contacts the skin, the area should be immediately and thoroughly washed with soap and water. If the solution accidentally contacts mucous membranes, they should be thoroughly rinsed with water (see below).
Preparation of Thiotepa for Injection Solution
Proper handling and disposal procedures for cytotoxic drugs should be observed. All preparation procedures must strictly adhere to aseptic techniques, preferably using a biological safety cabinet with vertical laminar airflow.
As with other cytotoxic compounds, care should be taken during handling and preparation of thiotepa for injection solution to avoid accidental contact with skin or mucous membranes. Local reactions may occur if the solution comes into contact with skin or mucous membranes. Gloves are recommended when preparing the infusion solution. If the solution accidentally contacts the skin, the area should be immediately and thoroughly washed with soap and water. If the medicinal product solution accidentally contacts mucous membranes, they should be thoroughly rinsed with water.
Reconstitution of Thiotepa for Injection
Thiotepa for injection 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 syringe contents into the vial through the rubber stopper. Remove the syringe and needle and mix manually by repeated inversions. Only clear, particle-free solutions should be used. Reconstituted solutions may occasionally exhibit opalescence; such solutions are still suitable for administration.
Further Dilution in Infusion Bag / Vial
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 drug concentration of 0.5 to 1 mg/mL.
Administration
Prior to administration, the thiotepa for injection solution should be visually inspected for particulate matter. Solutions containing precipitate should be discarded.
The catheter line should 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 should be administered to patients using an infusion set equipped with an integrated 0.2 µm filter. Filtration does not affect the efficacy of the solution.
Disposal
Thiotepa for injection is intended for single use only. Any unused medicinal product or waste must be disposed of in accordance with local requirements.
Children
The medicinal product is indicated for use in children (see section "Method of Administration and Dosage").
Overdose
There is no experience with thiotepa overdose. The most significant adverse reactions expected in case of overdose are myeloablation and pancytopenia. There is no antidote for this medicinal product. 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 commonly 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 thiotepa in adult and pediatric patients previously treated with multiple chemotherapy regimens, including methotrexate and radiation therapy. Some cases were fatal.
List of adverse reactions is presented below
Adults
Adverse reactions at least possibly related to thiotepa treatment reported in adult patients as individual cases are listed below by system organ classes and frequency. Within each frequency category, 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).
| System Organ Class |
Very common |
Common |
Uncommon |
Frequency unknown |
| Infections and infestations |
increased susceptibility to infection, sepsis |
toxic shock syndrome |
||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
secondary malignancy related to treatment |
|||
| Blood and lymphatic system disorders |
leukopenia, thrombocytopenia, febrile neutropenia, anemia, pancytopenia, granulocytopenia |
|||
| Immune system disorders |
acute graft-versus-host disease, chronic graft-versus-host disease |
hypersensitivity |
||
| Endocrine disorders |
hypopituitarism |
|||
| Metabolism and nutrition disorders |
anorexia, decreased appetite, hyperglycemia |
|||
| Psychiatric disorders |
confusion, mental status changes |
anxiety |
delirium, nervousness, hallucinations, agitation |
|
| Nervous system disorders |
dizziness, headache, blurred vision, encephalopathy, seizures, paraesthesia |
intracranial aneurysm, extrapyramidal disorder, cognitive disorder, intracranial hemorrhage |
leukoencephalopathy |
|
| Eye disorders |
conjunctivitis |
cataract |
||
| Ear and labyrinth disorders |
hearing disorder, ototoxicity, ear ringing |
|||
| Cardiac disorders |
arrhythmia |
tachycardia, heart failure |
cardiomyopathy, myocarditis |
|
| Vascular disorders |
lymphedema, arterial hypertension |
hemorrhage, embolism |
||
| Respiratory, thoracic and mediastinal disorders |
idiopathic pneumonia syndrome, epistaxis |
pulmonary edema, cough, pneumonitis |
hypoxia |
|
| Gastrointestinal disorders |
nausea, stomatitis, esophagitis, vomiting, diarrhea, dyspepsia, abdominal pain, enteritis, colitis |
constipation, gastrointestinal perforation, ileus |
gastrointestinal ulceration |
|
| Hepatobiliary disorders |
veno-occlusive liver disease, hepatomegaly, jaundice |
|||
| Skin and subcutaneous tissue disorders |
rash, pruritus, alopecia |
erythema |
pigmentation disorder, erythrodermic psoriasis |
severe toxic skin reactions, including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders |
back pain, myalgia, arthralgia |
|||
| Renal and urinary disorders |
hemorrhagic cystitis |
dysuria, oliguria, renal failure, cystitis, hematuria |
||
| Reproductive system and breast disorders |
azoospermia, amenorrhea, vaginal bleeding |
menopausal symptoms, female infertility, male infertility |
||
| General disorders and administration site conditions |
pyrexia, asthenia, chills, generalized edema, injection site inflammation, injection site pain, mucosal inflammation |
multiple organ failure, pain |
||
| Investigations |
weight increased, blood bilirubin increased, transaminases increased, blood amylase increased |
blood creatinine increased, blood urea increased, gamma-glutamyltransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased |
Pediatric patients
Adverse reactions that have at least a possible association with the use of thiotepa, reported as single cases in pediatric patients, are listed below by system organ class and frequency. Within each group, the frequency of adverse reactions is presented in decreasing order of 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).
| System organ class |
Very common |
Common |
Frequency unknown |
| Infections and infestations |
increased susceptibility to infection, sepsis |
thrombocytopenic purpura |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
secondary malignant neoplasm related to treatment |
||
| Blood and lymphatic system disorders |
thrombocytopenia, febrile neutropenia, anemia, pancytopenia, granulocytopenia |
||
| Immune system disorders |
acute graft-versus-host disease, chronic graft-versus-host disease |
||
| Endocrine disorders |
hypopituitarism, hypogonadism, hypothyroidism |
||
| Metabolism and nutrition disorders |
anorexia, hyperglycemia |
||
| Psychiatric disorders |
mental status changes |
psychiatric disorders |
|
| Nervous system disorders |
headache, encephalopathy, convulsions, intracranial hemorrhage, memory impairment, paresis |
ataxia |
leukoencephalopathy |
| Ear and labyrinth disorders |
hearing impairment |
||
| Cardiac disorders |
cardiac arrest |
cardiovascular failure, heart failure |
|
| Vascular disorders |
hemorrhage |
arterial hypertension |
|
| Respiratory, thoracic and mediastinal disorders |
pneumonitis |
idiopathic pneumonia syndrome, pulmonary hemorrhage, pulmonary edema, epistaxis, hypoxia, respiratory arrest |
pulmonary arterial hypertension |
| Gastrointestinal disorders |
nausea, stomatitis, vomiting, diarrhea, abdominal pain |
enteritis, intestinal obstruction |
|
| Hepatobiliary disorders |
veno-occlusive liver disease |
hepatic failure |
|
| Skin and subcutaneous tissue disorders |
rash, erythema, desquamation, pigmentation disorder |
severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis |
|
| Musculoskeletal and connective tissue disorders |
growth retardation |
||
| Renal and urinary disorders |
bladder disorders |
renal failure, hemorrhagic cystitis |
|
| General disorders and administration site conditions |
pyrexia, mucositis, pain, multi-organ failure |
||
| Investigations |
increased blood bilirubin, increased transaminases, increased blood creatinine, increased aspartate aminotransferase, increased alanine aminotransferase |
increased blood urea, electrolyte imbalance, increased prothrombin time ratio |
Reporting of suspected adverse reactions
Reporting of adverse reactions following marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare 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 via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
After reconstitution
Chemical and physical in-use stability has been demonstrated for 8 hours.
Store at 2–8 °C.
After dilution
Chemical and physical in-use stability 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 product should be used immediately after dilution. If not used immediately, responsibility for storage conditions and duration prior to use lies with the physician; however, such storage should generally not exceed the above-mentioned time limits after dilution under controlled and aseptic conditions.
Storage conditions. Store in the original packaging at 2–8 °C. Do not freeze. Keep out of reach of children.
Packaging. 1 vial in a cardboard box.
Prescription status. Prescription only.
Manufacturer. MSN Laboratories Private Limited.
Manufacturer's address and place of business
Formulations Division, Unit-II, Survey Nos. 1277 and 1319 to 1324, Nandigama (Village), Nandigama (Mandal), Rangareddy District, Telangana, 509228, India.