Tepadina

1 
 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

 
 

 



2 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
TEPADINA 15 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
One vial of powder contains 15 mg thiotepa.  
After reconstitution with 1.5 ml of water for injections, each ml of solution contains 10 mg thiotepa 
(10 mg/ml). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
White crystalline powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
TEPADINA is indicated, in combination with other chemotherapy medicinal products:  
• with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or 
autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult 
and paediatric patients; 
• when high dose chemotherapy with HPCT support is appropriate for the treatment of solid 
tumours in adult and paediatric patients. 
 
4.2 Posology and method of administration 
 
TEPADINA administration must be supervised by a physician experienced in conditioning treatment 
prior to haematopoietic progenitor cell transplantation. 
 
Posology 
 
TEPADINA is administered at different doses, in combination with other chemotherapeutic medicinal 
products, in patients with haematological diseases or solid tumours prior to HPCT.  
 
TEPADINA posology is reported, in adult and paediatric patients, according to the type of HPCT 
(autologous or allogeneic) and disease. 
 
Adults 
 
AUTOLOGOUS HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases 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 from 2 up to 4 consecutive 
days before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during 
the time of the entire conditioning treatment.  



3 
 

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 from 2 up to 4 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during the time 
of the entire conditioning treatment.  
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 before autologous HPCT, without exceeding the total maximum cumulative dose of 
370 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
Solid tumours 
 
The recommended dose in solid tumours ranges from 120 mg/m2/day (3.24 mg/kg/day) to  
250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from 2 up to 5 
consecutive days before autologous HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 
mg/kg), during the time of the entire conditioning treatment.  
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 from 3 up to 5 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 mg/kg), during the time 
of the entire conditioning treatment.  
CNS TUMOURS 
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 in one or two daily infusions, administered from 3 up to 4 consecutive days 
before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during 
the time of the entire conditioning treatment.  
OVARIAN CANCER 
The recommended dose is 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered in 
2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose 
of 500 mg/m2 (13.51 mg/kg), during the time of the entire conditioning treatment.  
GERM CELL TUMOURS 
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 185 mg/m2/day (5 mg/kg/day) to  
481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  



4 
 

LYMPHOMA 
The recommended dose in lymphoma is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
MULTIPLE MYELOMA 
The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before allogeneic 
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m2 (5 mg/kg), during the 
time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day (13 mg/kg/day) 
divided in one or two daily infusions, administered from 1 up to 2 consecutive days before allogeneic 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), during the time of the entire 
conditioning treatment.  
THALASSEMIA 
The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment. 
 
Paediatric population 
 
AUTOLOGOUS HPCT 
 
Solid tumours 
 
The recommended dose in solid tumours 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 from 2 up to 3 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of 
the entire conditioning treatment.  
CNS TUMOURS 
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 before autologous HPCT 
depending on the combination with other chemotherapeutic medicinal products, without exceeding the 
total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of the entire conditioning 
treatment. 
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to 
 250 mg/m2/day (10 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 375 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
THALASSEMIA 
The recommended dose ranges from 200 mg/m2/day (8 mg/kg/day) to 250 mg/m2/day (10 mg/kg/day) 
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total 
maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning 
treatment.  



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REFRACTORY CYTOPENIA 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 3 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of  
375 mg/m2 (15 mg/kg), during the time of the entire conditioning treatment.  
GENETIC DISEASES 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 
250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
SICKLE CELL ANAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
 
Special populations 
 
Renal impairment 
Studies in renally impaired patients have not been conducted. As thiotepa and its metabolites are 
poorly excreted in the urine, dose modification is not recommended in patients with mild or moderate 
renal insufficiency. However, caution is recommended (see sections 4.4 and 5.2).   
 
Hepatic impairment 
Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly 
metabolized through the liver, caution needs to be exercised when thiotepa is used in patients with pre-
existing impairment of liver function, especially in those with severe hepatic impairment. Dose 
modification is not recommended for transient alterations of hepatic parameters (see section 4.4). 
 
Elderly  
The administration of thiotepa has not been specifically investigated in elderly patients. However, in 
clinical studies, a proportion of patients over the age of 65 received the same cumulative dose as the 
other patients. No dose adjustment was deemed necessary. 
 
Method of administration 
 
TEPADINA must be administered by a qualified healthcare professional as a 2-4 hours intravenous 
infusion via a central venous catheter. 
Each TEPADINA vial must be reconstituted with 1.5 ml of sterile water for injection. The total 
volume of reconstituted vials to be administered should be further diluted in 500 ml of sodium 
chloride 9 mg/ml (0.9%) solution for injection prior to administration (1,000 ml if the dose is higher 
than 500 mg). In children, if the dose is lower than 250 mg, an appropriate volume of sodium chloride 
9 mg/ml (0.9%) solution for injection may be used in order to obtain a final TEPADINA concentration 
between 0.5 and 1 mg/ml. For instructions on reconstitution and further dilution prior to 
administration, see section 6.6. 
 
Precautions to be taken before handling or administering the medicinal product 
Topical reactions associated with accidental exposure to thiotepa may occur. Therefore, the use of 
gloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contacts 
the skin, the skin must be immediately thoroughly washed with soap and water. If thiotepa 
accidentally contacts mucous membranes, they must be flushed thoroughly with water (see section 
6.6). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance. 
Pregnancy and lactation (see section 4.6). 
Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5). 
 



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4.4 Special warnings and precautions for use 
 
The consequence of treatment with thiotepa at the recommended dose and schedule is profound 
myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia or 
any combination thereof may develop. Frequent complete blood counts, including differential white 
blood cell counts, and platelet counts need to be performed during the treatment and until recovery is 
achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte-
colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell 
counts and platelet counts are recommended during therapy with thiotepa and after transplant for at 
least 30 days. 
 
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the 
prevention and management of infections during the neutropenic period. 
 
Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly 
metabolized through the liver, caution needs to be observed when thiotepa is used in patients with pre-
existing impairment of liver function, especially in those with severe hepatic impairment. When 
treating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubin 
are monitored regularly following transplant, for early detection of hepatotoxicity. 
 
Patients who have received prior radiation therapy, greater than or equal to three cycles of 
chemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusive 
disease (see section 4.8). 
 
Caution must be used in patients with history of cardiac diseases, and cardiac function must be 
monitored regularly in patients receiving thiotepa.  
 
Caution must be used in patients with history of renal diseases and periodic monitoring of renal 
function should be considered during therapy with thiotepa.  
 
Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by other 
cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see section 4.8). 
 
Previous brain irradiation or craniospinal irradiation may contribute to severe toxic reactions (e.g. 
encephalopathy). 
 
The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be 
explained to the patient. 
 
Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin and 
fosphenytoin is not recommended (see section 4.5). 
 
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal 
products are present in the same conditioning treatment. TEPADINA must be delivered after the 
completion of any cyclophosphamide infusion (see section 4.5). 
 
During the concomitant use of thiotepa and inhibitors of CYP2B6 or CYP3A4, patients should be 
carefully monitored clinically (see section 4.5). 
 
As most alkylating agents, thiotepa might impair male or female fertility. Male patients should seek 
for sperm cryopreservation before therapy is started and should not father a child while treated and 
during the year after cessation of treatment (see section 4.6). 
 



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4.5 Interactions with other medicinal products and other forms of interaction 
 
Specific interactions with thiotepa  
Live virus and bacterial vaccines must not be administered to a patient receiving an 
immunosuppressive chemotherapeutic agent and at least three months must elapse between 
discontinuation of therapy and vaccination.  
 
Thiotepa appears to be metabolised via CYP2B6 and CYP3A4. Co-administration with inhibitors of 
CYP2B6 (for example clopidogrel and ticlopidine) or CYP3A4 (for example azole antifungals, 
macrolides like erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase the 
plasma concentrations of thiotepa and potentially decrease the concentrations of the active metabolite 
TEPA. Co-administration of inducers of cytochrome P450 (such as rifampicin, carbamazepine, 
phenobarbital) may increase the metabolism of thiotepa leading to increased plasma concentrations of 
the active metabolite. Therefore, during the concomitant use of thiotepa and these medicinal products, 
patients should be carefully monitored clinically. 
 
Thiotepa is a weak inhibitor for CYP2B6, and may thereby potentially increase plasma concentrations 
of substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz and 
cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active 
form 4-hydroxycyclophosphamide (4-OHCP) and co-administration of thiotepa may therefore lead to 
decreased concentrations of the active 4-OHCP. Therefore, a clinical monitoring should be exercised 
during the concomitant use of thiotepa and these medicinal products. 
 
Contraindications of concomitant use 
Yellow fever vaccine: risk of fatal generalized vaccine-induced disease. 
 
More generally, live virus and bacterial vaccines must not be administered to a patient receiving an 
immunosuppressive chemotherapeutic agent and at least three months must elapse between 
discontinuation of therapy and vaccination. 
 
Concomitant use not recommended 
Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk is 
increased in subjects who are already immunosuppressed by their underlying disease. 
 
An inactivated virus vaccine should be used instead, whenever possible (poliomyelitis). 
 
Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive 
absorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of the 
cytotoxic medicinal product due to increased hepatic metabolism by phenytoin. 
 
Concomitant use to take into consideration 
Ciclosporine, tacrolimus: excessive immunosuppression with risk of lymphoproliferation. 
 
Alkylating chemotherapeutic agents, including thiotepa, inhibit plasma pseudocholinesterase by 35% 
to 70%. The action of succinyl-choline can be prolonged by 5 to 15 minutes. 
 
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal 
products are present in the same conditioning treatment. TEPADINA must be delivered after the 
completion of any cyclophosphamide infusion. 
 
The concomitant use of thiotepa and other myelosuppressive or myelotoxic agents (i.e. 
cyclophosphamide, melphalan, busulfan, fludarabine, treosulfan) may potentiate the risk of 
haematologic adverse reactions due to overlapping toxicity profiles of these medicinal products. 
 



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Interaction common to all cytotoxics 
Due to the increase of thrombotic risk in case of malignancy, the use of anticoagulative treatment is 
frequent. The high intra-individual variability of the coagulation state during malignancy, and the 
potential interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided 
to treat the patient with oral anticoagulants, to increase the frequency of the INR (International 
Normalised Ratio) monitoring. 
 
4.6 Fertility, pregnancy and lactation  
 
Women of childbearing potential 
Women of childbearing potential have to use effective contraception during treatment and a pregnancy 
test should be performed before treatment is started. 
 
Pregnancy 
There are no data on the use of thiotepa during pregnancy. In pre-clinical studies thiotepa, as most 
alkylating agents, has been shown to cause embryofoetal lethality and teratogenicity (see section 5.3). 
Therefore, thiotepa is contraindicated during pregnancy. 
 
Breast-feeding 
It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and 
its potential toxicity for breast-fed newborns/infants, breast-feeding is contraindicated during 
treatment with thiotepa. 
 
Fertility 
As most alkylating agents, thiotepa might impair male and female fertility. 
Male patients should seek for sperm cryopreservation before therapy is started and should not father a 
child while treated and during the year after cessation of treatment (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
TEPADINA may have major influence on the ability to drive and use machines. It is likely that certain 
adverse reactions of thiotepa like dizziness, headache and blurred vision could affect these functions.  
 
  
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of thiotepa has been examined through a review of adverse events reported in published 
data from clinical trials. In these studies, a total of 6,588 adult patients and 902 paediatric patients 
received thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation.  
 
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as 
expected consequences of the conditioning regimen and transplant process. These include infection 
and Graft-versus host disease (GvHD) which, although not directly related, were the major causes of 
morbidity and mortality, especially in allogeneic HPCT. 
The most frequently adverse reactions reported in the different conditioning treatments including 
thiotepa are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, 
haemorrhagic cystitis, mucosal inflammation. 
 
Leukoencephalopathy  
Cases of leukoencephalopathy have been observed following treatment with thiotepa in adult and 
paediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. 
Some cases had a fatal outcome. 

 



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Tabulated list of adverse reactions 
 
 Adults 
 
The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, 
reported in adult patients as more than an isolated case, are listed below by system organ class and by 
frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), 
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known 
(cannot be estimated from the available data). 
 
System organ 
class 
 

Very common  
 

Common 
 

Uncommon 
 

Not known 

Infections and 
infestations 

Infection 
susceptibility 
increased 
Sepsis 

 Toxic shock 
syndrome 

 

Neoplasms 
benign, 
malignant and 
unspecified 
(incl cysts and 
polyps) 

 Treatment related 
second malignancy 

  

Blood and 
lymphatic 
system 
disorders 
 

Leukopenia 
Thrombocytopenia 
Febrile 
neutropenia 
Anaemia 
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 
Hyperglycaemia 

   

Psychiatric 
disorders 

Confusional state 
Mental status 
changes 

Anxiety 
 

Delirium 
Nervousness 
Hallucination 
Agitation 

 

Nervous system 
disorders  

Dizziness 
Headache 
Vision blurred  
Encephalopathy 
Convulsion  
Paraesthesia 

Intracranial 
aneurysm 
Extrapyramidal 
disorder 
Cognitive disorder 
Cerebral 
haemorrhage  

 Leukoencephalopathy 

Eye disorders Conjunctivitis Cataract   
Ear and 
labyrinth 
disorders 

Hearing impaired 
Ototoxicity 
Tinnitus 

   



10 
 

Cardiac 
disorders 

Arrhythmia Tachycardia 
Cardiac failure 

Cardiomyopathy 
Myocarditis 

 

Vascular 
disorders 

Lymphoedema 
Hypertension 

Haemorrhage 
Embolism 

  

Respiratory, 
thoracic and 
mediastinal 
disorders  

Idiopathic 
pneumonia 
syndrome 
Epistaxis 

Pulmonary oedema 
Cough  
Pneumonitis 

Hypoxia  

Gastrointestinal 
disorders  

Nausea 
Stomatitis  
Oesophagitis  
Vomiting  
Diarrhoea  
Dyspepsia  
Abdominal pain 
Enteritis 
Colitis 

Constipation 
Gastrointestinal 
perforation 
Ileus 
 

Gastrointestinal 
ulcer 

 

Hepatobiliary 
disorders  

Venoocclusive 
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  

Cystitis 
haemorrhagic 

Dysuria 
Oliguria 
Renal failure 
Cystitis 
Haematuria 

 
 

 

Reproductive 
system and 
breast disorders 

Azoospermia 
Amenorrhoea 
Vaginal 
haemorrhage 

Menopausal 
symptoms 
Infertility female 
Infertility male 

  

General 
disorders and 
administration 
site conditions 
 

Pyrexia  
Asthenia 
Chills 
Generalised 
oedema 
Injection site 
inflammation 
Injection site pain 
Mucosal 
inflammation 

Multi-organ failure 
Pain 
 

  



11 
 

Investigation 
 

Weight increased 
Blood bilirubin 
increased 
Transaminases 
increased 
Blood amylase 
increased 

Blood creatinine 
increased  
Blood urea 
increased 
Gamma-
glutamyltransferase 
increased 
Blood alkaline 
phosphatase 
increased 
Aspartate 
aminotransferase 
increased 

  

 
Paediatric population 
  
The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, 
reported in paediatric patients as more than an isolated case, are listed below by system organ class 
and by frequency. Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. Frequencies are defined as: very common (≥1/10), common ((≥1/100 to 
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not 
known (cannot be estimated from the available data). 
 
System organ class 
 

Very common  
 

Common 
 

Not known 
 

Infections and infestations Infection 
susceptibility 
increased 
Sepsis 

Thrombocytopenic 
purpura 

 

Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) 

 Treatment related 
second 
malignancy 

 

Blood and lymphatic system 
disorders 
 

Thrombocytopenia 
Febrile 
neutropenia 
Anaemia 
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 
Hyperglycaemia 

  

Psychiatric disorders Mental status 
changes 

Mental disorder 
due to a general 
medical condition 

 



12 
 

Nervous system disorders  Headache 
Encephalopathy 
Convulsion  
Cerebral 
haemorrhage 
Memory 
impairment 
Paresis 

Ataxia Leukoencephalopathy 

Ear and labyrinth disorders Hearing impaired   
Cardiac disorders Cardiac arrest Cardiovascular 

insufficiency 
Cardiac failure 

 

Vascular disorders Haemorrhage Hypertension  
Respiratory, thoracic and 
mediastinal disorders  

Pneumonitis 
 

Idiopathic 
pneumonia 
syndrome 
Pulmunary 
haemorrage 
Pulmonary 
oedema 
Epistaxis  
Hypoxia 
Respiratory arrest 

Pulmonary arterial 
hypertension 

Gastrointestinal disorders  Nausea 
Stomatitis  
Vomiting  
Diarrhoea  
Abdominal pain 

Enteritis 
Intestinal 
obstruction 

 

Hepatobiliary disorders  Venoocclusive 
liver disease 

Liver failure  

Skin and subcutaneous tissue 
disorders  

Rash  
Erythema 
Desquamation 
Pigmentation 
disorder 

 Severe toxic skin 
reactions including 
cases of Stevens-
Johnson syndrome 
and toxic epidermal 
necrolysis 

Musculoskeletal and connective 
tissue disorders 

Growth 
retardation 

  

Renal and urinary disorders  Bladder disorders Renal failure 
Cystitis 
haemorrhagic 

 

General disorders and 
administration site conditions 
 

Pyrexia  
Mucosal 
inflammation Pain 
Multi-organ 
failure 

  



13 
 

Investigation 
 

Blood bilirubin 
increased 
Transaminases 
increased 
Blood creatinine 
increased  
Aspartate 
aminotransferase 
increased 
Alanine 
aminotransferase 
increased 

Blood urea 
increased 
Blood electrolytes 
abnormal 
Prothrombin time 
ratio increased 

 

 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no experience with overdoses of thiotepa. The most important adverse reactions expected in 
case of overdose is myeloablation and pancytopenia.  
There is no known antidote for thiotepa. 
The haematological status needs to be closely monitored and vigorous supportive measures instituted 
as medically indicated. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, Alkylating Agents, ATC code: L01AC01 
 
Mechanism of action 
Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogen 
mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene 
imine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylation 
of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating 
alkylated guanine. 
 
Clinical safety and efficacy 
The conditioning treatment must provide cytoreduction and ideally disease eradication. Thiotepa has 
marrow ablation as its dose-limiting toxicity, allowing significant dose escalation with the infusion of 
autologous HPCT. In allogeneic HPCT, the conditioning treatment must be sufficiently 
immunosuppressive and myeloablative to overcome host rejection of the graft. Due to its highly 
myeloablative characteristics, thiotepa enhances recipient immunosuppression and myeloablation, thus 
strengthening engraftment; this compensates for the loss of the GvHD-related GvL effects. As 
alkylating agent, thiotepa produces the most profound inhibition of tumour cell growth in vitro with 
the smallest increase in medicinal product concentration. Due to its lack of extramedullary toxicity 
despite dose escalation beyond myelotoxic doses, thiotepa has been used for decades in combination 
with other chemotherapy medicinal products prior to autologous and allogeneic HPCT.  
The results of published clinical studies supporting the efficacy of thiotepa are summarised: 
 



14 
 

Autologous HPCT 
Haematological diseases 
Engraftment:  Conditioning treatments including thiotepa have proved to be myeloablative. 
Disease Free Survival (DFS): An estimated 43% at five years has been reported, confirming that 
conditioning treatments containing thiotepa following autologous HPCT are effective therapeutic 
strategies for treating patients with haematological diseases. 
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been 
reported as being 60% or lower, which was considered by the physicians as the threshold to prove 
efficacy. In some of the conditioning treatments evaluated, relapse rates lower than 60% have also 
been reported at 5 years. 
Overall Survival (OS): OS ranged from 29% to 87% with a follow-up ranging from 22 up to 63 
months. 
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 2.5% to 29% have been reported. TRM values ranged from 0% to 21% at 1 year, confirming the 
safety of the conditioning treatment including thiotepa for autologous HPCT in adult patients with 
haematological diseases. 
Solid tumours 
Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative. 
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year 
confirm that conditioning treatments containing thiotepa following autologous HPCT are effective 
choices for treating patients with solid tumours. 
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been 
reported as being lower than 60%, which was considered by the physicians as the threshold to prove 
efficacy. In some cases, relapse rates of 35% and of 45% have been reported at 5 years and 6 years 
respectively. 
Overall Survival: OS ranged from 30% to 87% with a follow-up ranging from 11.7 up to 87 months. 
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 0% to 2% have been reported. TRM values ranged from 0% to 7.4% confirming the safety of the 
conditioning treatment including thiotepa for autologous HPCT in adult patients with solid tumours. 
 
Allogeneic HPCT 
Haematological diseases 
Engraftment: Engraftment has been achieved (92%-100%) in all reported conditioning treatments and 
it was considered to occur at the expected time. Therefore it can be concluded that conditioning 
treatments including thiotepa are myeloablative. 
GvHD (graft versus host disease): all conditioning treatments evaluated assured a low incidence of 
acute GvHD grade III-IV (from 4% to 24%). 
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year and up 
to 5 years confirm that conditioning treatments containing thiotepa following allogeneic HPCT are 
effective choices for treating patients with haematological diseases.  
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been 
reported as being lower than 40% (which was considered by the physicians as the threshold to prove 
efficacy). In some cases, relapse rates lower than 40% have also been reported at 5 years and 10 years. 
Overall Survival: OS ranged from 31% to 81% with a follow-up ranging from 7.3 up to 120 months.  
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): low values have been 
reported, confirming the safety of the conditioning treatments including thiotepa for allogeneic HPCT 
in adult patients with haematological diseases. 
 
Paediatric population 
 
Autologous HPCT 
Solid tumours 
Engraftment: It has been achieved with all reported conditioning regimens including thiotepa.  
Disease Free Survival (DFS): With a follow-up of 36 to 57 months, DFS ranged from 46% to 70% in 
the reported studies. Considering that all patients were treated for high risk solid tumours, DFS results 
confirm that conditioning treatments containing thiotepa following autologous HPCT are effective 
therapeutic strategies for treating paediatric patients with solid tumours.  



15 
 

Relapse: In all the reported conditioning regimens containing thiotepa, relapse rates at 12 to 57 months 
ranged from 33% to 57%. Considering that all patients suffer of recurrence or poor prognosis solid 
tumours, these rates support the efficacy of conditioning regimens based on thiotepa.  
Overall Survival (OS): OS ranged from 17% to 84% with a follow-up ranging from 12.3 up to 99.6 
months.  
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 0% to 26.7% have been reported. TRM values ranged from 0% to 18% confirming the safety of 
the conditioning treatments including thiotepa for autologous HPCT in paediatric patients with solid 
tumours. 
 
Allogeneic HPCT 
Haematological diseases 
Engraftment:  It has been achieved with all evaluated conditioning regimens including thiotepa with a 
success rate of 96% - 100%. The haematological recovery is in the expected time.  
Disease Free Survival (DFS): Percentages of 40% - 75% with follow-up of more than 1 year have 
been reported. DFS results confirm that conditioning treatment containing thiotepa following 
allogeneic HPCT are effective therapeutic strategies for treating paediatric patients with 
haematological diseases.  
Relapse: In all the reported conditioning regimens containing thiotepa, the relapse rate was in the 
range of 15% - 44%. These data support the efficacy of conditioning regimens based on thiotepa in all 
haematological diseases. 
Overall Survival (OS): OS ranged from 50% to 100% with a follow-up ranging from 9.4 up to 121 
months.  
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 0% to 2.5% have been reported. TRM values ranged from 0% to 30% confirming the safety of 
the conditioning treatment including thiotepa for allogeneic HPCT in paediatric patients with 
haematological diseases. 
 
5.2 Pharmacokinetic properties  
 
Absorption 
Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa from 
being administered orally.  
 
Distribution 
Thiotepa is a highly lipophilic compound. After intravenous administration, plasma concentrations of 
the active substance fit a two compartment model with a rapid distribution phase. The volume of 
distribution of thiotepa is large and it has been reported as ranging from 40.8 l/m2 to 75 l/m2, 
indicating distribution to total body water. The apparent volume of distribution of thiotepa appears 
independent of the administered dose. The fraction unbound to proteins in plasma is 70-90%; 
insignificant binding of thiotepa to gamma globulin and minimal albumin binding (10-30%) has been 
reported. 
After intravenous administration, CSF medicinal product exposure is nearly equivalent to that 
achieved in plasma; the mean ratio of AUC in CSF to plasma for thiotepa is 0.93. CSF and plasma 
concentrations of TEPA, the first reported active metabolite of thiotepa, exceed the concentrations of 
the parent compound. 
 



16 
 

Biotransformation 
Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected in 
urine within 1 hour after infusion. The metabolites are active alkylating agents but the role they play 
in the antitumor activity of thiotepa remains to be elucidated. Thiotepa undergoes oxidative 
desulphuration via the cytochrome P450 CYP2B and CYP3A isoenzyme families to the major and 
active metabolite TEPA (triethylenephosphoramide). The total excreted amount of thiotepa and its 
identified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence of 
other alkylating metabolites. During conversion of GSH conjugates to N-acetylcysteine conjugates, 
GSH, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not found in urine, 
and, if formed, are probably excreted in bile or as intermediate metabolites rapidly converted into 
thiotepa-mercapturate. 
 
Elimination 
The total clearance of thiotepa ranged from 11.4 to 23.2 l/h/m2. The elimination half-life varied from 
1.5 to 4.1 hours. The identified metabolites TEPA, monochlorotepa and thiotepa-mercapturate are all 
excreted in the urine. Urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hours 
respectively. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchanged 
medicinal product and monochlorotepa, and 11% for TEPA and thiotepa-mercapturate. 
 
Linearity/non-linearity  
There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.  
 
Special populations 
 
Paediatric population 
The pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appear 
to vary from those reported in children receiving 75 mg/m2 or adults receiving similar doses. 
 
Renal impairment 
The effects of renal impairment on thiotepa elimination have not been assessed. 
 
Hepatic impairment 
The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed. 
 
5.3 Preclinical safety data 
 
No conventional acute and repeat dose toxicity studies were performed. 
Thiotepa was shown to be genotoxic in vitro and in vivo, and carcinogenic in mice and rats. 
Thiotepa was shown to impair fertility and interfere with spermatogenesis in male mice, and to impair 
ovarian function in female mice. It was teratogenic in mice and in rats, and foeto-lethal in rabbits. 
These effects were seen at doses lower than those used in humans. 
 
   
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
None. 
6.2 Incompatibilities 
 
TEPADINA is unstable in acid medium. 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 



17 
 

6.3 Shelf life 
 
Unopened vial 
18 months. 
 
After reconstitution 
Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours when 
stored at 2°C-8°C. 
 
After dilution 
Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored 
at 2°C-8°C and for 4 hours when stored at 25°C. 
 
From a microbiological point of view, the product should be used immediately after dilution. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than the above mentioned conditions when dilution has taken place 
in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Unopened vial 
Store and transport refrigerated (2°C – 8°C). 
Do not freeze.  
 
After reconstitution and dilution 
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I clear glass vial with a rubber stopper (bromobutyl or chlorobutyl), containing 15 mg thiotepa.  
Pack size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Preparation of TEPADINA 
Procedures for proper handling and disposal of anticancer medicinal products must be considered. All 
transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical 
laminar flow safety hood. 
As with other cytotoxic compounds, caution needs to be exercised in handling and preparation of 
TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactions 
associated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommended 
in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, the skin must 
be immediately and thoroughly washed with soap and water. If thiotepa accidentally contacts mucous 
membranes, they must be flushed thoroughly with water. 
 
Reconstitution 
TEPADINA must be reconstituted with 1.5 ml of sterile water for injection. 
Using a syringe fitted with a needle, aseptically withdraw 1.5 ml of sterile water for injection. 
Inject the content of the syringe into the vial through the rubber stopper. 
Remove the syringe and the needle and mix manually by repeated inversions. 
Only colourless solutions, without any particulate matter, must be used. Reconstituted solutions may 
occasionally show opalescence; such solutions can still be administered. 
 



18 
 

Further dilution in the infusion bag 
The reconstituted solution is hypotonic and must be further diluted prior to administration with 500 ml 
sodium chloride 9 mg/ml (0.9%) solution for injection (1000 ml if the dose is higher than 500 mg) or 
with an appropriate volume of sodium chloride 9 mg/ml (0.9%) in order to obtain a final TEPADINA 
concentration between 0.5 and 1 mg/ml. 
 
Administration  
TEPADINA infusion solution should be inspected visually for particulate matter prior to 
administration. Solutions containing a precipitate should be discarded.  
Prior to and following each infusion, the indwelling catheter line should be flushed with 
approximately 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection. 
The infusion solution must be administered to patients using an infusion set equipped with a 0.2 µm 
in-line filter. Filtering does not alter solution potency. 
 
Disposal 
TEPADINA is for single use only.  
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ADIENNE S.r.l. S.U. 
Via Galileo Galilei, 19 
20867 Caponago (MB) Italy 
Tel: +39-02 40700445 
adienne@adienne.com  
 
 
8. MARKETING AUTHORISATION  NUMBER 
 
EU/1/10/622/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 15 March 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



19 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
TEPADINA 100 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
One vial of powder contains 100 mg thiotepa.  
After reconstitution with 10 ml of water for injections, each ml of solution contains 10 mg thiotepa 
(10 mg/ml). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
White crystalline powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
TEPADINA is indicated, in combination with other chemotherapy medicinal products:  
• with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or 
autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult 
and paediatric patients; 
• when high dose chemotherapy with HPCT support is appropriate for the treatment of solid 
tumours in adult and paediatric patients. 
 
4.2 Posology and method of administration 
 
TEPADINA administration must be supervised by a physician experienced in conditioning treatment 
prior to haematopoietic progenitor cell transplantation. 
 
Posology 
 
TEPADINA is administered at different doses, in combination with other chemotherapeutic medicinal 
products, in patients with haematological diseases or solid tumours prior to HPCT.  
 
TEPADINA posology is reported, in adult and paediatric patients, according to the type of HPCT 
(autologous or allogeneic) and disease. 
 
Adults 
 
AUTOLOGOUS HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases 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 from 2 up to 4 consecutive 
days before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during 
the time of the entire conditioning treatment.  



20 
 

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 from 2 up to 4 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during the time 
of the entire conditioning treatment.  
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 before autologous HPCT, without exceeding the total maximum cumulative dose of 
370 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
Solid tumours 
 
The recommended dose in solid tumours ranges from 120 mg/m2/day (3.24 mg/kg/day) to  
250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from 2 up to 5 
consecutive days before autologous HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 
mg/kg), during the time of the entire conditioning treatment.  
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 from 3 up to 5 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 mg/kg), during the time 
of the entire conditioning treatment.  
CNS TUMOURS 
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 in one or two daily infusions, administered from 3 up to 4 consecutive days 
before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during 
the time of the entire conditioning treatment.  
OVARIAN CANCER 
The recommended dose is 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered in 
2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose 
of 500 mg/m2 (13.51 mg/kg), during the time of the entire conditioning treatment.  
GERM CELL TUMOURS 
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 185 mg/m2/day (5 mg/kg/day) to  
481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  



21 
 

LYMPHOMA 
The recommended dose in lymphoma is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
MULTIPLE MYELOMA 
The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before allogeneic 
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m2 (5 mg/kg), during the 
time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day (13 mg/kg/day) 
divided in one or two daily infusions, administered from 1 up to 2 consecutive days before allogeneic 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), during the time of the entire 
conditioning treatment.  
THALASSEMIA 
The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment. 
 
Paediatric population 
 
AUTOLOGOUS HPCT 
 
Solid tumours 
 
The recommended dose in solid tumours 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 from 2 up to 3 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of 
the entire conditioning treatment.  
CNS TUMOURS 
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 before autologous HPCT 
depending on the combination with other chemotherapeutic medicinal products, without exceeding the 
total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of the entire conditioning 
treatment. 
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to 
250 mg/m2/day (10 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 375 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
THALASSEMIA 
The recommended dose ranges from 200 mg/m2/day (8 mg/kg/day) to 250 mg/m2/day (10 mg/kg/day) 
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total 
maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning 
treatment.  



22 
 

REFRACTORY CYTOPENIA 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 3 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 
375 mg/m2 (15 mg/kg), during the time of the entire conditioning treatment.  
GENETIC DISEASES 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of  
250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
SICKLE CELL ANAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
 
Special populations 
 
Renal impairment 
Studies in renally impaired patients have not been conducted. As thiotepa and its metabolites are 
poorly excreted in the urine, dose modification is not recommended in patients with mild or moderate 
renal insufficiency. However, caution is recommended (see sections 4.4 and 5.2).   
 
Hepatic impairment 
Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly 
metabolized through the liver, caution needs to be exercised when thiotepa is used in patients with pre-
existing impairment of liver function, especially in those with severe hepatic impairment. Dose 
modification is not recommended for transient alterations of hepatic parameters (see section 4.4). 
 
Elderly 
The administration of thiotepa has not been specifically investigated in elderly patients. However, in 
clinical studies, a proportion of patients over the age of 65 received the same cumulative dose as the 
other patients. No dose adjustment was deemed necessary. 
 
Method of administration 
TEPADINA must be administered by a qualified healthcare professional as a 2-4 hours intravenous 
infusion via a central venous catheter. 
Each TEPADINA vial must be reconstituted with 10 ml of sterile water for injection. The total volume 
of reconstituted vials to be administered 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 is higher than 500 
mg). In children, if the dose is lower than 250 mg, an appropriate volume of sodium chloride 9 mg/ml 
(0.9%) solution for injection may be used in order to obtain a final TEPADINA concentration between 
0.5 and 1 mg/ml. For instructions on reconstitution and further dilution prior to administration, see 
section 6.6. 
 
Precautions to be taken before handling or administering the medicinal product 
Topical reactions associated with accidental exposure to thiotepa may occur. Therefore, the use of 
gloves is recommended in preparing the solution for infusion. If thiotepa solution accidentally contacts 
the skin, the skin must be immediately thoroughly washed with soap and water. If thiotepa 
accidentally contacts mucous membranes, they must be flushed thoroughly with water (see section 
6.6). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance. 
Pregnancy and lactation (see section 4.6). 
Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5). 
 



23 
 

4.4 Special warnings and precautions for use 
 
The consequence of treatment with thiotepa at the recommended dose and schedule is profound 
myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia or 
any combination thereof may develop. Frequent complete blood counts, including differential white 
blood cell counts, and platelet counts need to be performed during the treatment and until recovery is 
achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte-
colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell 
counts and platelet counts are recommended during therapy with thiotepa and after transplant for at 
least 30 days. 
 
Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the 
prevention and management of infections during the neutropenic period. 
 
Thiotepa has not been studied in patients with hepatic impairment. Since thiotepa is mainly 
metabolized through the liver, caution needs to be observed when thiotepa is used in patients with pre-
existing impairment of liver function, especially in those with severe hepatic impairment. When 
treating such patients it is recommended that serum transaminase, alkaline phosphatase and bilirubin 
are monitored regularly following transplant, for early detection of hepatotoxicity. 
 
Patients who have received prior radiation therapy, greater than or equal to three cycles of 
chemotherapy, or prior progenitor cell transplant may be at an increased risk of hepatic veno-occlusive 
disease (see section 4.8). 
 
Caution must be used in patients with history of cardiac diseases, and cardiac function must be 
monitored regularly in patients receiving thiotepa.  
 
Caution must be used in patients with history of renal diseases and periodic monitoring of renal 
function should be considered during therapy with thiotepa.  
 
Thiotepa might induce pulmonary toxicity that may be additive to the effects produced by other 
cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see section 4.8). 
 
Previous brain irradiation or craniospinal irradiation may contribute to severe toxic reactions (e.g. 
encephalopathy). 
 
The increased risk of a secondary malignancy with thiotepa, a known carcinogen in humans, must be 
explained to the patient. 
 
Concomitant use with live attenuated vaccines (except yellow fever vaccines), phenytoin and 
fosphenytoin is not recommended (see section 4.5). 
 
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal 
products are present in the same conditioning treatment. TEPADINA must be delivered after the 
completion of any cyclophosphamide infusion (see section 4.5). 
 
During the concomitant use of thiotepa and inhibitors of CYP2B6 or CYP3A4, patients should be 
carefully monitored clinically (see section 4.5). 
 
As most alkylating agents, thiotepa might impair male or female fertility. Male patients should seek 
for sperm cryopreservation before therapy is started and should not father a child while treated and 
during the year after cessation of treatment (see section 4.6). 
 



24 
 

4.5 Interactions with other medicinal products and other forms of interaction 
 
Specific interactions with thiotepa  
Live virus and bacterial vaccines must not be administered to a patient receiving an 
immunosuppressive chemotherapeutic agent and at least three months must elapse between 
discontinuation of therapy and vaccination.  
 
Thiotepa appears to be metabolised via CYP2B6 and CYP3A4. Co-administration with inhibitors of 
CYP2B6 (for example clopidogrel and ticlopidine) or CYP3A4 (for example azole antifungals, 
macrolides like erythromycin, clarithromycin, telithromycin, and protease inhibitors) may increase the 
plasma concentrations of thiotepa and potentially decrease the concentrations of the active metabolite 
TEPA. Co-administration of inducers of cytochrome P450 (such as rifampicin, carbamazepine, 
phenobarbital) may increase the metabolism of thiotepa leading to increased plasma concentrations of 
the active metabolite. Therefore, during the concomitant use of thiotepa and these medicinal products, 
patients should be carefully monitored clinically. 
 
Thiotepa is a weak inhibitor for CYP2B6, and may thereby potentially increase plasma concentrations 
of substances metabolised via CYP2B6, such as ifosfamide, tamoxifen, bupropion, efavirenz and 
cyclophosphamide. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active 
form 4-hydroxycyclophosphamide (4-OHCP) and co-administration of thiotepa may therefore lead to 
decreased concentrations of the active 4-OHCP. Therefore, a clinical monitoring should be exercised 
during the concomitant use of thiotepa and these medicinal products. 
 
Contraindications of concomitant use 
Yellow fever vaccine: risk of fatal generalized vaccine-induced disease. 
 
More generally, live virus and bacterial vaccines must not be administered to a patient receiving an 
immunosuppressive chemotherapeutic agent and at least three months must elapse between 
discontinuation of therapy and vaccination. 
 
Concomitant use not recommended 
Live attenuated vaccines (except yellow fever): risk of systemic, possibly fatal disease. This risk is 
increased in subjects who are already immunosuppressed by their underlying disease. 
 
An inactivated virus vaccine should be used instead, whenever possible (poliomyelitis). 
 
Phenytoin: risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive 
absorption by cytotoxic medicinal product or risk of toxicity enhancement and loss of efficacy of the 
cytotoxic medicinal product due to increased hepatic metabolism by phenytoin. 
 
Concomitant use to take into consideration 
Ciclosporine, tacrolimus: excessive immunosuppression with risk of lymphoproliferation. 
 
Alkylating chemotherapeutic agents, including thiotepa, inhibit plasma pseudocholinesterase by 35% 
to 70%. The action of succinyl-choline can be prolonged by 5 to 15 minutes. 
 
Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal 
products are present in the same conditioning treatment. TEPADINA must be delivered after the 
completion of any cyclophosphamide infusion. 
 
The concomitant use of thiotepa and other myelosuppressive or myelotoxic agents (i.e. 
cyclophosphamide, melphalan, busulfan, fludarabine, treosulfan) may potentiate the risk of 
haematologic adverse reactions due to overlapping toxicity profiles of these medicinal products. 
 



25 
 

Interaction common to all cytotoxics 
Due to the increase of thrombotic risk in case of malignancy, the use of anticoagulative treatment is 
frequent. The high intra-individual variability of the coagulation state during malignancy, and the 
potential interaction between oral anticoagulants and anticancer chemotherapy require, if it is decided 
to treat the patient with oral anticoagulants, to increase the frequency of the INR (International 
Normalised Ratio) monitoring. 
 
4.6 Fertility, pregnancy and lactation  
 
Women of childbearing potential  
Women of childbearing potential have to use effective contraception during treatment and a pregnancy 
test should be performed before treatment is started. 
 
Pregnancy 
There are no data on the use of thiotepa during pregnancy. In pre-clinical studies thiotepa, as most 
alkylating agents, has been shown to cause embryofoetal lethality and teratogenicity (see section 5.3). 
Therefore, thiotepa is contraindicated during pregnancy. 
 
Breast-feeding 
It is unknown whether thiotepa is excreted in human milk. Due to its pharmacological properties and 
its potential toxicity for breast-fed newborns/ infants, breast-feeding is contraindicated during 
treatment with thiotepa. 
 
Fertility 
As most alkylating agents, thiotepa might impair male and female fertility. 
Male patients should seek for sperm cryopreservation before therapy is started and should not father a 
child while treated and during the year after cessation of treatment (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
TEPADINA may have major influence on the ability to drive and use machines. It is likely that certain 
adverse reactions of thiotepa like dizziness, headache and blurred vision could affect these functions.   
 
  
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The safety of thiotepa has been examined through a review of adverse events reported in published 
data from clinical trials. In these studies, a total of 6,588 adult patients and 902 paediatric patients 
received thiotepa for conditioning treatment prior to haematopoietic progenitor cell transplantation.  
 
Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as 
expected consequences of the conditioning regimen and transplant process. These include infection 
and Graft-versus host disease (GvHD) which, although not directly related, were the major causes of 
morbidity and mortality, especially in allogeneic HPCT. 
The most frequently adverse reactions reported in the different conditioning treatments including 
thiotepa are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, 
haemorrhagic cystitis, mucosal inflammation. 
 
Leukoencephalopathy  
Cases of leukoencephalopathy have been observed following treatment with thiotepa in adult and 
paediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. 
Some cases had a fatal outcome. 

 



26 
 

Tabulated list of adverse reactions 
 
Adults 
 
The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, 
reported in adult patients as more than an isolated case, are listed below by system organ class and by 
frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. Frequencies are defined as: very common (≥1/10), common ((≥1/100 to <1/10), 
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known 
(cannot be estimated from the available data). 
 
System organ 
class 
 

Very common  
 

Common 
 

Uncommon 
 

Not known 

Infections and 
infestations 

Infection 
susceptibility 
increased 
Sepsis 

 Toxic shock 
syndrome 

 

Neoplasms 
benign, 
malignant and 
unspecified 
(incl cysts and 
polyps) 

 Treatment related 
second malignancy 

  

Blood and 
lymphatic 
system 
disorders 
 

Leukopenia 
Thrombocytopenia 
Febrile 
neutropenia 
Anaemia 
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 
Hyperglycaemia 

   

Psychiatric 
disorders 

Confusional state 
Mental status 
changes 

Anxiety 
 

Delirium 
Nervousness 
Hallucination 
Agitation 

 

Nervous system 
disorders  

Dizziness 
Headache 
Vision blurred  
Encephalopathy 
Convulsion  
Paraesthesia 

Intracranial 
aneurysm 
Extrapyramidal 
disorder 
Cognitive disorder 
Cerebral 
haemorrhage  

 Leukoencephalopathy 

Eye disorders Conjunctivitis Cataract   
Ear and 
labyrinth 
disorders 

Hearing impaired 
Ototoxicity 
Tinnitus 

   



27 
 

Cardiac 
disorders 

Arrhythmia Tachycardia 
Cardiac failure 

Cardiomyopathy 
Myocarditis 

 

Vascular 
disorders 

Lymphoedema 
Hypertension 

Haemorrhage 
Embolism 

  

Respiratory, 
thoracic and 
mediastinal 
disorders  

Idiopathic 
pneumonia 
syndrome 
Epistaxis 

Pulmonary oedema 
Cough  
Pneumonitis 

Hypoxia  

Gastrointestinal 
disorders  

Nausea 
Stomatitis  
Oesophagitis  
Vomiting  
Diarrhoea  
Dyspepsia  
Abdominal pain 
Enteritis 
Colitis 

Constipation 
Gastrointestinal 
perforation 
Ileus 
 

Gastrointestinal 
ulcer 

 

Hepatobiliary 
disorders  

Venoocclusive 
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  

Cystitis 
haemorrhagic 

Dysuria 
Oliguria 
Renal failure 
Cystitis 
Haematuria 

 
 

 

Reproductive 
system and 
breast disorders 

Azoospermia 
Amenorrhoea 
Vaginal 
haemorrhage 

Menopausal 
symptoms 
Infertility female 
Infertility male 

  

General 
disorders and 
administration 
site conditions 
 

Pyrexia  
Asthenia 
Chills 
Generalised 
oedema 
Injection site 
inflammation 
Injection site pain 
Mucosal 
inflammation 

Multi-organ failure 
Pain 
 

  



28 
 

Investigation 
 

Weight increased 
Blood bilirubin 
increased 
Transaminases 
increased 
Blood amylase 
increased 

Blood creatinine 
increased  
Blood urea 
increased 
Gamma-
glutamyltransferase 
increased 
Blood alkaline 
phosphatase 
increased 
Aspartate 
aminotransferase 
increased 

  

 
Paediatric population 
 
The adverse reactions considered at least possibly related to conditioning treatment including thiotepa, 
reported in paediatric patients as more than an isolated case, are listed below by system organ class 
and by frequency. Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. Frequencies are defined as: very common (≥1/10), common ((≥1/100 to 
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not 
known (cannot be estimated from the available data). 
 
System organ class 
 

Very common  
 

Common 
 

Not known 
 

Infections and infestations Infection 
susceptibility 
increased 
Sepsis 

Thrombocytopenic 
purpura 

 

Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) 

 Treatment related 
second 
malignancy 

 

Blood and lymphatic system 
disorders 
 

Thrombocytopenia 
Febrile 
neutropenia 
Anaemia 
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 
Hyperglycaemia 

  

Psychiatric disorders Mental status 
changes 

Mental disorder 
due to a general 
medical condition 

 



29 
 

Nervous system disorders  Headache 
Encephalopathy 
Convulsion  
Cerebral 
haemorrhage 
Memory 
impairment 
Paresis 

Ataxia Leukoencephalopathy 

Ear and labyrinth disorders Hearing impaired   
Cardiac disorders Cardiac arrest Cardiovascular 

insufficiency 
Cardiac failure 

 

Vascular disorders Haemorrhage Hypertension  
Respiratory, thoracic and 
mediastinal disorders  

Pneumonitis 
 

Idiopathic 
pneumonia 
syndrome 
Pulmunary 
haemorrage 
Pulmonary 
oedema 
Epistaxis  
Hypoxia 
Respiratory arrest 

Pulmonary arterial 
hypertension 

Gastrointestinal disorders  Nausea 
Stomatitis  
Vomiting  
Diarrhoea  
Abdominal pain 

Enteritis 
Intestinal 
obstruction 

 

Hepatobiliary disorders  Venoocclusive 
liver disease 

Liver failure  

Skin and subcutaneous tissue 
disorders  

Rash  
Erythema 
Desquamation 
Pigmentation 
disorder 

 Severe toxic skin 
reactions including 
cases of Stevens-
Johnson syndrome 
and toxic epidermal 
necrolysis 

Musculoskeletal and connective 
tissue disorders 

Growth 
retardation 

  

Renal and urinary disorders  Bladder disorders Renal failure 
Cystitis 
haemorrhagic 

 

General disorders and 
administration site conditions 
 

Pyrexia  
Mucosal 
inflammation Pain 
Multi-organ 
failure 

  



30 
 

Investigation 
 

Blood bilirubin 
increased 
Transaminases 
increased 
Blood creatinine 
increased  
Aspartate 
aminotransferase 
increased 
Alanine 
aminotransferase 
increased 

Blood urea 
increased 
Blood electrolytes 
abnormal 
Prothrombin time 
ratio increased 

 

 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no experience with overdoses of thiotepa. The most important adverse reactions expected in 
case of overdose is myeloablation and pancytopenia.  
There is no known antidote for thiotepa. 
 
The haematological status needs to be closely monitored and vigorous supportive measures instituted 
as medically indicated. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, Alkylating Agents, ATC code: L01AC01 
 
Mechanism of action 
Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogen 
mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene 
imine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylation 
of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating 
alkylated guanine. 
 
Clinical safety and efficacy 
The conditioning treatment must provide cytoreduction and ideally disease eradication. Thiotepa has 
marrow ablation as its dose-limiting toxicity, allowing significant dose escalation with the infusion of 
autologous HPCT. In allogeneic HPCT, the conditioning treatment must be sufficiently 
immunosuppressive and myeloablative to overcome host rejection of the graft. Due to its highly 
myeloablative characteristics, thiotepa enhances recipient immunosuppression and myeloablation, thus 
strengthening engraftment; this compensates for the loss of the GvHD-related GvL effects. As 
alkylating agent, thiotepa produces the most profound inhibition of tumour cell growth in vitro with 
the smallest increase in medicinal product concentration. Due to its lack of extramedullary toxicity 
despite dose escalation beyond myelotoxic doses, thiotepa has been used for decades in combination 
with other chemotherapy medicinal products prior to autologous and allogeneic HPCT.  
The results of published clinical studies supporting the efficacy of thiotepa are summarised: 
 



31 
 

Autologous HPCT 
Haematological diseases 
Engraftment:  Conditioning treatments including thiotepa have proved to be myeloablative. 
Disease Free Survival (DFS): An estimated 43% at five years has been reported, confirming that 
conditioning treatments containing thiotepa following autologous HPCT are effective therapeutic 
strategies for treating patients with haematological diseases. 
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been 
reported as being 60% or lower, which was considered by the physicians as the threshold to prove 
efficacy. In some of the conditioning treatments evaluated, relapse rates lower than 60% have also 
been reported at 5 years. 
Overall Survival (OS): OS ranged from 29% to 87% with a follow-up ranging from 22 up to 63 
months. 
Regimen Related Mortality (RRM) and Transplant Related Mortality TRM : RRM values ranging from 
2.5% to 29% have been reported. TRM values ranged from 0% to 21% at 1 year, confirming the safety 
of the conditioning treatment including thiotepa for autologous HPCT in adult patients with 
haematological diseases. 
Solid tumours 
Engraftment:  Conditioning treatments including thiotepa have proved to be myeloablative. 
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year 
confirm that conditioning treatments containing thiotepa following autologous HPCT are effective 
choices for treating patients with solid tumours. 
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been 
reported as being lower than 60%, which was considered by the physicians as the threshold to prove 
efficacy. In some cases, relapse rates of 35% and of 45% have been reported at 5 years and 6 years 
respectively. 
Overall Survival: OS ranged from 30% to 87% with a follow-up ranging from 11.7 up to 87 months. 
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 0% to 2% have been reported. TRM values ranged from 0% to 7.4% confirming the safety of the 
conditioning treatment including thiotepa for autologous HPCT in adult patients with solid tumours. 
 
Allogeneic HPCT 
Haematological diseases 
Engraftment: Engraftment has been achieved (92%-100%) in all reported conditioning treatments and 
it was considered to occur at the expected time. Therefore it can be concluded that conditioning 
treatments including thiotepa are myeloablative. 
GvHD (graft versus host disease): all conditioning treatments evaluated assured a low incidence of 
acute GvHD grade III-IV (from 4% to 24%). 
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year and up 
to 5 years confirm that conditioning treatments containing thiotepa following allogeneic HPCT are 
effective choices for treating patients with haematological diseases.  
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been 
reported as being lower than 40% (which was considered by the physicians as the threshold to prove 
efficacy). In some cases, relapse rates lower than 40% have also been reported at 5 years and 10 years. 
Overall Survival: OS ranged from 31% to 81% with a follow-up ranging from 7.3 up to 120 months.  
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): low values have been 
reported, confirming the safety of the conditioning treatments including thiotepa for allogeneic HPCT 
in adult patients with haematological diseases. 
 
Paediatric population 
 
Autologous HPCT 
Solid tumours 
Engraftment:  It has been achieved with all reported conditioning regimens including thiotepa.  
Disease Free Survival (DFS): With a follow-up of 36 to 57 months, DFS ranged from 46% to 70% in 
the reported studies. Considering that all patients were treated for high risk solid tumours, DFS results 
confirm that conditioning treatments containing thiotepa following autologous HPCT are effective 
therapeutic strategies for treating paediatric patients with solid tumours.  



32 
 

Relapse: In all the reported conditioning regimens containing thiotepa, relapse rates at 12 to 57 months 
ranged from 33% to 57%. Considering that all patients suffer of recurrence or poor prognosis solid 
tumours, these rates support the efficacy of conditioning regimens based on thiotepa.  
Overall Survival (OS): OS ranged from 17% to 84% with a follow-up ranging from 12.3 up to 99.6 
months.  
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 0% to 26.7% have been reported. TRM values ranged from 0% to 18% confirming the safety of 
the conditioning treatments including thiotepa for autologous HPCT in paediatric patients with solid 
tumours. 
 
Allogeneic HPCT 
Haematological diseases 
Engraftment:  It has been achieved with all evaluated conditioning regimens including thiotepa with a 
success rate of 96% - 100%. The haematological recovery is in the expected time.  
Disease Free Survival (DFS): Percentages of 40% - 75% with follow-up of more than 1 year have 
been reported. DFS results confirm that conditioning treatment containing thiotepa following 
allogeneic HPCT are effective therapeutic strategies for treating paediatric patients with 
haematological diseases.  
Relapse: In all the reported conditioning regimens containing thiotepa, the relapse rate was in the 
range of 15% - 44%. These data support the efficacy of conditioning regimens based on thiotepa in all 
haematological diseases. 
Overall Survival (OS): OS ranged from 50% to 100% with a follow-up ranging from 9.4 up to 121 
months.  
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging 
from 0% to 2.5% have been reported. TRM values ranged from 0% to 30% confirming the safety of 
the conditioning treatment including thiotepa for allogeneic HPCT in paediatric patients with 
haematological diseases. 
 
5.2 Pharmacokinetic properties  
 
Absorption 
Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa from 
being administered orally.  
 
Distribution 
Thiotepa is a highly lipophilic compound. After intravenous administration, plasma concentrations of 
the active substance fit a two compartment model with a rapid distribution phase. The volume of 
distribution of thiotepa is large and it has been reported as ranging from 40.8 l/m2 to 75 l/m2, 
indicating distribution to total body water. The apparent volume of distribution of thiotepa appears 
independent of the administered dose. The fraction unbound to proteins in plasma is 70-90%; 
insignificant binding of thiotepa to gamma globulin and minimal albumin binding (10-30%) has been 
reported. 
After intravenous administration, CSF medicinal product exposure is nearly equivalent to that 
achieved in plasma; the mean ratio of AUC in CSF to plasma for thiotepa is 0.93. CSF and plasma 
concentrations of TEPA, the first reported active metabolite of thiotepa, exceed the concentrations of 
the parent compound. 
 



33 
 

Biotransformation 
Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected in 
urine within 1 hour after infusion. The metabolites are active alkylating agents but the role they play 
in the antitumor activity of thiotepa remains to be elucidated. Thiotepa undergoes oxidative 
desulphuration via the cytochrome P450 CYP2B and CYP3A isoenzyme families to the major and 
active metabolite TEPA (triethylenephosphoramide). The total excreted amount of thiotepa and its 
identified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence of 
other alkylating metabolites. During conversion of GSH conjugates to N-acetylcysteine conjugates, 
GSH, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not found in urine, 
and, if formed, are probably excreted in bile or as intermediate metabolites rapidly converted into 
thiotepa-mercapturate. 
 
Elimination 
The total clearance of thiotepa ranged from 11.4 to 23.2 l/h/m2. The elimination half-life varied from 
1.5 to 4.1 hours. The identified metabolites TEPA, monochlorotepa and thiotepa-mercapturate are all 
excreted in the urine. Urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hours 
respectively. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchanged 
medicinal product and monochlorotepa, and 11% for TEPA and thiotepa-mercapturate. 
 
Linearity /non linearity 
There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.  
 
Special populations 
 
Paediatric population 
The pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appear 
to vary from those reported in children receiving 75 mg/m2 or adults receiving similar doses. 
 
Renal impairment 
The effects of renal impairment on thiotepa elimination have not been assessed. 
 
Hepatic impairment 
The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed. 
 
5.3 Preclinical safety data 
 
No conventional acute and repeat dose toxicity studies were performed. 
Thiotepa was shown to be genotoxic in vitro and in vivo, and carcinogenic in mice and rats. 
Thiotepa was shown to impair fertility and interfere with spermatogenesis in male mice, and to impair 
ovarian function in female mice. It was teratogenic in mice and in rats, and foeto-lethal in rabbits. 
These effects were seen at doses lower than those used in humans. 
 
   
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
None. 
 
6.2 Incompatibilities 
 
TEPADINA is unstable in acid medium. 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 



34 
 

6.3 Shelf life 
 
Unopened vial 
18 months. 
 
After reconstitution 
Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours when 
stored at 2°C-8°C. 
 
After dilution 
Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored 
at 2°C -8°C and for 4 hours when stored at 25°C. 
 
From a microbiological point of view, the product should be used immediately after dilution. If not 
used immediately, in-use storage times and conditions prior to use are the responsibility of the user 
and would normally not be longer than the above mentioned conditions when dilution has taken place 
in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
Unopened vial 
Store and transport refrigerated (2°C – 8°C). 
Do not freeze.  
 
After reconstitution and dilution 
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I clear glass vial with a rubber stopper (bromobutyl or buthyl), containing 100 mg thiotepa.  
Pack size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Preparation of TEPADINA 
Procedures for proper handling and disposal of anticancer medicinal products must be considered. All 
transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical 
laminar flow safety hood. 
As with other cytotoxic compounds, caution needs to be exercised in handling and preparation of 
TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactions 
associated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommended 
in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, the skin must 
be immediately and thoroughly washed with soap and water. If thiotepa accidentally contacts mucous 
membranes, they must be flushed thoroughly with water. 
 
Reconstitution 
TEPADINA must be reconstituted with 10 ml of sterile water for injection. 
Using a syringe fitted with a needle, aseptically withdraw 10 ml of sterile water for injection. 
Inject the content of the syringe into the vial through the rubber stopper. 
Remove the syringe and the needle and mix manually by repeated inversions. 
Only colourless solutions, without any particulate matter, must be used. Reconstituted solutions may 
occasionally show opalescence; such solutions can still be administered. 
 



35 
 

Further dilution in the infusion bag 
The reconstituted solution is hypotonic and must be further diluted prior to administration with 500 ml 
sodium chloride 9 mg/ml (0.9%) solution for injection (1000 ml if the dose is higher than 500 mg) or 
with an appropriate volume of sodium chloride 9 mg/ml (0.9%) in order to obtain a final TEPADINA 
concentration between 0.5 and 1 mg/ml. 
 
Administration  
TEPADINA infusion solution should be inspected visually for particulate matter prior to 
administration. Solutions containing a precipitate should be discarded. 
Prior to and following each infusion, the indwelling catheter line should be flushed with 
approximately 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection. 
The infusion solution must be administered to patients using an infusion set equipped with a 0.2 µm 
in-line filter. Filtering does not alter solution potency. 
 
Disposal 
TEPADINA is for single use only.  
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ADIENNE S.r.l. S.U. 
Via Galileo Galilei, 19 
20867 Caponago (MB) Italy 
Tel: +39-02 40700445 
adienne@adienne.com  
 
 
8. MARKETING AUTHORISATION  NUMBER 
 
EU/1/10/622/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 March 2010 
Date of latest renewal: 15 March 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



36 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT   

 



37 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
RIEMSER Pharma GmbH 
Bahnhofstraße 44b 
D-17489 Greifswald  
Germany 
 
ADIENNE S.r.l. S.U.  
Via Galileo Galilei, 19  
20867 Caponago (MB) Italy  
 

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 

 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in  the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
 
 



38 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



39 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



40 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TEPADINA 15 mg powder for concentrate for solution for infusion 
Thiotepa 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 15 mg thiotepa. After reconstitution with 1.5 ml of water for injection, each ml 
contains 10 mg thiotepa. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use, after reconstitution and dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
 
 
8. EXPIRY DATE 
 
EXP 
After reconstitution, use within 8 hours when stored in a refrigerator. 
After dilution, use within 24 hours when stored in a refrigerator. 
 
 
 9. SPECIAL STORAGE CONDITIONS 
 
Store and transport refrigerated (2°C-8°C). Do not freeze. 
 
 



41 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ADIENNE S.r.l. S.U. 
Via Galileo Galilei, 19 
20867 Caponago (MB) Italy 
adienne@adienne.com 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/622/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TEPADINA 15 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  
 
 



42 
 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
TEPADINA 15 mg powder for concentrate for solution for infusion 
Thiotepa 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
15 mg  
 
 
6. OTHER 
 
ADIENNE S.r.l. S.U. 



43 
 

 PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TEPADINA 100 mg powder for concentrate for solution for infusion 
Thiotepa 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 100 mg thiotepa. After reconstitution with 10 ml of water for injection, each ml 
contains 10 mg thiotepa. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use, after reconstitution and dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
 
 
8. EXPIRY DATE 
 
EXP 
After reconstitution, use within 8 hours when stored in a refrigerator. 
After dilution, use within 24 hours when stored in a refrigerator. 
 
 
 9. SPECIAL STORAGE CONDITIONS 
 
Store and transport refrigerated (2°C-8°C). Do not freeze. 
 
 



44 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ADIENNE S.r.l. S.U. 
Via Galileo Galilei, 19 
20867 Caponago (MB) Italy 
adienne@adienne.com 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/622/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TEPADINA 100 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number}] 
SN: {number}  
NN: {number} [ 
 



45 
 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
TEPADINA 100 mg powder for concentrate for solution for infusion 
Thiotepa 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg  
 
 
6. OTHER 
 
ADIENNE S.r.l. S.U. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



46 
 

 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



47 
 

Package leaflet: Information for the user 
 

TEPADINA 15 mg powder for concentrate for solution for infusion 
thiotepa 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 
this leaflet. See section 4. 
 
 
 What is in this leaflet  
 
1. What TEPADINA is and what it is used for 
2. What you need to know before you use TEPADINA 
3. How to use TEPADINA 
4. Possible side effects 
5. How to store TEPADINA 
6. Contents of the pack and other information 
 
 
1. What TEPADINA is and what it is used for 
 
TEPADINA contains the active substance thiotepa, which belongs to a group of medicines called 
alkylating agents. 
 
TEPADINA is used to prepare patients for bone marrow transplantation. It works by destroying bone 
marrow cells. This enables the transplantation of new bone marrow cells (haematopoietic progenitor 
cells), which in turn enable the body to produce healthy blood cells. 
TEPADINA can be used in adults and children and adolescents. 
 
 
2. What you need to know before you use TEPADINA 
 
Do not use TEPADINA 
- if you are allergic to thiotepa, 
- if you are pregnant or think you may be pregnant, 
- if you are breast-feeding, 
- if you are receiving yellow fever vaccination, live virus and bacterial vaccines. 
 
Warning and precautions 
You should tell your doctor if you have: 
- liver or kidney problems, 
- heart or lung problems, 
- seizures/fits (epilepsy) or have had them in the past (if treated with phenytoin or fosphenytoin). 
 
Because TEPADINA destroys bone marrow cells responsible for producing blood cells, regular blood 
tests will be taken during treatment to check your blood cell counts. 
  
In order to prevent and manage infections, you will be given anti-infectives. 
 
TEPADINA may cause another type of cancer in the future. Your doctor will discuss this risk with 
you. 
 



48 
 

Other medicines and TEPADINA 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy, breast-feeding and fertility 
You must tell your doctor if you are pregnant or you think you may be pregnant before you receive 
TEPADINA. You must not use TEPADINA during pregnancy. 
 
Both women and men using TEPADINA must use effective contraceptive methods during treatment. 
 
It is not known whether this medicinal product is excreted in breast milk. As a precautionary measure, 
women must not breast-feed during treatment with TEPADINA. 
 
TEPADINA can impair male and female fertility. Male patients should seek for sperm preservation 
before therapy is started and should not father a child while treated and during the year after cessation 
of treatment. 
 
Driving and using machines 
It is likely that certain adverse reactions of thiotepa like dizziness, headache and blurred vision could 
affect your ability to drive and use machines. 
 
 
3. How to use TEPADINA 
 
Your doctor will calculate the dose according to your body surface or weight and your disease. 
 
How TEPADINA is given 
TEPADINA is administered by a qualified healthcare professional as an intravenous infusion (drip in a 
vein) after dilution of the individual vial. Each infusion will last 2-4 hours. 
 
Frequency of administration 
You will receive your infusions every 12 or 24 hours. The duration of treatment can last up to 5 days. 
Frequency of administration and duration of treatment depend on your disease. 
 
 
4. Possible side effects  
 
Like all medicines, TEPADINA can cause side effects, although not everybody gets them. 
 
The most serious side effects of TEPADINA therapy or the transplant procedure may include 
- decrease in circulating blood cell counts (intended effect of the medicine to prepare you for your 
transplant infusion) 
- infection 
- liver disorders including blocking of a liver vein 
- the graft attacks your body (graft versus host disease) 
- respiratory complications 
Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these 
events. 
 
Side effects of TEPADINA may occur with certain frequencies, which are defined as follows:   
 



49 
 

Very common side effects (may affect more than 1 in 10 people)  
- increased susceptibility to infection 
- whole-body inflammatory state (sepsis) 
- decreased counts of white blood cells, platelets and red blood cells (anaemia) 
- the transplanted cells attack your body (graft versus host disease) 
- dizziness, headache, blurred vision 
- uncontrolled shaking of the body (convulsion) 
- sensation of tingling, pricking or numbness (paraesthesia) 
- partial loss of movement 
- cardiac arrest 
- nausea, vomiting, diarrhoea 
- inflammation of the mucosa of the mouth (mucositis)  
- irritated stomach, gullet, intestine 
- inflammation of the colon 
- anorexia, decreased appetite 
- high glucose in the blood 
- skin rash, itching, shedding 
- skin colour disorder (do not confuse with jaundice - see below) 
- redness of the skin (erythema) 
- hair loss 
- back and abdominal pain, pain  
- muscle and joint pain  
- abnormal electrical activity in the heart (arrhythmia) 
- inflammation of lung tissue 
- enlarged liver 
- altered organ function 
- blocking of a liver vein (Veno-Occlusive Disease, VOD) 
- yellowing of the skin and eyes (jaundice) 
- hearing impaired 
- lymphatic obstruction 
-  high blood pressure 
- increased liver, renal and digestive enzymes  
- abnormal blood electrolytes 
- weight gain 
- fever, general weakness, chills  
- bleeding (haemorrhage) 
- nasal bleeding 
- general swelling due to fluid retention (oedema)  
- pain or inflammation at the injection site 
-  eye infection (conjunctivitis) 
- decreased sperm cell count 
- vaginal bleeding 
- absence of menstrual periods (amenorrhea) 
- memory loss 
- delaying in weight and height increase 
- bladder disfunction 
- underproduction of testosterone 
- insufficient production of thyroid hormone 
- deficient activity of the pituitary gland 
- confusional state 
 



50 
 

Common side effects (may affect up to 1 in 10 people) 
- anxiety, confusion  
- abnormal bulging outward of one of the arteries in the brain (intracranial aneurysm) 
- creatinine elevated  
- allergic reactions 
- occlusion of a blood vessel (embolism) 
- heart rhythm disorder 
- heart inability 
- cardiovascular inability 
- oxygen deficiency 
- fluid accumulation in the lungs (pulmonary oedema) 
- pulmonary bleeding 
- respiratory arrest 
- blood in the urine (haematuria) and moderate renal insufficiency 
- inflammation of the urinary bladder 
- discomfort in urination and decrease in urine output (disuria and oliguria) 
- increase in the amount of nitrogen components in the blood stream (BUN increase) 
- cataract  
- inability of the liver 
- cerebral haemorrhage 
- cough 
- constipation and upset stomach 
- obstruction of the bowel 
- perforation of stomach 
- changes in muscle tone 
- gross lack of coordination of muscle movements 
- bruises due to a low platelet count 
- menopausal symptoms 
- cancer (second primary malignancies) 
- abnormal brain function 
- male and female infertility 
 
Uncommon side effects (may affect up to 1 in 100 people) 
- inflammation and exfoliation of the skin (erythrodermic psoriasis) 
- delirium, nervousness, hallucination, agitation  
- gastrointestinal ulcer 
- inflammation of the muscular tissue of the heart (myocarditis) 
- abnormal heart condition (cardiomyopathy) 
 
Not known: frequency cannot be estimated from the available data 
- increased blood pressure in the arteries (blood vessels) of the lungs (pulmonary arterial 
hypertension) 
- severe skin damage (e.g. severe lesions, bullae, etc.) potentially involving the full body surface 
which can be even life-threatening 
- damage to a component of the brain (the so called white matter) which can be even life-
threatening (leukoencephalopathy). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store  TEPADINA 
 
Keep out of the sight and reach of children. 



51 
 

 
Do not use TEPADINA after the expiry date which is stated on the carton and vial label, after EXP. 
The expiry date refers to the last day of that month. 
 
Store and transport refrigerated (2°C-8°C). 
Do not freeze. 
 
After reconstitution the product is stable for 8 hours when stored at 2°C -8°C. 
 
After dilution the product is stable for 24 hours when stored at 2°C -8°C and for 4 hours when stored 
at 25°C. From a microbiological point of view, the product should be used immediately. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
6. Contents of the pack and other information 
 
What TEPADINA contains 
- The active substance is thiotepa. One vial contains 15 mg thiotepa. After reconstitution, each ml 
contains 10 mg thiotepa (10 mg/ml).  
- TEPADINA does not contain any other ingredients. 
 
What TEPADINA looks like and contents of the pack 
TEPADINA is a white crystalline powder supplied in a glass vial containing 15 mg thiotepa. 
Each carton contains 1 vial. 
 
Marketing Authorisation Holder 
ADIENNE S.r.l. S.U. 
Via Galileo Galilei, 19 
20867 Caponago (MB) Italy 
Tel: +39 02 40700445  
adienne@adienne.com 
 
Manufacturer 
RIEMSER Pharma GmbH  
Bahnhofstraße 44b 
17489 Greifswald  
Germany 
 
Marketing Authorisation Holder and Manufacturer  
ADIENNE S.r.l. S.U.  
Via Galileo Galilei, 19  
20867 Caponago (MB) Italy  
Tel: +39 02 40700445  
adienne@adienne.com 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Accord Healthcare bvba 
Tèl/Tel: +32 51 79 40 12 

Lietuva 
Accord Healthcare AB 
Tel: +46 8 624 00 25 
 

България 
Accord Healthcare Polska Sp. z o.o. 
Teл.: +48 22 577 28 00 

Luxembourg/Luxemburg 
Accord Healthcare bvba 
Tèl/Tel: +32 51 79 40 12 
 



52 
 

 
Česká republika 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

Magyarország 
Accord Healthcare Polska Sp. z o.o. 
Tel.: +48 22 577 28 00 

Danmark 
Immedica Pharma AB 
Tlf: +46 (0)8 533 39 500 
 

Malta 
Accord Healthcare Ireland Ltd 
Tel: +44 (0) 208 901 3370 
 

Deutschland 
Accord Healthcare GmbH 
Tel: +49 89 700 9951 0 

Nederland 
Accord Healthcare B.V. 
Tel: +31 30 850 6014 
 

Eesti 
Accord Healthcare AB 
Tel: +46 8 624 00 25 

Norge 
Immedica Pharma AB 
Tlf: +46 (0)8 533 39 500 
 

Ελλάδα 
aVIPHARMA International S.A. 
Τηλ: +30-210 6194 170 
  

Österreich 
Accord Healthcare GmbH 
Tel: +43 (0)662 424899-0 
 

España 
Accord Healthcare S.L.U. 
Tel: +34 93 301 00 64 

Polska 
Accord Healthcare Polska Sp. z o.o. 
Tel.: +48 22 577 28 00 
  

France 
Accord Healthcare France SAS 
Tel: +33 (0)320 401 770 

Portugal 
Accord Healthcare, Unipessoal Lda 
Tel: +351 214 697 835 
 

Hrvatska  
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

România 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 
 

Ireland 
Accord Healthcare Ireland Ltd 
Tel: +44 (0)1271 385257 
 

Slovenija 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

Ísland 
Immedica Pharma AB 
Sími: +46 (0)8 533 39 500 
 

Slovenská republika 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

Italia 
Accord Healthcare Italia Srl 
Tel: +39 02 943 23 700 

Suomi/Finland 
Immedica Pharma AB 
Puh/Tel: +46 (0)8 533 39 500 

 
Κύπρος 
aVIPHARMA International S.A. 
Τηλ: +30-210 6194 170 
 

 
Sverige 
Immedica Pharma AB 
Tel: +46 (0)8 533 39 500 
 

Latvija 
Accord Healthcare AB 
Tel: +46 8 624 00 25  

United Kingdom 
Accord-UK Ltd 
Tel: +44 (0)1271 385257 
 

 
This leaflet was last revised in  
 
 



53 
 

 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 
The following information is intended for healthcare professionals only. 
 
 
PREPARATION GUIDE 
 
TEPADINA 15 mg powder for concentrate for solution for infusion 
Thiotepa 
 
Read this guide prior to the preparation and administration of TEPADINA.  
   
 
1. PRESENTATION 
 
TEPADINA is supplied as 15 mg powder for concentrate for solution for infusion.  
TEPADINA must be reconstituted and diluted prior to administration. 
 
 
2. SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING 
 
General 
Procedures for proper handling and disposal of anticancer medicinal products should be considered. 
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical 
laminar flow safety hood. 
As with other cytotoxic compounds, caution need to be exercised in handling and preparation of 
TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactions 
associated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommended 
in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, immediately 
the skin must be thoroughly washed with soap and water. If thiotepa accidentally contacts mucous 
membranes, they must be flushed thoroughly with water. 
 
Calculation of dose of TEPADINA 
TEPADINA is administered at different doses in combination with other chemotherapeutic medicinal 
products in patients prior to conventional haematopoietic progenitor cell transplantation (HPCT) for 
haematological diseases or solid tumours.  
TEPADINA posology is reported, in adult and paediatric patients, according to the type of HPCT 
(autologous or allogeneic) and disease. 
 
Posology in adults 
 
AUTOLOGOUS HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases 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 from 2 up to 4 consecutive 
days before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during 
the time of the entire conditioning treatment.  
 
LYMPHOMA 
The recommended dose ranges from 125 mg/m2/day (3.38 mg/kg/day) to 300 mg/m2/day  



54 
 

(8.10 mg/kg/day) as a single daily infusion, administered from 2 up to 4 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during the time 
of the entire conditioning treatment.  
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 before autologous HPCT, without exceeding the total maximum cumulative dose of 
370 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
Solid tumours 
 
The recommended dose in solid tumours ranges from 120 mg/m2/day (3.24 mg/kg/day) to  
250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from 2 up to 5 
consecutive days before autologous HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 
mg/kg), during the time of the entire conditioning treatment.  
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 from 3 up to 5 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 mg/kg), during the time 
of the entire conditioning treatment.  
CNS TUMOURS 
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 in one or two daily infusions, administered from 3 up to 4 consecutive days 
before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during 
the time of the entire conditioning treatment.  
OVARIAN CANCER 
The recommended dose is 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered in 
2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose 
of 500 mg/m2 (13.51 mg/kg), during the time of the entire conditioning treatment.  
GERM CELL TUMOURS 
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 185 mg/m2/day (5 mg/kg/day) to  
481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  
LYMPHOMA 
The recommended dose in lymphoma is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  



55 
 

(10 mg/kg), during the time of the entire conditioning treatment.  
MULTIPLE MYELOMA 
The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before allogeneic 
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m2 (5 mg/kg), during the 
time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day  
(13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 2 consecutive days 
before allogeneic HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), during the 
time of the entire conditioning treatment.  
THALASSEMIA 
The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment. 
 
Posology in paediatric patients 
 
AUTOLOGOUS HPCT 
 
Solid tumours 
 
The recommended dose in solid tumours 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 from 2 up to 3 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of 
the entire conditioning treatment.  
CNS TUMOURS 
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 before autologous HPCT 
depending on the combination with other chemotherapeutic medicinal products, without exceeding the 
total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of the entire conditioning 
treatment. 
 
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to  
250 mg/m2/day (10 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 375 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2 (10 
mg/kg), during the time of the entire conditioning treatment.  
THALASSEMIA 
The recommended dose ranges from 200 mg/m2/day (8 mg/kg/day) to 250 mg/m2/day (10 mg/kg/day) 
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total 
maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning 
treatment.  
REFRACTORY CYTOPENIA 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 3 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 
375 mg/m2 (15 mg/kg), during the time of the entire conditioning treatment.  



56 
 

GENETIC DISEASES 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 
250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
SICKLE CELL ANAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
 
Reconstitution 
TEPADINA must be reconstituted with 1.5 ml of sterile water for injections. 
Using a syringe fitted with a needle, aseptically withdraw 1.5 ml of sterile water for injections. 
Inject the content of the syringe into the vial through the rubber stopper. 
Remove the syringe and the needle and mix manually by repeated inversions. 
Only colourless solutions, without any particulate matter, must be used. Reconstituted solutions may 
occasionally show opalescence; such solutions can still be administered. 
 
Further dilution in the infusion bag 
The reconstituted solution is hypotonic and must be further diluted prior to administration with 500 ml 
sodium chloride 9 mg/ml (0.9%) solution for injection (1000 ml if the dose is higher than 500 mg) or 
with an appropriate volume of sodium chloride 9 mg/ml (0.9%) in order to obtain a final TEPADINA 
concentration between 0.5 and 1 mg/ml.  
 
Administration  
TEPADINA infusion solution should be inspected visually for particulate matter prior to 
administration. Solutions containing a precipitate should be discarded. 
 
The infusion solution must be administered to patients using an infusion set equipped with a 0.2 µm 
in-line filter. Filtering does not alter solution potency. 
 
TEPADINA should be aseptically administered as a 2-4 hours infusion under room temperature (about 
25°C) and normal light conditions. 
  
Prior to and following each infusion, the indwelling catheter line should be flushed with 
approximately 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection. 
 
Disposal 
TEPADINA is for single use only.  
Any unused product or waste material should be disposed of in accordance with local requirements



57 
 

Package leaflet: Information for the user 
 

TEPADINA 100 mg powder for concentrate for solution for infusion 
thiotepa 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 
this leaflet. See section 4. 
 
 
What is in this leaflet:  
 
1. What TEPADINA is and what it is used for 
2. What you need to know before you use TEPADINA 
3. How to use TEPADINA 
4. Possible side effects 
5. How to store TEPADINA 
6. Contents of the pack and other information 
 
 
1. What TEPADINA  is and what it is used for 
 
TEPADINA contains the active substance thiotepa, which belongs to a group of medicines called 
alkylating agents. 
 
TEPADINA is used to prepare patients for bone marrow transplantation. It works by destroying bone 
marrow cells. This enables the transplantation of new bone marrow cells (haematopoietic progenitor 
cells), which in turn enable the body to produce healthy blood cells. 
TEPADINA can be used in adults and children and adolescents. 
 
 
2. What you need to know before you use  TEPADINA 
 
Do not use TEPADINA 
- if you are allergic to thiotepa, 
- if you are pregnant or think you may be pregnant,  
- if you are breast-feeding, 
- if you are receiving yellow fever vaccination, live virus and bacterial vaccines. 
 
Warning and precautions  
You should tell your doctor if you have: 
- liver or kidney problems, 
- heart or lung problems, 
-  seizures/fits (epilepsy) or have had them in the past (if treated with phenytoin or fosphenytoin). 
 
 
Because TEPADINA destroys bone marrow cells responsible for producing blood cells, regular blood 
tests will be taken during treatment to check your blood cell counts. 
 
In order to prevent and manage infections, you will be given anti-infectives. 
 
TEPADINA may cause another type of cancer in the future. Your doctor will discuss this risk with 
you. 



58 
 

 
Other medicines and TEPADINA 
Tell your doctor if you are taking, have recently taken or might take any other medicines  
 
Pregnancy, breast-feeding and fertility 
You must tell your doctor if you are pregnant or you think you may be pregnant before you receive 
TEPADINA. You must not use TEPADINA during pregnancy. 
 
Both women and men using TEPADINA must use effective contraceptive methods during treatment. 
 
It is not known whether this medicinal product is excreted in breast milk. As a precautionary measure, 
women must not breast-feed during treatment with TEPADINA. 
 
TEPADINA can impair male and female fertility. Male patients should seek for sperm preservation 
before therapy is started and should not father a child while treated and during the year after cessation 
of treatment. 
 
Driving and using machines 
It is likely that certain adverse events of thiotepa like dizziness, headache and blurred vision could 
affect your ability to drive and use machines. 
 
 
3. How to use TEPADINA 
 
Your doctor will calculate the dose according to your body surface or weight and your disease. 
 
How TEPADINA is given 
TEPADINA is administered by a qualified healthcare professional as an intravenous infusion (drip in a 
vein) after dilution of the individual vial. Each infusion will last 2-4 hours. 
 
Frequency of administration 
You will receive your infusions every 12 or 24 hours. The duration of treatment can last up to 5 days. 
Frequency of administration and duration of treatment depend on your disease. 
 
 
4. Possible side effects  
 
Like all medicines, TEPADINA can cause side effects, although not everybody gets them. 
 
The most serious side effects of TEPADINA therapy or the transplant procedure may include 
-       decrease in circulating blood cell counts (intended effect of the medicine to prepare you for your 
         transplant infusion) 
-       infection 
-       liver disorders including blocking of a liver vein 
-       the graft attacks your body (graft versus host disease) 
-       respiratory complications 
Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these 
events. 
 
Side effects of TEPADINA may occur with certain frequencies, which are defined as follows:   
 



59 
 

Very common side effects (may affect more than 1 in 10 people) 
-       increased susceptibility to infection 
-       whole-body inflammatory state (sepsis) 
-       decreased counts of white blood cells, platelets and red blood cells (anaemia) 
-       the transplanted cells attack your body (graft versus host disease) 
-       dizziness, headache, blurred vision 
-       uncontrolled shaking of the body (convulsion) 
-       sensation of tingling, pricking or numbness (paraesthesia) 
-       partial loss of movement 
-       cardiac arrest 
-       nausea, vomiting, diarrhoea 
-       inflammation of the mucosa of the mouth (mucositis)  
-       irritated stomach, gullet, intestine 
-       inflammation of the colon 
-       anorexia, decreased appetite 
-       high glucose in the blood 
-       skin rash, itching, shedding 
-       skin colour disorder (do not confuse with jaundice - see below) 
-       redness of the skin (erythema) 
-       hair loss 
-       back and abdominal pain, pain  
-       muscle and joint pain  
-       abnormal electrical activity in the heart (arrhythmia) 
-       inflammation of lung tissue 
-       enlarged liver 
-       altered organ function 
-       blocking of a liver vein (Veno-Occlusive Disease, VOD) 
-       yellowing of the skin and eyes (jaundice) 
-       hearing impaired 
-       lymphatic obstruction 
-       high blood pressure 
-       increased liver, renal and digestive enzymes  
-       abnormal blood electrolytes 
-       weight gain 
-       fever, general weakness, chills  
-       bleeding (haemorrhage) 
-       nasal bleeding 
-       general swelling due to fluid retention (oedema)  
-       pain or inflammation at the injection site 
-       eye infection (conjunctivitis) 
-       decreased sperm cell count 
-       vaginal bleeding 
-       absence of menstrual periods (amenorrhea) 
-       memory loss 
-       delaying in weight and height increase 
-       bladder disfunction 
-       underproduction of testosterone 
-       insufficient production of thyroid hormone 
-       deficient activity of the pituitary gland 
-       confusional state 
 



60 
 

Common side effects (may affect up to 1 in 10 people) 
-       anxiety, confusion  
-       abnormal bulging outward of one of the arteries in the brain (intracranial aneurysm) 
-       creatinine elevated  
-       allergic reactions 
-       occlusion of a blood vessel (embolism) 
-       heart rhythm disorder 
-       heart inability 
-       cardiovascular inability 
-       oxygen deficiency 
-       fluid accumulation in the lungs (pulmonary oedema) 
-       pulmonary bleeding 
-       respiratory arrest 
-       blood in the urine (haematuria) and moderate renal insufficiency 
-       inflammation of the urinary bladder 
-       discomfort in urination and decrease in urine output (disuria and oliguria) 
-       increase in the amount of nitrogen components in the blood stream (BUN increase) 
-       cataract  
-       inability of the liver 
-       cerebral haemorrhage 
-       cough 
-       constipation and upset stomach 
-       obstruction of the bowel 
-       perforation of stomach 
-       changes in muscle tone 
-       gross lack of coordination of muscle movements 
-       bruises due to a low platelet count 
-       menopausal symptoms 
-       cancer (second primary malignancies) 
-       abnormal brain function 
-       male and female infertility 
 
Uncommon side effects  (may affect up to 1 in 100 people) 
-       inflammation and exfoliation of the skin (erythrodermic psoriasis) 
-       delirium, nervousness, hallucination, agitation  
-       gastrointestinal ulcer 
-       inflammation of the muscular tissue of the heart (myocarditis) 
-       abnormal heart condition (cardiomyopathy) 
 
Not known: frequency cannot be estimated from the available data 
-       increased blood pressure in the arteries (blood vessels) of the lungs (pulmonary arterial 
hypertension) 
-      severe skin damage (e.g. severe lesions, bullae, etc.) potentially involving the full body surface 
which can be even life-threatening 
- damage to a component of the brain (the so called white matter) which can be even life-
threatening (leukoencephalopathy). 
 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via  the national reporting system listed 
in Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 



61 
 

5. How to store TEPADINA 
 
Keep out of the sight and reach  of children. 
 
Do not use TEPADINA after the expiry date which is stated on the carton and vial label, after EXP. 
The expiry date refers to the last day of that month. 
 
Store and transport refrigerated (2°C-8°C). 
Do not freeze. 
 
After reconstitution the product is stable for 8 hours when stored at 2°C -8°C. 
 
After dilution the product is stable for 24 hours when stored at 2°C -8°C and for 4 hours when stored 
at 25°C. From a microbiological point of view, the product should be used immediately. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
6. Contents of the pack and other information 
 
What TEPADINA contains 
- The active substance is thiotepa. One vial contains 100 mg thiotepa. After reconstitution, each ml 
contains 10 mg thiotepa (10 mg/ml).  
- TEPADINA does not contain any other ingredients. 
 
What TEPADINA looks like and contents of the pack 
TEPADINA is a white crystalline powder supplied in a glass vial containing 100 mg thiotepa. 
Each carton contains 1 vial. 
 
Marketing Authorisation Holder 
ADIENNE S.r.l. S.U. 
Via Galileo Galilei, 19 
20867 Caponago (MB) Italy 
Tel: +39 02 40700445 
adienne@adienne.com 
 
Manufacturer 
RIEMSER Pharma GmbH 
Bahnhofstraße 44b 
17489 Greifswald  
Germany 
 
Marketing Authorisation Holder and Manufacturer  
ADIENNE S.r.l. S.U.  
Via Galileo Galilei, 19  
20867 Caponago (MB) Italy  
Tel: +39 02 40700445  
adienne@adienne.com 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Accord Healthcare bvba 
Tèl/Tel: +32 51 79 40 12 

Lietuva 
Accord Healthcare AB 
Tel: +46 8 624 00 25 
 
 



62 
 

България 
Accord Healthcare Polska Sp. z o.o. 
Teл.: +48 22 577 28 00 

Luxembourg/Luxemburg 
Accord Healthcare bvba 
Tèl/Tel: +32 51 79 40 12 

 
Česká republika 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

 
Magyarország 
Accord Healthcare Polska Sp. z o.o. 
Tel.: +48 22 577 28 00 

Danmark 
Immedica Pharma AB 
Tlf: +46 (0)8 533 39 500 
 

Malta 
Accord Healthcare Ireland Ltd 
Tel: +44 (0) 208 901 3370 
 

Deutschland 
Accord Healthcare GmbH 
Tel: +49 89 700 9951 0 

Nederland 
Accord Healthcare B.V. 
Tel: +31 30 850 6014 
 

Eesti 
Accord Healthcare AB 
Tel: +46 8 624 00 25 

Norge 
Immedica Pharma AB 
Tlf: +46 (0)8 533 39 500 
 

Ελλάδα 
aVIPHARMA International S.A. 
Τηλ: +30-210 6194 170 
  

Österreich 
Accord Healthcare GmbH 
Tel: +43 (0)662 424899-0 
 

España 
Accord Healthcare S.L.U. 
Tel: +34 93 301 00 64 

Polska 
Accord Healthcare Polska Sp. z o.o. 
Tel.: +48 22 577 28 00 
  

France 
Accord Healthcare France SAS 
Tél: +33 (0)320 401 770 

Portugal 
Accord Healthcare, Unipessoal Lda 
Tel: +351 214 697 835 
 

Hrvatska  
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

România 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 
 

Ireland 
Accord Healthcare Ireland Ltd 
Tel: +44 (0)1271 385257 
 

Slovenija 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

Ísland 
Immedica Pharma AB 
Sími: +46 (0)8 533 39 500 
 

Slovenská republika 
Accord Healthcare Polska Sp. z o.o. 
Tel: +48 22 577 28 00 

Italia 
Accord Healthcare Italia Srl 
Tel: +39 02 943 23 700 

Suomi/Finland 
Immedica Pharma AB 
Puh/Tel: +46 (0)8 533 39 500 

 
Κύπρος 
aVIPHARMA International S.A. 
Τηλ: +30-210 6194 170 
 

 
Sverige 
Immedica Pharma AB 
Tel: +46 (0)8 533 39 500 
 

Latvija 
Accord Healthcare AB 
Tel: +46 8 624 00 25  

United Kingdom 
Accord-UK Ltd 
Tel: +44 (0)1271 385257 
 

This leaflet was last revised in:  



63 
 

 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site:  
http://www.ema.europa.eu. 
 
 
The following information is intended for healthcare professionals only. 
 
 
PREPARATION GUIDE 
 
TEPADINA 100 mg powder for concentrate for solution for infusion 
Thiotepa 
 
Read this guide prior to the preparation and administration of TEPADINA.  
   
 
1. PRESENTATION 
 
TEPADINA is supplied as 100 mg powder for concentrate for solution for infusion.  
TEPADINA must be reconstituted and diluted prior to administration. 
 
 
2. SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING 
 
General 
Procedures for proper handling and disposal of anticancer medicinal products should be considered. 
All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical 
laminar flow safety hood. 
As with other cytotoxic compounds, caution need to be exercised in handling and preparation of 
TEPADINA solutions to avoid accidental contact with skin or mucous membranes. Topical reactions 
associated with accidental exposure to thiotepa may occur. In fact, the use of gloves is recommended 
in preparing the solution for infusion. If thiotepa solution accidentally contacts the skin, immediately 
the skin must be thoroughly washed with soap and water. If thiotepa accidentally contacts mucous 
membranes, they must be flushed thoroughly with water. 
 
Calculation of dose of TEPADINA 
TEPADINA is administered at different doses in combination with other chemotherapeutic medicinal 
products in patients prior to conventional haematopoietic progenitor cell transplantation (HPCT) for 
haematological diseases or solid tumours.  
TEPADINA posology is reported, in adult and paediatric patients, according to the type of HPCT 
(autologous or allogeneic) and disease. 
 
Posology in adults 
 
AUTOLOGOUS HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases 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 from 2 up to 4 consecutive 
days before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during 
the time of the entire conditioning treatment.  
 
LYMPHOMA 



64 
 

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 from 2 up to 4 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 900 mg/m2 (24.32 mg/kg), during the time 
of the entire conditioning treatment.  
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 before autologous HPCT, without exceeding the total maximum cumulative dose of 
370 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
Solid tumours 
 
The recommended dose in solid tumours ranges from 120 mg/m2/day (3.24 mg/kg/day) to  
250 mg/m2/day (6.76 mg/kg/day) divided in one or two daily infusions, administered from 2 up to 5 
consecutive days before autologous HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 
mg/kg), during the time of the entire conditioning treatment.  
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 from 3 up to 5 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 800 mg/m2 (21.62 mg/kg), during the time 
of the entire conditioning treatment.  
CNS TUMOURS 
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 in one or two daily infusions, administered from 3 up to 4 consecutive days 
before autologous HPCT depending on the combination with other chemotherapeutic medicinal 
products, without exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during 
the time of the entire conditioning treatment.  
OVARIAN CANCER 
The recommended dose is 250 mg/m2/day (6.76 mg/kg/day) as a single daily infusion, administered in 
2 consecutive days before autologous HPCT, without exceeding the total maximum cumulative dose 
of 500 mg/m2 (13.51 mg/kg), during the time of the entire conditioning treatment.  
GERM CELL TUMOURS 
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 before autologous 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 750 mg/m2 (20.27 mg/kg), during the time of the 
entire conditioning treatment.  
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 185 mg/m2/day (5 mg/kg/day) to  
481 mg/m2/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  
LYMPHOMA 
The recommended dose in lymphoma is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions 



65 
 

before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
MULTIPLE MYELOMA 
The recommended dose is 185 mg/m2/day (5 mg/kg/day) as a single daily infusion before allogeneic 
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m2 (5 mg/kg), during the 
time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose ranges from 185 mg/m2/day (5 mg/kg/day) to 481 mg/m2/day (13 mg/kg/day) 
divided in one or two daily infusions, administered from 1 up to 2 consecutive days before allogeneic 
HPCT depending on the combination with other chemotherapeutic medicinal products, without 
exceeding the total maximum cumulative dose of 555 mg/m2 (15 mg/kg), during the time of the entire 
conditioning treatment.  
THALASSEMIA 
The recommended dose is 370 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment. 
 
Posology in paediatric patients 
 
AUTOLOGOUS HPCT 
 
Solid tumours 
 
The recommended dose in solid tumours 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 from 2 up to 3 consecutive days before 
autologous HPCT depending on the combination with other chemotherapeutic medicinal products, 
without exceeding the total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of 
the entire conditioning treatment.  
CNS TUMOURS 
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 before autologous HPCT 
depending on the combination with other chemotherapeutic medicinal products, without exceeding the 
total maximum cumulative dose of 1050 mg/m2 (42 mg/kg), during the time of the entire conditioning 
treatment. 
 
ALLOGENEIC HPCT 
 
Haematological diseases 
 
The recommended dose in haematological diseases ranges from 125 mg/m2/day (5 mg/kg/day) to 
 250 mg/m2/day (10 mg/kg/day) divided in one or two daily infusions, administered from 1 up to 3 
consecutive days before allogeneic HPCT depending on the combination with other chemotherapeutic 
medicinal products, without exceeding the total maximum cumulative dose of 375 mg/m2 (15 mg/kg), 
during the time of the entire conditioning treatment.  
LEUKAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
THALASSEMIA 
The recommended dose ranges from 200 mg/m2/day (8 mg/kg/day) to 250 mg/m2/day (10 mg/kg/day) 
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total 
maximum cumulative dose of 250 mg/m2 (10 mg/kg), during the time of the entire conditioning 
treatment.  
REFRACTORY CYTOPENIA 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 3 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of 
375 mg/m2 (15 mg/kg), during the time of the entire conditioning treatment.  



66 
 

GENETIC DISEASES 
The recommended dose is 125 mg/m2/day (5 mg/kg/day) as a single daily infusion, administered for 2 
consecutive days before allogeneic HPCT, without exceeding the total maximum cumulative dose of  
250 mg/m2 (10 mg/kg), during the time of the entire conditioning treatment.  
SICKLE CELL ANAEMIA 
The recommended dose is 250 mg/m2/day (10 mg/kg/day) divided in two daily infusions, administered 
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m2  
(10 mg/kg), during the time of the entire conditioning treatment.  
 
Reconstitution 
TEPADINA must be reconstituted with 10 ml of sterile water for injections. 
Using a syringe fitted with a needle, aseptically withdraw 10 ml of sterile water for injections. 
Inject the content of the syringe into the vial through the rubber stopper. 
Remove the syringe and the needle and mix manually by repeated inversions. 
Only colourless solutions, without any particulate matter, must be used. Reconstituted solutions may 
occasionally show opalescence; such solutions can still be administered. 
 
Further dilution in the infusion bag 
The reconstituted solution is hypotonic and must be further diluted prior to administration with 500 ml 
sodium chloride 9 mg/ml (0.9%) solution for injection (1000 ml if the dose is higher than 500 mg) or 
with an appropriate volume of sodium chloride 9 mg/ml (0.9%) in order to obtain a final TEPADINA 
concentration between 0.5 and 1 mg/ml.  
 
Administration  
TEPADINA infusion solution should be inspected visually for particulate matter prior to 
administration. Solutions containing a precipitate should be discarded. 
 
The infusion solution must be administered to patients using an infusion set equipped with a 0.2 µm 
in-line filter. Filtering does not alter solution potency. 
 
TEPADINA should be aseptically administered as a 2-4 hours infusion under room temperature (about 
25°C) and normal light conditions. 
  
Prior to and following each infusion, the indwelling catheter line should be flushed with 
approximately 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection. 
 
Disposal 
TEPADINA is for single use only.  
Any unused product or waste material should be disposed of in accordance with local requirements. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET