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Product information for human medicinal products  
Bern, 03.12.2024  
TEPADINA® 200 mg / TEPADINA® 400 mg  
Composition  
Active substances  
Thiotepa.  
Excipients  
TEPADINA® 200 mg  
Powder: None  
Solvent: Sodium chloride (corresponds to 709 mg sodium per 200 mL) and Water for injections  
TEPADINA® 400 mg  
Powder: None  
Solvent: Sodium chloride (corresponds to 1 418 mg sodium per 400 mL) and Water for injections  
Pharmaceutical form and active substance quantity per unit  
Powder and solvent for solution for infusion  
White powder.  
TEPADINA® 200 mg:  
one bag contains 200 mg thiotepa.  
TEPADINA® 400 mg:  
one bag contains 400 mg thiotepa.  
After reconstitution with the solvent, each mL of solution contains 1 mg of thiotepa.  
Indications/Uses  
TEPADINA® is indicated, in combination with other chemotherapy medicinal products:  
1) 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;  
2) when high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours  
in adult and paediatric patients.  
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Product information for human medicinal products  
Dosage/Administration  
TEPADINA® administration must be supervised by a physician experienced in conditioning treatment  
prior to haematopoietic progenitor cell transplantation.  
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.  
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  
(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  
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Product information for human medicinal products  
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  
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Product information for human medicinal products  
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  
(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.  
Patients with hepatic disorders  
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  
Warnings and precautions).  
Patients with renal disorders  
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 section Warnings and precautions and  
Pharmacokinetics).  
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Product information for human medicinal products  
Elderly patients  
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.  
Children and adolescents  
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  
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Product information for human medicinal products  
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.  
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.  
Mode of administration  
TEPADINA® is for intravenous use only. It must be administered by a qualified healthcare  
professional as a 2-4 hours intravenous infusion via a central venous catheter.  
The bag must only be removed from the aluminum wrapper immediately before the use.  
TEPADINA® 200 mg  
If necessary, dose adjustment of TEPADINA® must be operated as per specific application.  
In case the calculated dose required is higher than 200 mg but less than a multiple thereof, the user is  
requested to add the required mg from TEPADINA® vials by using a dedicated port of TEPADINA®  
200 mg.  
In case the calculated dose required is lower than 200 mg, the user is requested to remove the  
unnecessary mg of fully reconstituted 1 mg/ml solution or to set an infusion pump with the amount of  
medicinal product to be administered in ml.  
TEPADINA® 400 mg  
If necessary, dose adjustment of TEPADINA® must be operated as per specific application.  
In case the calculated dose required is higher than 400 mg but less than a multiple thereof, the user is  
requested to add the required mg from TEPADINA® vials by using a dedicated port of TEPADINA®  
400 mg.  
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Product information for human medicinal products  
In case the calculated dose required is lower than 400 mg, the user is requested to remove the  
unnecessary mg of fully reconstituted 1 mg/ml solution or to set an infusion pump with the amount of  
medicinal product to be administered in ml.  
For instructions on reconstitution prior to administration, see section Other information - Instructions  
for handling.  
Precautions to be taken before handling or administering the 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  
Other information - Instructions for handling).  
Contraindications  
Hypersensitivity to the active substance.  
Pregnancy and lactation (see section Pregnancy, lactation).  
Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section  
Interactions).  
Warnings and precautions  
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.  
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Product information for human medicinal products  
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 Undesirable effects).  
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 Undesirable effects).  
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 Interactions).  
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 Interactions).  
During the concomitant use of thiotepa and inhibitors of CYP2B6 or CYP3A4, patients should be  
carefully monitored clinically (see section Interactions).  
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 Pregnancy, lactation).  
TEPADINA® 200 mg contains 709 mg (30.8 mmol) sodium per bag, equivalent to 35.5% of the WHO  
recommended maximum daily intake of 2 g sodium for an adult.  
TEPADINA® 400 mg contains 1 418 mg (61.6 mmol) sodium per bag, equivalent to 70.9% of the  
WHO recommended maximum daily intake of 2 g sodium for an adult.  
Interactions  
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  
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Product information for human medicinal products  
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.  
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  
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Product information for human medicinal products  
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.  
Pregnancy, lactation  
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 embryo foetal lethality and teratogenicity (see Preclinical  
data section). Therefore, thiotepa is contraindicated during pregnancy.  
Women of childbearing potential have to use effective contraception during treatment and a  
pregnancy test should be performed before treatment is started.  
Lactation  
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 Warning and  
precautions).  
Effects on ability to drive and use machines  
TEPADINA® has a 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.  
Undesirable effects  
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 6588 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.  
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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.  
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).  
Very common  
(≥10%)  
Common  
(≥1%, <10%)  
Uncommon  
(≥0,1%, <1%)  
System organ  
class  
Not known  
Infections and  
infestations  
Infection  
Toxic shock  
syndrome  
susceptibility  
increased  
Sepsis  
Neoplasms  
benign,  
Treatment related  
second  
malignant and  
unspecified  
(incl cysts and  
polyps)  
malignancy  
Blood and  
lymphatic  
system  
Leukopenia  
Thrombocytopeni  
a
disorders  
Febrile  
neutropenia  
Anaemia  
Pancytopenia  
Granulocytopenia  
Immune  
system  
Acute graft versus Hypersensitivity  
host disease  
disorders  
Chronic graft  
versus host  
disease  
Endocrine  
disorders  
Hypopituitarism  
Metabolism  
and nutrition  
disorders  
Anorexia  
Decreased  
appetite  
Hyperglycaemia  
Confusional state Anxiety  
Mental status  
changes  
Psychiatric  
disorders  
Delirium  
Nervousness  
Hallucination  
Agitation  
Nervous  
system  
disorders  
Dizziness  
Headache  
Vision blurred  
Intracranial  
aneurysm  
Leukoencephalopathy  
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Very common  
(≥10%)  
Common  
(≥1%, <10%)  
Uncommon  
(≥0,1%, <1%)  
System organ  
class  
Not known  
Encephalopathy  
Convulsion  
Extrapyramidal  
disorder  
Paraesthesia  
Cognitive disorder  
Cerebral  
haemorrhage  
Eye disorders  
Ear and  
labyrinth  
Conjunctivitis  
Hearing impaired  
Ototoxicity  
Cataract  
disorders  
Tinnitus  
Cardiac  
disorders  
Arrhythmia  
Tachycardia  
Cardiac failure  
Cardiomyopat  
hy  
Myocarditis  
Vascular  
disorders  
Respiratory,  
thoracic and  
mediastinal  
disorders  
Lymphoedema  
Hypertension  
Idiopathic  
pneumonia  
syndrome  
Haemorrhage  
Embolism  
Pulmonary  
oedema  
Hypoxia  
Cough  
Epistaxis  
Pneumonitis  
Constipation  
Gastrointestinal  
perforation  
Ileus  
Gastrointestina Nausea  
l disorders  
Gastrointestin  
al ulcer  
Stomatitis  
Oesophagitis  
Vomiting  
Diarrhoea  
Dyspepsia  
Abdominal pain  
Enteritis  
Colitis  
Hepatobiliary  
disorders  
Venoocclusive  
liver disease  
Hepatomegaly  
Jaundice  
Skin and  
subcutaneous  
tissue  
Rash  
Pruritus  
Alopecia  
Erythema  
Pigmentation  
disorder  
Erythrodermic cases of Stevens-  
Severe toxic skin  
reactions including  
disorders  
psoriasis  
Johnson syndrome  
and toxic epidermal  
necrolysis  
Musculoskeleta Back pain  
l and  
Myalgia  
connective  
tissue  
Arthralgia  
disorders  
Renal and  
urinary  
Cystitis  
haemorrhagic  
Dysuria  
Oliguria  
disorders  
Renal failure  
Cystitis  
Haematuria  
Menopausal  
symptoms  
Infertility female  
Infertility male  
Multi-organ failure  
Pain  
Reproductive  
system and  
breast  
disorders  
General  
Azoospermia  
Amenorrhoea  
Vaginal  
haemorrhage  
Pyrexia  
disorders and  
Asthenia  
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Very common  
(≥10%)  
Common  
(≥1%, <10%)  
Uncommon  
(≥0,1%, <1%)  
System organ  
class  
Not known  
administration  
site conditions  
Chills  
Generalised  
oedema  
Injection site  
inflammation  
Injection site pain  
Mucosal  
inflammation  
Investigations  
Weight increased Blood creatinine  
Blood bilirubin  
increased  
Transaminases  
increased  
increased  
Blood urea  
increased  
Gamma-  
Blood amylase  
increased  
glutamyltransferas  
e 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).  
Very common  
(≥10%)  
Infection  
susceptibility  
increased  
Sepsis  
Common  
System organ class  
Not Known  
(≥1%, <10%)  
Thrombocytopenic  
purpura  
Infections and infestations  
Neoplasms benign, malignant  
and unspecified (incl cysts and  
polyps)  
Treatment related  
second  
malignancy  
Blood and lymphatic system  
disorders  
Thrombocytopenia  
Febrile  
neutropenia  
Anaemia  
Pancytopenia  
Granulocytopenia  
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Very common  
(≥10%)  
Common  
(≥1%, <10%)  
System organ class  
Not Known  
Immune system disorders  
Acute graft versus  
host disease  
Chronic graft  
versus host  
disease  
Endocrine disorders  
Hypopituitarism  
Hypogonadism  
Hypothyroidism  
Anorexia  
Hyperglycaemia  
Mental status  
changes  
Metabolism and nutrition  
disorders  
Psychiatric disorders  
Mental disorder  
due to a general  
medical condition  
Ataxia  
Nervous system disorders  
Headache  
Leukoencephalopathy  
Encephalopathy  
Convulsion  
Cerebral  
haemorrhage  
Memory  
impairment  
Paresis  
Ear and labyrinth disorders  
Cardiac disorders  
Hearing impaired  
Cardiac arrest  
Cardiovascular  
insufficiency  
Cardiac failure  
Hypertension  
Idiopathic  
Vascular disorders  
Respiratory, thoracic and  
mediastinal disorders  
Haemorrhage  
Pneumonitis  
Pulmonary arterial  
hypertension  
pneumonia  
syndrome  
Pulmunary  
haemorrage  
Pulmonary  
oedema  
Epistaxis  
Hypoxia  
Respiratory arrest  
Gastrointestinal disorders  
Hepatobiliary disorders  
Nausea  
Stomatitis  
Vomiting  
Diarrhoea  
Abdominal pain  
Venoocclusive  
liver disease  
Rash  
Enteritis  
Intestinal  
obstruction  
Liver failure  
Skin and subcutaneous tissue  
disorders  
Severe toxic skin  
reactions including  
cases of Stevens-  
Johnson syndrome  
and toxic epidermal  
necrolysis  
Erythema  
Desquamation  
Pigmentation  
disorder  
Musculoskeletal and connective  
tissue disorders  
Growth retardation  
Renal and urinary disorders  
Bladder disorders Renal failure  
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Product information for human medicinal products  
Very common  
(≥10%)  
Common  
(≥1%, <10%)  
Cystitis  
System organ class  
Not Known  
haemorrhagic  
General disorders and  
Pyrexia  
administration site conditions  
Mucosal  
inflammation  
Pain  
Multi-organ failure  
Blood bilirubin  
increased  
Investigations  
Blood urea  
increased  
Transaminases  
increased  
Blood electrolytes  
abnormal  
Blood creatinine  
increased  
Prothrombin time  
ratio increased  
Aspartate  
aminotransferase  
increased  
Alanine  
aminotransferase  
increased  
Reporting suspected adverse reactions after authorisation of the medicinal product is very important.  
It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare  
professionals are asked to report any suspected adverse reactions online via the ElViS portal  
(Electronic Vigilance System). You can obtain information about this at www.swissmedic.ch.  
Overdose  
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.  
Properties/Effects  
ATC code  
L01AC01  
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents  
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  
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Product information for human medicinal products  
guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating  
alkylated guanine.  
Pharmacodynamics  
No information available.  
Clinical 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:  
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  
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Product information for human medicinal products  
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 adults patients with haematological diseases.  
Safety and efficacy in paediatric patients  
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  
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Product information for human medicinal products  
therapeutic strategies for treating paediatric patients with solid tumours.  
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.  
Pharmacokinetics  
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  
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Product information for human medicinal products  
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.  
Metabolism  
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.  
Kinetics in specific patient groups  
Hepatic impairment  
The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed.  
Renal impairment  
The effects of renal impairment on thiotepa elimination have not been assessed.  
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Product information for human medicinal products  
Children and adolescents  
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.  
Preclinical 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.  
Other information  
Incompatibilities  
TEPADINA® is unstable in acid medium.  
This medicinal product may be mixed only with those medicinal products listed under Instructions for  
handling.  
Shelf life  
Do not use this medicine after the expiry date ("EXP") stated on the container.  
Shelf life after activation of the bag and reconstitution  
Chemical and physical in-use stability of the reconstituted product in the activated bag has been  
demonstrated for up to 48 hours when stored at 2°C-8°C and for up to 6 hours at 25°C.  
For microbiological reasons, the ready-to-use preparation should be used immediately after activation  
and reconstitution. If this is not possible, in-use storage times and conditions are the responsibility of  
the user and should normally be no longer than the above mentioned conditions, unless dilution has  
taken place in controlled and validated aseptic conditions.  
Special precautions for storage  
Store and transport refrigerated (2°C-8°C).  
Do not freeze.  
Keep the bag in the aluminum wrapper in order to protect from activation.  
Keep out of the reach of children.  
Instructions for handling  
Preparation of TEPADINA®  
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Product information for human medicinal products  
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.  
Activation and reconstitution  
TEPADINA® bag must be reconstituted with sodium chloride 9 mg/ml (0.9%) solution for injection. The  
final reconstituted solution is obtained after breaking the peelable seal of the dual chamber bag and  
mixing the contents (powder and solvent) until complete dissolution of the powder.  
After reconstitution with the solvent, each ml of solution contains 1 mg of thiotepa.  
Only colourless solutions, without any particulate matter, must be used.  
Dose adjustments calculated according to posology (section Dosage/Administration)  
TEPADINA® 200 mg  
If necessary, dose adjustment of TEPADINA® must be operated as per specific application. In case  
the calculated dose required is higher than 200 mg but less than a multiple thereof, the user is  
requested to add the required mg from TEPADINA® vials by using a dedicated port (luer port) of  
TEPADINA® 200 mg (Step 5 of the Instruction for Use). In case the calculated dose required is lower  
than 200 mg the user is requested to remove the unnecessary mg of fully reconstituted 1 mg/mL  
solution.  
TEPADINA® 400 mg  
If necessary, dose adjustment of TEPADINA® must be operated as per specific application. In case  
the calculated dose required is higher than 400 mg but less than a multiple thereof, the user is  
requested to add the required mg from TEPADINA® vials by using a dedicated port (luer port) of  
TEPADINA® 400 mg (Step 5 of the Instruction for Use). In case the calculated dose required is lower  
than 400 mg the user is requested to remove the unnecessary mg of fully reconstituted 1 mg/mL  
solution.  
Administration  
TEPADINA® infusion solution should be inspected visually for particulate matter prior to  
administration. Solutions containing a precipitate should be discarded.  
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Product information for human medicinal products  
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.  
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Product information for human medicinal products  
Instructions for Use – TEPADINA®/bag  
Figure A  
Figure B  
1 - Overpouch Notch  
2 – Blind Port (NEVER use this port)  
3 – Luer Port  
4 – Twist off Port  
5 – Label Area  
6 – Peel Seal (Must break to activate)  
7 – Hole (For hanging the bag)  
8 – Solvent chamber  
9 – Powder chamber  
TEPADINA® 200 mg  
TEPADINA® 400 mg  
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Product information for human medicinal products  
1 – REMOVE OVERPOUCH  
a)  
b)  
c)  
Place bag on a clean, stable surface  
before opening.  
Tear from Overpouch Notch located  
close to the ports (Figure A – point 1).  
Tear short sides open to access the  
inner bag as per Figure C.  
d) Remove the dual chamber flexible bag from the  
aluminum secondary packaging and unfold the  
bag Figure D.  
Figure C  
Figure D  
2 - INSPECT BAG PRIOR TO ACTIVATION  
3 – ACTIVATE THE BAG  
Place bag on a clean, stable surface with text  
side up and ports pointing away from you, as  
per Figure E.  
Overlap your hands, on the lower portion of chamber  
8 (as per Figure F).  
Press firmly in order to apply uniform pressure until  
peel seal 6 is completely activated (it may take up to 5  
Check that there are no liquid or product  
leakages from the connection ports 2, 3, 4 and seconds of continued pressure to break the peel seal  
from the chamber 8, 9.  
6).  
Check the integrity of peel seal 6, verifying the  
absence of liquid in the chamber 9.  
Figure E  
Figure F  
TEPADINA® 200 mg  
TEPADINA® 200 mg  
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Product information for human medicinal products  
TEPADINA® 400 mg  
TEPADINA® 400 mg  
BAG BEFORE ACTIVATION  
BAG AFTER ACTIVATION  
Figure H  
Figure G  
Do NOT squeeze or press strongly.  
Figure I  
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Product information for human medicinal products  
4 – INSPECT BAG TO CONFIRM ACTIVATION.  
Check the peel seal 6 is now completely  
activated.  
Mix gently until complete dissolution of product.  
Chamber 8 and 9 are merged.  
Figure K  
Figure J  
5 – DOSE ADJUSTMENT - Please refer to the sections “Dosage/Administration”  
and “Instructions for handling”  
Identify the Luer Port 3 if  
Screw the luer lock device as per  
Figure M.  
Do not use unproper non luer  
lock devices on port 3.  
Operate dose adjustment as per  
sections  
“Dosage/Administration” and  
“Instructions for handling”.  
correcting dose is needed.  
Remove the plastic cap from  
Luer Port.  
Figure L  
Figure N  
Figure M  
Unscrew the device once  
finished.  
Ensure that the connection is fully  
seated and tighten.  
Put the plastic cap on Luer Port 3  
before proceeding with infusion.  
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Product information for human medicinal products  
6 – CONNECTION - The infusion set may be connected to the bag through either of the luer connector  
or the spike connector.  
OPTION A – SPIKE CONNECTION  
OPTION B– LUER CONNECTION  
Identify Twist off Port 4 in case of spike  
infusion set.  
Select luer cap port 3 in case of luer connector infusion  
set.  
Twist off the plastic cap before inserting the Remove the plastic cap from Luer Port 3 before connect  
spike. the luer connector.  
Figure O  
Insert the spike connector.  
Figure Q  
Insert the luer connector.  
Figure R  
Ensure that the connection is fully seated and tighten.  
Figure P  
7 – HANG THE BAG  
Figure S  
Hang the bag by the hole 7.  
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Product information for human medicinal products  
Authorisation number  
68397 [Swissmedic]  
Packs  
TEPADINA® 200 mg and TEPADINA® 400 mg: Pack size of 1 bag [A].  
To be used in hospitals only.  
Marketing authorisation holder  
ADIENNE SA, 6900 Lugano  
Date of revision of the text  
August 2024  
Revision history  
Created on  
Change  
February 2021  
First Information for Professionals for TEPADINA® 400 mg  
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