ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
TEPADINA 15 mg powder for concentrate for solution for infusion
One vial contains 15 mg thiotepa.
After reconstitution with 1.5 ml of water for injection, each ml of solution contains 10 mg thiotepa
(10 mg/ml).
For a full list of excipients, see section 6.1.
Powder for concentrate for solution for infusion.
White crystalline powder.
4.1 Therapeuticindications
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.
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.
Posology in adults
AUTOLOGOUS HPCT:
Haematological diseases
The recommended dose in haematological diseases ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to
300 mg/m
2
/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/m
2
(24.32 mg/kg), during
the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 300 mg/m
2
/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/m
2
(24.32 mg/kg), during the time of
the entire conditioning treatment.
CNS LYMPHOMA
The recommended dose is 185 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during the time of the entire
conditioning treatment.
Solid tumours
The recommended dose in solid tumours ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to
250 mg/m
2
/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/m
2
(21.62 mg/kg),
during the time of the entire conditioning treatment.
BREAST CANCER
The recommended dose ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to 250 mg/m
2
/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/m
2
(21.62 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during
the time of the entire conditioning treatment.
OVARIAN CANCER
The recommended dose is 250 mg/m
2
/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/m
2
(13.51 mg/kg), during the time of the entire conditioning treatment.
GERM CELL TUMOURS
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
481 mg/m
2
/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 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 555 mg/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose in lymphoma is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose is 185 mg/m
2
/day (5 mg/kg/day) as a single daily infusion before allogeneic
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m
2
(5 mg/kg), during the time
of the entire conditioning treatment.
LEUKEMIA
The recommended dose ranges from 185 mg/m
2
/day (5 mg/kg/day) to 481 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire
conditioning treatment.
THALASSEMIA
The recommended dose is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(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/m
2
/day (6 mg/kg/day) to 350 mg/m
2
/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/m
2
(42 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 250 mg/m
2
/day (10 mg/kg/day) to 350 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
250 mg/m
2
/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/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LEUKEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
THALASSEMIA
The recommended dose ranges from 200 mg/m
2
/day (8 mg/kg/day) to 250 mg/m
2
/day (10 mg/kg/day)
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total
maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning
treatment.
REFRACTORY CYTOPENIA
The recommended dose is 125 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire conditioning treatment.
GENETIC DISEASES
The recommended dose is 125 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
SICKLE CELL ANAEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(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 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.
Method of administration
TEPADINA must be administered by a qualified healthcare professional as a 2-4 hours intravenous
infusion via a central venous catheter.
TEPADINA must be reconstituted with 1.5 ml of sterile water for injection and further diluted with
500 ml of sodium chloride 9 mg/ml (0.9%) solution for injection prior to administration. For instructions
on reconstitution and further dilution prior to administration, see section 6.6.
Precautions to be taken before manipulating 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 6.6).
Hypersensitivity to the active substance.
Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5).
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 while treated and during the year
after cessation of treatment (see section 4.6).
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.
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
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
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 section 5.3).
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 not known whether thiotepa is excreted in human milk. Due to its pharmacological properties and its
potential toxicity for nursing infant, 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
while treated and during the year after cessation of treatment (see section 4.4).
No studies on the effects on the ability to drive and use machines have been performed, but it is likely
that certain adverse events of thiotepa like dizziness, headache and blurred vision could affect these
functions.
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 events reported in the different conditioning treatments including thiotepa
are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, haemorrhagic
cystitis, mucosal inflammation.
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
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
Eye disorders
Conjunctivitis
Cataract
Ear and labyrinth disorders
Hearing impaired
Ototoxicity
Tinnitus
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
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
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 patients
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
Uncommon
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
Nervous system disorders
Headache
Encephalopathy
Convulsion
Cerebral
haemorrhage
Memory
impairment
Paresis
Ataxia
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
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
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
Investigation
Blood bilirubin
increased
Transaminases
increased
Blood creatinine
increased
Aspartate
aminotransferase
Blood urea
increased
Blood electrolytes
abnormal
Prothrombin time
ratio increased
increased
Alanine
aminotransferase
increased
The most important adverse reaction 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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Ethylene imines, 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:
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%).
D
isease 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.
Studies 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
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.
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/m
2
to 75 l/m
2
, 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.
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/m
2
. 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
There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.
Special populations
Paediatric patients
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/m
2
or adults receiving similar doses.
Patients with renal dysfunction
The effects of renal dysfunction on thiotepa elimination have not been assessed.
Patients with hepatic dysfunction
The effects of hepatic dysfunction 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.
6.1
List of excipients
TEPADINA does not contain any excipients.
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.
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 2-8 °C.
After dilution
Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored at
2-8°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 (2C – 8C).
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 bromobutyl stopper, 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 clear colourless solutions, without any particulate matter, must be used.
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.
Administration
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.
It is recommended that the infusion solution be administered to patients using an infusion set equipped
with a 0.2 µm in-line filter.
Disposal
TEPADINA is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
ADIENNE S.r.l.
Via Broseta 64/B
24128 Bergamo
Italy
8.
MARKETING AUTHORISATION NUMBER
TEPADINA 100 mg powder for concentrate for solution for infusion
One vial contains 100 mg thiotepa.
After reconstitution with 10 ml of water for injection, each ml of solution contains 10 mg thiotepa
(10 mg/ml).
For a full list of excipients, see section 6.1.
Powder for concentrate for solution for infusion.
White crystalline powder.
4.1 Therapeuticindications
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.
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.
Posology in adults
AUTOLOGOUS HPCT:
Haematological diseases
The recommended dose in haematological diseases ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to
300 mg/m
2
/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/m
2
(24.32 mg/kg), during
the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 300 mg/m
2
/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/m
2
(24.32 mg/kg), during the time of
the entire conditioning treatment.
CNS LYMPHOMA
The recommended dose is 185 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during the time of the entire
conditioning treatment.
Solid tumours
The recommended dose in solid tumours ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to
250 mg/m
2
/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/m
2
(21.62 mg/kg),
during the time of the entire conditioning treatment.
BREAST CANCER
The recommended dose ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to 250 mg/m
2
/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/m
2
(21.62 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during
the time of the entire conditioning treatment.
OVARIAN CANCER
The recommended dose is 250 mg/m
2
/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/m
2
(13.51 mg/kg), during the time of the entire conditioning treatment.
GERM CELL TUMOURS
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
481 mg/m
2
/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 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 555 mg/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose in lymphoma is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose is 185 mg/m
2
/day (5 mg/kg/day) as a single daily infusion before allogeneic
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m
2
(5 mg/kg), during the time
of the entire conditioning treatment.
LEUKEMIA
The recommended dose ranges from 185 mg/m
2
/day (5 mg/kg/day) to 481 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire
conditioning treatment.
THALASSEMIA
The recommended dose is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(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/m
2
/day (6 mg/kg/day) to 350 mg/m
2
/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/m
2
(42 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 250 mg/m
2
/day (10 mg/kg/day) to 350 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
250 mg/m
2
/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/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LEUKEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
THALASSEMIA
The recommended dose ranges from 200 mg/m
2
/day (8 mg/kg/day) to 250 mg/m
2
/day (10 mg/kg/day)
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total
maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning
treatment.
REFRACTORY CYTOPENIA
The recommended dose is 125 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire conditioning treatment.
GENETIC DISEASES
The recommended dose is 125 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
SICKLE CELL ANAEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(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 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.
Method of administration
TEPADINA must be administered by a qualified healthcare professional as a 2-4 hours intravenous
infusion via a central venous catheter.
TEPADINA must be reconstituted with 10 ml of sterile water for injection and further diluted with
500 ml of sodium chloride 9 mg/ml (0.9%) solution for injection prior to administration. For instructions
on reconstitution and further dilution prior to administration, see section 6.6.
Precautions to be taken before manipulating 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 6.6).
Hypersensitivity to the active substance.
Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines (see section 4.5).
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 while treated and during the year
after cessation of treatment (see section 4.6).
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.
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
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
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.
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 not known whether thiotepa is excreted in human milk. Due to its pharmacological properties and its
potential toxicity for nursing infant, 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
while treated and during the year after cessation of treatment (see section 4.4).
No studies on the effects on the ability to drive and use machines have been performed, but it is likely
that certain adverse events of thiotepa like dizziness, headache and blurred vision could affect these
functions.
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 events reported in the different conditioning treatments including thiotepa
are: infections, cytopenia, acute GvHD and chronic GvHD, gastrointestinal disorders, haemorrhagic
cystitis, mucosal inflammation.
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
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
Eye disorders
Conjunctivitis
Cataract
Ear and labyrinth disorders
Hearing impaired
Ototoxicity
Tinnitus
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
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
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 patients
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
Uncommon
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
Nervous system disorders
Headache
Encephalopathy
Convulsion
Cerebral
haemorrhage
Memory
impairment
Paresis
Ataxia
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
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
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
Investigation
Blood bilirubin
increased
Transaminases
increased
Blood creatinine
increased
Aspartate
aminotransferase
Blood urea
increased
Blood electrolytes
abnormal
Prothrombin time
ratio increased
increased
Alanine
aminotransferase
increased
The most important adverse reaction 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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Ethylene imines, 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:
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%).
D
isease 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.
Studies 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
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.
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/m
2
to 75 l/m
2
, 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.
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/m
2
. 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
There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.
Special populations
Paediatric patients
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/m
2
or adults receiving similar doses.
Patients with renal dysfunction
The effects of renal dysfunction on thiotepa elimination have not been assessed.
Patients with hepatic dysfunction
The effects of hepatic dysfunction 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.
6.1
List of excipients
TEPADINA does not contain any excipients.
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.
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 2-8°C.
After dilution
Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored at
2-8°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 (2C – 8C).
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 bromobutyl stopper, 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 clear colourless solutions, without any particulate matter, must be used.
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.
Administration
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.
It is recommended that the infusion solution be administered to patients using an infusion set equipped
with a 0.2 µm in-line filter.
Disposal
TEPADINA is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
ADIENNE S.r.l.
Via Broseta 64/B
24128 Bergamo
Italy
8.
MARKETING AUTHORISATION NUMBER
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
RIEMSER Arzneimittel AG
7 An der Wiek
D-17493 Greifswald – Insel Riems
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version ADN 004
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning
before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version ADN 005 of the Risk Management Plan (RMP)
presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of
the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the EMEA
ANNEX III
LABELLING AND PACKAGE LEAFLET
A. LABELLING
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
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
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
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.
ADIENNE S.r.l.
24128 Bergamo
Italy
adienne@adienne.com
12. MARKETINGAUTHORISATIONNUMBER(S)
13. BATCHNUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATIONINBRAILLE
TEPADINA 15 mg
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
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.
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
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
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
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.
ADIENNE S.r.l.
24128 Bergamo
Italy
adienne@adienne.com
12. MARKETINGAUTHORISATIONNUMBER(S)
13. BATCHNUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATIONINBRAILLE
TEPADINA 100 mg
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
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.
B. PACKAGE LEAFLET
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.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
In this leaflet
:
1.
What TEPADINA is and what it is used for
2.
Before you use TEPADINA
3.
How to use TEPADINA
4.
Possible side effects
5.
How to store TEPADINA
6.
Further 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.
2.
BEFORE YOU USE TEPADINA
Do not use TEPADINA
-
if you are pregnant or think you may be pregnant (see below),
-
if you are breast-feeding,
-
if you are receiving yellow fever vaccination.
Take special care with TEPADINA
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.
You will have to take regular blood tests during treatment to check your blood cell counts.
You will have to use anti-infectives to prevent and manage infections.
TEPADINA may cause another type of cancer in the future. Your doctor will discuss this risk with you.
Pregnancy and breast-feeding
You must tell your doctor if you are or think you may be pregnant before you receive TEPADINA. You
must not use TEPADINA during pregnancy.
-
if you are allergic (hypersensitive) to thiotepa,
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 while treated and during the year after cessation of
treatment.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including medicines
obtained without a prescription.
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 3 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:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.
Very common side effects
- 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 (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
Common side effects
- 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
Uncommon side effects
- 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)
- male and female infertility
If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet,
please tell your doctor or nurse.
5. HOW TO STORE TEPADINA
Keep out of the reach and sight 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. 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.
FURTHER 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.
Via Broseta 64/B
24128 Bergamo
Italy
+39 035 19964047
adienne@adienne.com
Manufacturer
RIEMSER Arzneimittel AG
7 An der Wiek
17493 Greifswald
Insel Riems
Germany
This leaflet was last approved in:
{MM/YYYY}
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
The following information is intended for medical or 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/m
2
/day (3.38 mg/kg/day) to
300 mg/m
2
/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/m
2
(24.32 mg/kg), during
the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 300 mg/m
2
/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/m
2
(24.32 mg/kg), during the time of
the entire conditioning treatment.
CNS LYMPHOMA
The recommended dose is 185 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during the time of the entire
conditioning treatment.
Solid tumours
The recommended dose in solid tumours ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to
250 mg/m
2
/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/m
2
(21.62 mg/kg),
during the time of the entire conditioning treatment.
BREAST CANCER
The recommended dose ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to 250 mg/m
2
/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/m
2
(21.62 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during
the time of the entire conditioning treatment.
OVARIAN CANCER
The recommended dose is 250 mg/m
2
/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/m
2
(13.51 mg/kg), during the time of the entire conditioning treatment.
GERM CELL TUMOURS
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
481 mg/m
2
/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 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 555 mg/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose in lymphoma is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose is 185 mg/m
2
/day (5 mg/kg/day) as a single daily infusion before allogeneic
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m
2
(5 mg/kg), during the time
of the entire conditioning treatment.
LEUKEMIA
The recommended dose ranges from 185 mg/m
2
/day (5 mg/kg/day) to 481 mg/m
2
/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/m
2
(15 mg/kg), during the time of the
entire conditioning treatment.
THALASSEMIA
The recommended dose is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(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/m
2
/day (6 mg/kg/day) to 350 mg/m
2
/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/m
2
(42 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 250 mg/m
2
/day (10 mg/kg/day) to 350 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
250 mg/m
2
/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/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LEUKEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(10
mg/kg), during the time of the entire conditioning treatment.
THALASSEMIA
The recommended dose ranges from 200 mg/m
2
/day (8 mg/kg/day) to 250 mg/m
2
/day (10 mg/kg/day)
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total
maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning
treatment.
REFRACTORY CYTOPENIA
The recommended dose is 125 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire conditioning treatment.
GENETIC DISEASES
The recommended dose is 125 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
SICKLE CELL ANAEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(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 clear colourless solutions, without any particulate matter, must be used.
Further dilution in the infusion bag
The reconstituted solution is hypotonic and should be further diluted prior to administration with 500 ml
sodium chloride 9 mg/ml (0.9%) solution for injection.
Administration
TEPADINA infusion solution should be inspected visually for particulate matter and opalescence prior
to administration. Solutions containing a precipitate should be discarded.
It is recommended that the infusion solution be administered to patients using an infusion set equipped
with a 0.2 µm in-line filter.
TEPADINA should be aseptically administered as a 2-4 hours infusion under room temperature 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.
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.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
In this leaflet
:
1.
What TEPADINA is and what it is used for
2.
Before you use TEPADINA
3.
How to use TEPADINA
4.
Possible side effects
5.
How to store TEPADINA
6.
Further 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.
2.
BEFORE YOU USE TEPADINA
Do not use TEPADINA
-
if you are pregnant or think you may be pregnant (see below),
-
if you are breast-feeding,
-
if you are receiving yellow fever vaccination.
Take special care with TEPADINA
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.
You will have to take regular blood tests during treatment to check your blood cell counts.
You will have to use anti-infectives to prevent and manage infections.
TEPADINA may cause another type of cancer in the future. Your doctor will discuss this risk with you.
Pregnancy and breast-feeding
You must tell your doctor if you are or think you may be pregnant before you receive TEPADINA. You
must not use TEPADINA during pregnancy.
-
if you are allergic (hypersensitive) to thiotepa,
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 while treated and during the year after cessation of
treatment.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including medicines
obtained without a prescription.
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 3 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:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.
Very common side effects
- 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 (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
Common side effects
- 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
Uncommon side effects
- 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)
- male and female infertility
If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet,
please tell your doctor or nurse.
5. HOW TO STORE TEPADINA
Keep out of the reach and sight 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. 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.
FURTHER 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).
-
What TEPADINA looks like and contents of the pack
TEPADINA is a white crystalline powder supplied in a glass vial containing 100 mg thiotepa.
TEPADINA does not contain any other ingredients.
Each carton contains 1 vial.
Marketing Authorisation Holder
ADIENNE S.r.l.
Via Broseta 64/B
24128 Bergamo
Italy
Manufacturer
RIEMSER Arzneimittel AG
7 An der Wiek
17493 Greifswald
Insel Riems
Germany
This leaflet was last approved in:
{MM/YYYY}
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
The following information is intended for medical or 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/m
2
/day (3.38 mg/kg/day) to
300 mg/m
2
/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/m
2
(24.32 mg/kg), during
the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 300 mg/m
2
/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/m
2
(24.32 mg/kg), during the time of
the entire conditioning treatment.
CNS LYMPHOMA
The recommended dose is 185 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during the time of the entire
conditioning treatment.
Solid tumours
The recommended dose in solid tumours ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to
250 mg/m
2
/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/m
2
(21.62 mg/kg),
during the time of the entire conditioning treatment.
BREAST CANCER
The recommended dose ranges from 120 mg/m
2
/day (3.24 mg/kg/day) to 250 mg/m
2
/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/m
2
(21.62 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 125 mg/m
2
/day (3.38 mg/kg/day) to 250 mg/m
2
/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/m
2
(20.27 mg/kg), during
the time of the entire conditioning treatment.
OVARIAN CANCER
The recommended dose is 250 mg/m
2
/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/m
2
(13.51 mg/kg), during the time of the entire conditioning treatment.
GERM CELL TUMOURS
The recommended dose ranges from 150 mg/m
2
/day (4.05 mg/kg/day) to 250 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
481 mg/m
2
/day (13 mg/kg/day) divided in one or two daily infusions, administered from 1 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 555 mg/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LYMPHOMA
The recommended dose in lymphoma is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
MULTIPLE MYELOMA
The recommended dose is 185 mg/m
2
/day (5 mg/kg/day) as a single daily infusion before allogeneic
HPCT, without exceeding the total maximum cumulative dose of 185 mg/m
2
(5 mg/kg), during the time
of the entire conditioning treatment.
LEUKEMIA
The recommended dose ranges from 185 mg/m
2
/day (5 mg/kg/day) to 481 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire
conditioning treatment.
THALASSEMIA
The recommended dose is 370 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 370 mg/m
2
(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/m
2
/day (6 mg/kg/day) to 350 mg/m
2
/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/m
2
(42 mg/kg), during the time of
the entire conditioning treatment.
CNS TUMOURS
The recommended dose ranges from 250 mg/m
2
/day (10 mg/kg/day) to 350 mg/m
2
/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/m
2
(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/m
2
/day (5 mg/kg/day) to
250 mg/m
2
/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/m
2
(15 mg/kg),
during the time of the entire conditioning treatment.
LEUKEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
THALASSEMIA
The recommended dose ranges from 200 mg/m
2
/day (8 mg/kg/day) to 250 mg/m
2
/day (10 mg/kg/day)
divided in two daily infusions, administered before allogeneic HPCT without exceeding the total
maximum cumulative dose of 250 mg/m
2
(10 mg/kg), during the time of the entire conditioning
treatment.
REFRACTORY CYTOPENIA
The recommended dose is 125 mg/m
2
/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/m
2
(15 mg/kg), during the time of the entire conditioning treatment.
GENETIC DISEASES
The recommended dose is 125 mg/m
2
/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/m
2
(10 mg/kg), during the time of the entire conditioning treatment.
SICKLE CELL ANAEMIA
The recommended dose is 250 mg/m
2
/day (10 mg/kg/day) divided in two daily infusions, administered
before allogeneic HPCT, without exceeding the total maximum cumulative dose of 250 mg/m
2
(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 clear colourless solutions, without any particulate matter, must be used.
Further dilution in the infusion bag
The reconstituted solution is hypotonic and should be further diluted prior to administration with 500 ml
sodium chloride 9 mg/ml (0.9%) solution for injection.
Administration
TEPADINA infusion solution should be inspected visually for particulate matter and opalescence prior
to administration. Solutions containing a precipitate should be discarded.
It is recommended that the infusion solution be administered to patients using an infusion set equipped
with a 0.2 µm in-line filter.
TEPADINA should be aseptically administered as a 2-4 hours infusion under room temperature 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.
Source: European Medicines Agency
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