Trecondi

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Trecondi 1 g powder for solution for infusion 
Trecondi 5 g powder for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Trecondi 1 g powder for solution for infusion 
One vial contains 1 g of treosulfan. 
 
Trecondi 5 g powder for solution for infusion 
One vial contains 5 g of treosulfan. 
 
When reconstituted according to section 6.6, 1 mL of the solution for infusion contains 50 mg 
treosulfan. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for infusion. 
 
White crystalline powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to 
allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients with malignant and 
non-malignant diseases, and in paediatric patients older than one month with malignant diseases. 
 
4.2 Posology and method of administration 
 
Administration of treosulfan should be supervised by a physician experienced in conditioning 
treatment followed by alloHSCT. 
 
Posology 
 
Adults with malignant disease 
 
Treosulfan is given in combination with fludarabine. 
The recommended dose and schedule of administration is: 
• Treosulfan 10 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, given 

on three consecutive days (day -4, -3, -2) before stem cell infusion (day 0). The total treosulfan 
dose is 30 g/m²; 

• Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five 
consecutive days (day -6, -5, -4, -3, -2) before stem cell infusion (day 0). The total fludarabine 
dose is 150 mg/m²; 

• Treosulfan should be administered before fludarabine on days -4, -3, -2 (FT10 regimen). 
 
Adults with non-malignant disease 
 
Treosulfan is given in combination with fludarabine with or without thiotepa.  
The recommended dose and schedule of administration is: 



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• Treosulfan 14 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, given 
on three consecutive days (day -6, -5, -4) before stem cell infusion (day 0). The total treosulfan 
dose is 42 g/m²; 

• Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five 
consecutive days (day -7, -6, -5, -4, -3) before stem cell infusion (day 0). The total fludarabine 
dose is 150 mg/m²; 

• Treosulfan should be administered before fludarabine on days -6, -5, -4 (FT14 regimen). 
• Thiotepa 5 mg/kg twice a day, given as two intravenous infusions over 2–4 hours on day -2 

before stem cell infusion (day 0). 
 
Elderly 
 
No dose adjustment is necessary in any subset of the elderly population. 
 
Renal and hepatic impairment 
 
No dose adjustment is necessary for mild or moderate impairment, but treosulfan is contraindicated in 
patients with severe impairment (see section 4.3). 
 
Paediatric population 
 
Treosulfan is given in combination with fludarabine, with thiotepa (intensified regimen; 
FT10-14TT regimen) or without thiotepa (FT10-14 regimen).  
The recommended dose and schedule of administration is: 
• Treosulfan 10-14 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, 

given on three consecutive days (day -6, -5, -4) before stem cell infusion (day 0). The total 
treosulfan dose is 30-42 g/m²; 
The dose of treosulfan should be adapted to the patient’s BSA as follows (see section 5.2): 

 
Body surface area (m²) Treosulfan dose (g/m²) 
≤ 0.5 10.0 
> 0.5 – 1.0 12.0 
> 1.0 14.0 

 
• Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on five 

consecutive days (day -7, -6, -5, -4, -3) before stem cell infusion (day 0). The total fludarabine 
dose is 150 mg/m²; 

• Treosulfan should be administered before fludarabine; 
• Thiotepa (intensified regimen 5 mg/kg twice a day), given as two intravenous infusions over 2–

4 hours on day -2 before stem cell infusion (day 0). 
 
The safety and efficacy of treosulfan in children less than 1 month of age has not yet been established. 
 
Method of administration 
 
Treosulfan is for intravenous use as a two-hour infusion. 
 
Precautions to be taken before handling or administering the medicinal product 
 
When handling treosulfan, inhalation, skin contact or contact with mucous membranes should be 
avoided. Pregnant personnel should be excluded from handling cytotoxics. 
 
Intravenous administration should be performed using a safe technique to avoid extravasation (see 
section 4.4). 
 
For instructions on reconstitution of the medicinal product before administration, see section 6.6. 



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4.3 Contraindications 
 
• Hypersensitivity to the active substance 
• Active non-controlled infectious disease 
• Severe concomitant cardiac, lung, liver, and renal impairment 
• Fanconi anaemia and other DNA breakage repair disorders 
• Pregnancy (see section 4.6) 
• Administration of live vaccine 
 
4.4 Special warnings and precautions for use 
 
Myelosuppression 
 
Profound myelosuppression with pancytopenia is the desired therapeutic effect of treosulfan-based 
conditioning treatment, occurring in all patients. It is therefore recommended to monitor blood cell 
counts frequently until recovery of the haematopoietic system.  
During phases of severe neutropenia (median duration of neutropenic period is 14-17.5 days in adults 
and 21-24 days in paediatric patients) the risk of infection is increased. Prophylactic or empiric 
anti-infective treatment (bacterial, viral, fungal) should therefore be considered. Growth factors 
(G-CSF, GM-CSF), platelet and/or red blood cell support should be given as indicated. 
 
Secondary malignancies 
 
Secondary malignancies are well-established complications in long-term survivors after alloHSCT. 
How much treosulfan contributes to their occurrence is unknown. The possible risk of a second 
malignancy should be explained to the patient. On the basis of human data, treosulfan has been 
classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. 
 
Mucositis 
 
Oral mucositis (including high-grade severity) is a very common undesirable effect of 
treosulfan-based conditioning followed by alloHSCT (see section 4.8). Use of mucositis prophylaxis 
(e.g. topical antimicrobials, barrier protectants, ice and adequate oral hygiene) is recommended. 
 
Vaccines 
 
Concomitant use of live attenuated vaccines is not recommended. 
 
Fertility 
 
Treosulfan can impair fertility. Therefore, men treated with treosulfan are advised not to father a child 
during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to 
treatment because of the possibility of irreversible infertility due to therapy with treosulfan. 
Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in 
pre-menopausal patients (see section 4.6). 
 
Paediatric population 
 
Seizures 
 
There have been isolated reports of seizures in infants (≤ 4 months of age) with primary 
immunodeficiencies after conditioning treatment with treosulfan in combination with fludarabine or 
cyclophosphamide. Therefore, infants ≤ 4 months of age should be monitored for signs of neurological 
adverse reactions. Although it cannot be proved that treosulfan was the cause, the use of clonazepam 
prophylaxis for children younger than 1 year might be considered. 



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Respiratory, thoracic and mediastinal disorders 
 
There was a significant association between age and respiratory toxicity in paediatric patients treated 
with treosulfan-based conditioning. 
Children younger than one year (mainly non-malignant diseases, especially immunodeficiencies) 
experienced more respiratory grade III/IV toxicity, possibly due to pulmonary infections already 
existing before the start of conditioning treatment. 
 
Dermatitis diaper 
 
Dermatitis diaper may occur in small children because of excretion of treosulfan in the urine. 
Therefore, nappies should be changed frequently up to 6–8 hours after each infusion of treosulfan.  
 
Extravasation 
 
Treosulfan is considered an irritant. Intravenous application should be performed using a safe 
technique. If extravasation is suspected, general safety measures should be implemented. No specific 
measure has been proven to be recommendable. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction of treosulfan was observed in high-dose chemotherapy. 
 
Detailed in vitro studies did not completely exclude potential interactions between high plasma 
concentrations of treosulfan and CYP3A4, CYP2C19, or P-gp substrates. Therefore, medicinal 
products with a narrow therapeutic index (e.g. digoxin) that are substrates for CYP3A4, CYP2C19 or 
P-gp should not be given during treatment with treosulfan. 
 
The effect of treosulfan on the pharmacokinetics of fludarabine is not known. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
 
Both sexually active men and women of childbearing potential have to use effective contraception 
during and up to 6 months after treatment. 
 
Pregnancy 
 
There are no data from the use of treosulfan in pregnant women. Animal studies are insufficient with 
respect to reproductive toxicity (see section 5.3). Treosulfan is contraindicated during pregnancy (see 
section 4.3). 
 
Breast-feeding 
 
It is unknown whether treosulfan is excreted in human milk. Breast-feeding should be discontinued 
during treatment with treosulfan. 
 
Fertility 
 
Treosulfan might impair fertility in men and women. Men should seek advice on cryo-conservation of 
sperm prior to treatment because of the possibility of irreversible infertility.  
 
As known for other alkylating conditioning agents treosulfan can cause ovarian suppression and 
amenorrhoea with menopausal symptoms in pre-menopausal women. 



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4.7 Effects on ability to drive and use machines 
 
Treosulfan has moderate influence on the ability to drive and use machines. It is likely that certain 
adverse reactions of treosulfan like nausea, vomiting or dizziness could affect these functions.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Profound myelosuppression/pancytopenia is the desired therapeutic effect of conditioning therapy and 
occurs in all patients. Blood cell counts usually recover after HSCT. 
 
The most commonly observed adverse reactions (adults/paediatric patients) after treosulfan-based 
conditioning followed by alloHSCT include infections (13.1% /11.4%), gastrointestinal disorders 
(nausea [39.5%/30.7%], stomatitis [36.0%/69.3%], vomiting [22.5%/43.2%], diarrhoea 
[15.6%/33.0%], abdominal pain [10.4%/17%]), fatigue (15.1%/2.3%), febrile neutropenia 
(11.3%/1.1%), oedema (7.8%/0%), rash (7.2%/12.5%), and increases of alanine transaminase (ALT 
[5.1%/9.1%]), aspartate transaminase (AST [4.4%/8.0%]), gamma-glutamyl transferase (γGT 
[3.7%/2.3%]), and bilirubin (18.8%/5.7%). 
 
Adults 
 
Tabulated list of adverse reactions 
 
The frequencies of adverse reactions reported in the table below are derived from 5 clinical trials 
(including a total of 564 patients) where treosulfan combined with fludarabine was investigated as 
conditioning treatment prior to alloHSCT in adult patients. Treosulfan was administered in a dose 
range of 10-14 g/m² BSA on 3 consecutive days.  
 
Adverse reactions are listed below, by system organ class and by frequency: 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) and not known (cannot be estimated from the available data). Within each frequency 
group, undesirable effects are presented in order of decreasing seriousness. 
 
System Organ Class 
(SOC) 

All Adverse Reactions / Frequency Grade 3-4 Adverse Reactions / 
Frequency 

Infections and 
infestations* 

Very common 
Infections (bacterial, viral, fungal) 
 
Common 
Sepsisa 
 
Not known 
Septic shockc 

Common 
Infections (bacterial, viral, fungal), 
sepsisa 
 
Not known 
Septic shockc 

Neoplasms benign, 
malignant and 
unspecified 
(including cysts and 
polyps)* 

Not known 
Treatment-related second malignancy 

Not known 
Treatment-related second malignancy 

Blood and lymphatic 
system disorders* 

Very common 
Myelosuppression, pancytopenia, 
febrile neutropenia 

Very common 
Myelosuppression, pancytopenia, 
febrile neutropenia 

Immune system 
disorders* 

Common 
Hypersensitivity 

 



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System Organ Class 
(SOC) 

All Adverse Reactions / Frequency Grade 3-4 Adverse Reactions / 
Frequency 

Metabolism and 
nutrition disorders 

Common 
Decreased appetite  
 
Uncommon 
Hyperglycaemia 
 
Not known 
Acidosisb, glucose tolerance 
impaired, electrolyte imbalance 

Common 
Decreased appetite  
 
Uncommon 
Hyperglycaemia 
 
Not known 
Acidosisb, glucose tolerance 
impaired, electrolyte imbalance 

Psychiatric disorders Common 
Insomnia 
 
Uncommon 
Confusional state  
 
Not known 
Agitation 

Rare 
Confusional state  
 

Nervous system 
disorders 

Common 
Headache, dizziness 
 
Uncommon 
Peripheral sensory neuropathy 
 
Not known 
Encephalopathy, intracranial 
haemorrhage, extrapyramidal 
disorder, syncope, paraesthesia 

Rare 
Headache, peripheral sensory 
neuropathy 
 
Not known 
Encephalopathy, intracranial 
haemorrhage, syncope 

Eye disorders Not known 
Dry eye 

 

Cardiac disorders* Common 
Cardiac arrhythmias (e.g. atrial 
fibrillation, sinus arrhythmia) 
 
Not known 
Cardiac arrest, cardiac failure, 
myocardial infarction, pericardial 
effusion 

Uncommon 
Cardiac arrhythmias (e.g. atrial 
fibrillation, sinus arrhythmia) 
 
Not known 
Cardiac arrest, myocardial infarction 

Vascular disorders Common 
Hypertension, flushing 
 
Uncommon 
Haematoma, hypotension 
 
Not known 
Embolism, haemorrhage 

Uncommon 
Hypertension 
 
Not known 
Embolism, haemorrhage 



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System Organ Class 
(SOC) 

All Adverse Reactions / Frequency Grade 3-4 Adverse Reactions / 
Frequency 

Respiratory, thoracic 
and mediastinal 
disorders 

Common 
Dyspnoea, epistaxis 
 
Uncommon 
Pneumonitis, pleural effusion, 
pharyngeal or laryngeal 
inflammation, cough, laryngeal pain, 
hiccups 
 
Not known 
Oropharyngeal pain, hypoxia, 
dysphonia 

Uncommon 
Dyspnoea, pleural effusion, 
pharyngeal or laryngeal 
inflammation  
 
Rare 
Epistaxis, pneumonitis  
 
Not known 
Hypoxia 

Gastrointestinal 
disorders* 

Very common 
Stomatitis/mucositis, diarrhoea, 
nausea, vomiting, abdominal pain 
 
Common 
Oral pain, gastritis, dyspepsia, 
constipation, dysphagia 
 
Uncommon 
Mouth haemorrhage, abdominal 
distension, oesophageal or 
gastrointestinal pain, dry mouth 
 
Not known 
Gastrointestinal haemorrhage, 
neutropenic colitis, oesophagitis, anal 
inflammation, mouth ulceration 

Common 
Stomatitis/mucositis, diarrhoea, 
nausea, abdominal pain 
  
Uncommon 
Vomiting, oral pain, dysphagia, 
mouth haemorrhage, oesophageal or 
gastrointestinal pain 
 
Not known 
Gastrointestinal haemorrhage, 
neutropenic colitis 

Hepatobiliary 
disorders* 

Uncommon 
Veno-occlusive liver disease, 
hepatotoxicity  
 
Not known 
Hepatic failure, hepatomegaly, 
hepatic pain  

Rare 
Veno-occlusive liver disease, 
hepatotoxicity 
 
Not known 
Hepatic failure 

Skin and 
subcutaneous tissue 
disorders 

Common 
Maculo-papular rash, purpura, 
erythema, palmar-plantar 
erythrodysaesthesia syndrome, 
pruritus, alopecia  
 
Uncommon 
Erythema multiforme, dermatitis 
acneiform, rash, hyperhidrosis 
 
Not known 
Generalised erythema, dermatitis, 
skin necrosis or ulcer, skin 
hyperpigmentationd, dry skin 

Uncommon 
Maculo-papular rash, purpura, 
erythema 
 
Not known 
Skin necrosis 



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System Organ Class 
(SOC) 

All Adverse Reactions / Frequency Grade 3-4 Adverse Reactions / 
Frequency 

Musculoskeletal and 
connective tissue 
disorders 

Common 
Pain in extremities, back pain, bone 
pain, arthralgia, myalgia 
 
Not known 
Muscular weakness 

Rare 
Pain in extremities, bone pain 

Renal and urinary 
disorders 

Common 
Acute kidney injury, haematuria 
 
Not known 
Renal failure, cystitisc, dysuria 

Uncommon 
Acute kidney injury, haematuria 

General disorders 
and administration 
site conditions 

Very common 
Asthenic conditions (fatigue, 
asthenia, lethargy)  
 
Common 
Oedema, pyrexiae, chills 
 
Uncommon 
Non-cardiac chest pain, pain 
 
Not known 
Injection site reaction, feeling cold 

Common 
Fatigue 
 
Rare 
Non-cardiac chest pain, oedema 
pyrexiae 

Investigations Very common 
Bilirubin increased 
 
Common 
Transaminases (ALT/AST) 
increased, γGT increased, blood 
alkaline phosphatase increased, 
C-reactive protein increased, weight 
decreased, weight increased 
 
Not known 
Blood creatinine increased, blood 
lactate dehydrogenase (LDH) 
increased  

Common 
Bilirubin increased, transaminases 
(ALT/AST) increased, γGT increased 
 
Uncommon 
Blood alkaline phosphatase 
increased, C-reactive protein 
increased 
 
Not known 
Blood LDH increased 

* See detailed sections below 
a Clinically or microbiologically documented infection with grade 3 or 4 neutropenia (absolute 

neutrophil count [ANC] < 1.0 x 109/L) and sepsis 
b Acidosis might be a consequence of the release of methanesulfonic acid through treosulfan 

activation/cleavage in the plasma 
c Case reports (> 2) after treosulfan-based conditioning obtained from other sources 
d Bronze pigmentation 
e Fever in the absence of neutropenia where neutropenia is defined as ANC < 1.0 x 109/L 
 
Description of selected adverse reactions 
 



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Infections 
 
The overall incidence of infections was 13.1% (74/564). The most frequent type was lung infection 
(12/74 [16.2%]). Pathogens included bacteria (e.g. Staphylococcus, Enterococcus, Corynebacterium), 
viruses (e.g. cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes) as well as fungi (e.g. 
candida). The infection rate was lowest in patients treated with the dose regimen of 10 g/m² of 
treosulfan per day, from day -4 to -2 (7.7%). 
 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
 
One of 564 adult patients (0.2%) developed a second malignancy (breast cancer). A few further cases 
of second malignancies after treosulfan-based conditioning have been reported by other investigators. 
After long-term therapy with conventional doses of oral treosulfan in patients with solid tumours acute 
myeloid leukaemia was observed in 1.4% of 553 patients. 
 
Blood and lymphatic system disorders 
 
Blood disorders were observed in 67 of 564 adult patients (11.9%). The most frequent adverse reaction 
was febrile neutropenia (11.3%). The lowest incidence was noted with the dose regimen of 
10 g/m²/day, day -4 to -2 (4.1%). 
The median (25%/75% percentiles) duration of neutropenia was 14 (12, 20) days with the 10 g/m² 
treosulfan dose and 17.5 (14, 21) days with the 14 g/m² treosulfan dose. 
 
Cardiac disorders 
 
Cardiac disorders were observed in 25 patients (4.4%). The most frequent adverse reactions were 
cardiac arrhythmias, e.g. atrial fibrillation (1.2%), sinus tachycardia (0.9%), supraventricular 
tachycardia (0.4%), and ventricular extrasystole (0.4%). Isolated cases of cardiac arrest, cardiac 
failure, and myocardial infarction occurred. The lowest frequency of cardiac disorders was seen with 
the dose regimen of 10 g/m²/day, day -4 to -2 (2.7%). 
 
Gastrointestinal disorders 
 
Gastrointestinal disorders were observed in 357 patients (63.3%). The most frequent adverse reactions 
reported were nausea (39.5%), stomatitis (36%), vomiting (22.5%), diarrhoea (15.6%), and abdominal 
pain (10.4%). The lowest frequencies of these adverse reactions were seen with the dose regimen of 
10 g/m² per day, day -4 to -2 (20.4%, 30.3%, 13.1%, 5.0%, and 5.5% respectively). 
 
Hepatobiliary disorders 
 
The overall incidence of veno-occlusive liver disease (VOD) was 0.9% (5/564). VOD occurred only 
with the dose regimen of 14 g/m²/day treosulfan. None of these cases were fatal or life-threatening.  
 
Paediatric population 
 
Tabulated list of adverse reactions 
 
The adverse reactions reported in the table below are derived from two clinical trials (including a total 
of 88 patients; median age 8 years [range 0–17 years]) where treosulfan combined with fludarabine 
(and mostly with additional thiotepa) was administered as conditioning treatment prior to alloHSCT in 
paediatric patients with malignant or non-malignant diseases. Treosulfan was administered in a dose 
range of 10-14 g/m² BSA on three consecutive days. 
 
Adverse reactions are listed below, by system organ class and by frequency: 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 



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rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency 
group, undesirable effects are presented in order of decreasing seriousness. 
 
System Organ Class (SOC) All Adverse Reactions / 

Frequency 
Grade 3-4 Adverse Reactions / 
Frequency 

Infections and infestations* Very common 
Infections (bacterial, viral, 
fungal) 

Common 
Infections (bacterial, viral, 
fungal) 

Neoplasms benign, malignant 
and unspecified (including 
cysts and polyps)* 

Not known 
Treatment-related second 
malignancya  

Not known 
Treatment-related second 
malignancya 

Blood and lymphatic system 
disorders* 

Very common 
Myelosuppression, 
pancytopenia 
 
Not known 
Febrile neutropenia 

Very common 
Myelosuppression, 
pancytopenia 
 
Not known 
Febrile neutropenia 

Metabolism and nutrition 
disorders 

Not known 
Alkalosis, electrolyte imbalance, 
hypomagnesaemia 

Not known 
Alkalosis 

Nervous system disorders* Not known 
Headache, paraesthesia, seizure 

Not known 
Paraesthesia 

Eye disorders Not known 
Conjunctival haemorrhage, dry 
eye 

 

Vascular disorders Not known 
Capillary leak syndrome, 
hypertension, hypotension 

Not known 
Capillary leak syndrome, 
hypertension, hypotension 

Respiratory, thoracic and 
mediastinal disorders 

Common 
Oropharyngeal pain, epistaxis 
 
Not known 
Hypoxia 

Not known 
Hypoxia 

Gastrointestinal disorders* Very common 
Stomatitis/mucositis, diarrhoea, 
nausea, vomiting, abdominal 
pain 
 
Common 
Dysphagia, oral pain 
 
Not known 
Neutropenic colitis, anal 
inflammation, dyspepsia, 
proctitis, gastrointestinal pain, 
constipation 

Very common 
Stomatitis/mucositis, nausea  
 
Common 
Dysphagia, diarrhoea, vomiting, 
abdominal pain 
 
Not known 
Neutropenic colitis 

Hepatobiliary disorders Not known 
Veno-occlusive liver disease, 
hepatomegaly, hepatotoxicity 

Not known 
Veno-occlusive liver disease 



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System Organ Class (SOC) All Adverse Reactions / 
Frequency 

Grade 3-4 Adverse Reactions / 
Frequency 

Skin and subcutaneous tissue 
disorders 

Very common 
Pruritus  
 
Common 
Dermatitis exfoliative, 
maculo-papular rash, rash, 
erythema, pain of skin, skin 
hyperpigmentationb, alopecia  
 
Not known 
Skin ulcer, erythema 
multiforme, urticaria, dermatitis 
bullous, dermatitis acneiform, 
palmar-plantar 
erythrodysaesthesia syndrome, 
dermatitis diapera 

Common 
Dermatitis exfoliative, 
maculo-papular rash, erythema  
 

Musculoskeletal and 
connective tissue disorders 

Not known 
Pain in extremities  

 

Renal and urinary disorders Not known 
Acute kidney injury, renal 
failure, noninfective cystitis  

Not known 
Acute kidney injury, renal 
failure 

Reproductive system and 
breast disorders 

Not known 
Scrotal erythema 

 

General disorders and 
administration site conditions 

Very common 
Pyrexiac 
 
Not known 
Chills, fatigue, pain 

 

Investigations Common 
Transaminases (ALT/AST) 
increased, bilirubin increased 
 
Not known 
γGT increased 

Common 
Bilirubin increased 
 
Uncommon 
Transaminases (ALT/AST) 
increase 
 
Not known 
γGT increased 

* See detailed sections below 
a Case reports (> 1) after treosulfan-based conditioning obtained from other sources  
b Bronze pigmentation 
c Fever in the absence of neutropenia where neutropenia is defined as ANC < 1.0 x 109/L 
 
Description of selected adverse reactions 
 
Infections 
 
The overall incidence of infections in 88 paediatric patients was 11.4% (10/88) and thus comparable to 
that seen in adults. The frequency was higher in the paediatric age group 12–17 years (6/35 [17.1%]) 
compared to younger children (4/53 [7.5%]). 
 



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Neoplasms benign, malignant and unspecified (including cysts and polyps) 
 
Five cases of a second malignancy (myelodysplastic syndrome, acute lymphoblastic leukaemia, 
Ewing’s sarcoma) were reported by other investigators after treosulfan-based conditioning. All five 
paediatric patients received alloHSCT for primary immunodeficiencies, i.e. diseases with an increased 
risk for neoplasias per se. 
 
Blood and lymphatic system disorders 
 
The median (25%/75% percentiles) duration of neutropenia was 21 (16, 26) days in paediatric patients 
with malignant diseases and 24 (17, 26) days in patients with non-malignant disorders. 
 
Nervous system disorders 
 
Seizure in the context of an encephalitis infection was reported in one of 88 paediatric patients. A 
report from an investigator-initiated trial performed in children with primary immunodeficiencies lists 
four cases of seizures occurring after other treosulfan-based conditioning regimens (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The principal toxic effect of treosulfan is profound myeloablation and pancytopenia. In addition, 
acidosis, skin toxicity, nausea, vomiting and gastritis may occur. In the absence of haematopoietic 
stem cell transplantation, the recommended dose of treosulfan would constitute an overdose. No 
specific antidote of treosulfan overdose is known. The haematologic status should be closely 
monitored and vigorous supportive measures instituted as medically indicated.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, ATC code: L01AB02 
 
Mechanism of action 
 
Treosulfan is a prodrug of a bifunctional alkylating agent with cytotoxic activity to haematopoietic 
precursor cells. The activity of treosulfan is due to the spontaneous conversion into a mono-epoxide 
intermediate and L-diepoxybutan (see section 5.2). 
The epoxides formed alkylate nucleophilic centres of deoxyribonucleic acid (DNA) and are able to 
induce DNA cross-links which are considered responsible for the stem cell depleting and 
antineoplastic effects.  
 
Pharmacodynamic effects 
 
Treosulfan has a broad antineoplastic and antileukaemic activity. This was demonstrated against 
transplanted mouse and rat lymphomas/leukaemias, sarcomas and hepatomas, human tumour 
xenografts, human tumour biopsies and cell lines. 
The immunosuppressive effects of treosulfan are attributed to its toxicity against primitive and 
committed progenitor cells, T and NK cells, reduction of cellularity of primary and secondary 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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lymphatic organs and a preclusive effect on the ‘cytokine storm’ that precedes the development of 
Graft-versus-Host-Disease (GvHD) and is involved in the pathogenesis of veno-occlusive disease. 
 
Clinical efficacy and safety 
 
In the pivotal phase III trial, adult patients with acute myeloid leukaemia (AML) or myelodysplastic 
syndrome (MDS) and increased risk for standard conditioning therapies because of higher age 
(≥ 50 years) or comorbidities (haematopoietic cell transplantation comorbidity index [HCT-CI] score 
> 2) were randomised to receive a conditioning regimen with 3 × 10 g/m² treosulfan combined with 
fludarabine (FT10; n = 220) or a regimen of intravenous busulfan (total dose 6.4 mg/kg) combined with 
fludarabine (FB2; n = 240), followed by alloHSCT. 64% of patients had AML and 36% MDS. The 
median age of patients was 60 years (range 31–70 years); 25% of patients were older than 65 years. 
The primary endpoint of this study was event-free survival (EFS) after 2 years. Events were defined as 
relapse of disease, graft failure or death (whatever occurred first). Non-inferiority of FT10 versus the 
reference FB2 was statistically proven (Figure 1). 
 
Figure 1: Kaplan-Meier estimates of event-free survival (Full Analysis Set) 

 
a Adjusted for donor type as factor, and risk group and centre as strata using Cox regression model. 
b For testing non-inferiority of treosulfan compared to busulfan. 
c For testing superiority of treosulfan compared to busulfan. 
 
Analyses of EFS at 2 years for various pre-defined subgroups (donor type, risk group, disease, age 
group, HCT-CI score, remission status at study entry, and various combinations of these parameters) 
were always in favour of the treosulfan regimen (hazard ratio [HR] of FT10 vs. FB2 < 1), with only one 
exception (risk group I of MDS patients; HR 1.14 [95% CI 0.48, 2.63]). 
Further results are shown in Table 1. 
 



15 

Table 1: Treatment results at 24 months (Full analysis set) 
Parameter Treosulfan Busulfan Hazard ratiob  

(95% CI) 
P valueb 

Number of patients 220 240   
Overall survivala; % (95% CI) 71.3 (63.6, 

77.6) 
56.4 (48.4, 
63.6) 

0.61 (0.42, 
0.88) 

0.0082 

Cumulative incidence of 
relapse/progression; % (95% CI) 

24.6 (17.8, 
31.3) 

23.3 (17.6, 
29.0) 

0.87 (0.59, 
1.30) 0.5017 

Cumulative incidence of 
transplant-related mortality; % 
(95% CI) 

12.1 (8.1, 17.7) 28.2 (21.4, 36.5) 
0.54 (0.32, 
0.91) 0.0201 

a Based on Kaplan-Meier estimates; b adjusted for donor type, risk group and centre using Cox 
regression model  

 
Results of GvHD are shown in Table 2. 
 
Table 2: Cumulative incidence of GvHD (Full analysis set) 
Parameter Treosulfan Busulfan P value 
Number of patients 220 240  
Acute GvHD, all Grades; % (95% CI) 52.1 (45.5, 58.7) 58.8 (52.5, 65.0) 0.1276 
Acute GvHD, Grades III/IV; % (95% 
CI) 6.4 (3.2, 9.6) 9.6 (5.9, 13.3) 0.2099 

Chronic GvHDa; % (95% CI) 60.1 (49.8, 70.3) 60.7 (53.1, 68.4) 0.5236 
Extensive chronic GvHDa; % (95% CI) 18.4 (12.0, 24.8) 26.1 (19.2, 33.1) 0.1099 
a Up to 2 years after alloHSCT 



16 

There is limited information available on treosulfan-based conditioning (FT14 regimen ± thiotepa; see 
section 4.2) in adult patients with non-malignant disorders (NMD). The main indications for an 
alloHSCT with treosulfan conditioning in adult NMD patients are haemoglobinopathies (e.g. sickle 
cell disease, thalassaemia major [TM]), primary immune deficiency, hemophagocytic disorder, 
immune dysregulatory disorder and bone marrow failure). 
 
In one study, 31 NMD patients were treated with the FT14 regimen plus anti-thymocyte globulin. The 
age of the patients ranged from 0.4 to 30.5 years, and 29% had HCT-CI scores > 2. All patients 
engrafted, with a median time to neutrophil engraftment of 21 (range, 12–46) days. The two-year 
projected overall survival was 90%. Complete disease responses were observed in 28 patients (90%), 
as measured by clinical symptoms and laboratory assays (Burroughs LM et al., Biology of Blood and 
Marrow Transplantation 2014; 20(12):1996-2003). 
 
An Italian group treated 60 TM patients (age range 1-37 years; including 12 adults) with the FT14 plus 
thiotepa regimen. All patients engrafted except one, who died on day  +11; the median time to 
neutrophil and platelet recovery was 20 days. With a median follow-up of 36 months (range, 4-73), the 
5-year overall survival probability was 93% (95% CI 83-97%). No difference in terms of outcome was 
observed between children and adults (Bernardo ME et al.; Blood 2012; 120(2):473-6). 
 
A retrospective comparison of treosulfan-based (n = 16) versus busulfan-based (n = 81) conditioning 
in adult patients revealed quite comparable survival rates (70.3 ± 15.1% vs. 69.3 ± 5.5%), while risk 
for acute GvHD was lower in the treosulfan group (odds ratio 0.28; 95% CI 0.12-0.67; P = 0.004) 
(Caocci G et al.; American Journal of Hematology 2017; 92(12):1303-1310). 
 
Paediatric population 
 
The efficacy and safety of treosulfan-based conditioning was evaluated in 70 patients with acute 
lymphoblastic leukaemia (ALL), AML, MDS, or juvenile myelomonocytic leukaemia (JMML) who 
received a conditioning regimen with treosulfan and fludarabine with (n = 65) or without (n = 5) 
thiotepa (see section 4.2). A total of 37 patients (52.9%) were younger than 12 years. 
No patient experienced a primary graft failure but one patient with ALL experienced a secondary graft 
failure. The incidence of complete donor-type chimerism was 94.2% (90% CI 87.2-98.0%) at day +28 
visit, 91.3% (90% CI 83.6-96.1%) at day +100 visit and 91.2% (90% CI 82.4-96.5%) at month 12 
visit.  
The overall survival at 12 months is 91.4% (90% CI 83.9-95.5%). A total of 7 of the 70 patients 
(10.0%) died, two patients because of relapse/progression, three patients transplant-related and two 
further patients for other reasons. The freedom from transplant-related mortality until day +100 after 
HSCT (primary endpoint) is 98.6% (90% CI 93.4–99.7%) because one of the 70 patients died due to 
transplantation/treatment-related cause until day +100 after HSCT. Transplant-related mortality at 
12 months is 2.9% (90% CI 0.9 – 8.9%). Eleven patients had a relapse/progression. The cumulative 
incidence of relapse/progression is 15.7% (90% CI 8.6-22.9%) at month +12. 
 
The European Medicines Agency has deferred the obligation to submit the results of a study with 
treosulfan-based conditioning in paediatric patients with non-malignant diseases (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Treosulfan is a prodrug that is spontaneously converted under physiological conditions (pH 7.4; 
37 °C) into a monoepoxide intermediate and L-diepoxybutane with a half-life of 2.2 hours. 
 
Absorption 
 
After intravenous administration, peak plasma levels are reached at the end of the infusion time. 
Maximum plasma levels (mean ± SD) in adult patients after a 2-hour intravenous infusion of 10, 12, or 
14 g/m² treosulfan were 306 ± 94 µg/mL, 461 ± 102 µg/mL, and 494 ± 126 µg/mL, respectively. 



17 

 
Distribution 
 
Treosulfan is rapidly distributed in the body; however, its penetration through the blood-brain-barrier 
is quite limited (see section 5.3). The volume of distribution in adult patients is about 20–30 litres. No 
dose accumulation with the recommended daily treatment on three consecutive days was observed. 
Treosulfan does not bind to plasma proteins. 
 
Biotransformation 
 
Under physiological conditions (pH 7.4, temperature 37 °C), the pharmacologically inactive treosulfan 
is converted spontaneously (non-enzymatically) into the active monoepoxide intermediate 
(S,S-EBDM = (2S,3S)-1,2-epoxybutane-3,4-diol-4-methanesulfonate) and finally to L-diepoxibutane 
(S,S-DEB = (2S,3S)-1,2:3,4-diepoxybutane). 
At concentrations up to 100 µM, treosulfan has no unequivocal effect on CYP1A2, 2C9, 2C19, 2D6, 
or 3A4 activities in vitro. Therefore, treosulfan is unlikely to participate in, or contribute to, potential 
CYP450-mediated interactions in vivo. 
 
Elimination 
 
Plasma concentrations of treosulfan decline exponentially and are best described by a first order 
elimination process fitted by a two-compartment model.  
The terminal half-life (T1/2ß) of intravenously administered treosulfan (up to 47 g/m²) is approximately 
2 hours. Approximately 25–40% of the treosulfan dose is excreted unchanged with the urine within 
24 hours, nearly 90% of which within the first 6 hours after administration. 
 
Linearity/non-linearity 
 
Regression analysis of the area under the curve (AUC0-∞) versus treosulfan dose indicated a linear 
correlation. 
 
Renal and hepatic impairment 
 
No pharmacokinetic studies with treosulfan were done in patients with severe renal or hepatic 
impairment, because such patients are generally excluded from alloHSCT. About 25–40% of 
treosulfan is excreted in urine; however, an influence of renal function on renal clearance of treosulfan 
was not observed. 
 
Paediatric population 
 
Conventional dose calculation simply based on BSA results in a significantly higher exposure (AUC) 
of smaller children and infants with low BSA compared to adolescents or adults. Therefore, dosing of 
treosulfan in paediatric patients has to be adapted to the BSA (see section 4.2). 
Mean apparent terminal half-life of treosulfan was comparable between the different age groups and 
ranged between 1.3 and 1.6 hours. 
 
5.3 Preclinical safety data 
 
Due to its alkylating mechanism of action treosulfan is characterised as a genotoxic compound with 
carcinogenic potential. Specific reproductive and developmental toxicity studies on treosulfan in 
animals were not conducted. However, during chronic toxicity tests in rats spermatogenesis and 
ovarian function were significantly affected. Published literature data report on gonadotoxicity of 
treosulfan in pre-pubertal and pubertal male and female mice.  
Published data concerning treatment of mice and rats with L-diepoxibutane (the alkylating 
transformation product of treosulfan) revealed impairment of fertility, uterine-ovarian and sperm 
development. 



18 

 
Juvenile animal studies 
 
In juvenile rat toxicity studies treosulfan induced slight retardation of physical development and a 
slightly delayed time-point of vaginal opening in females. A very low penetration of 
blood-brain-barrier by treosulfan was observed in rats. The treosulfan concentrations in brain tissue 
were 95%–98% lower than in plasma. However, an approximately 3-fold higher exposure in brain 
tissue of juvenile rats in comparison to young adults was found. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
None. 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
Unopened vial 
5 years 
 
Reconstituted solution for infusion 
After reconstitution with sodium chloride 4.5 mg/mL (0.45%) solution, chemical and physical stability 
has been demonstrated for 2 days at 25 °C. 
 
From a microbiological point of view, unless the method of reconstitution precludes the risk of 
microbial contamination, the product should be used immediately. If not used immediately, in-use 
storage times and conditions are the responsibility of the user.  
Do not store in a refrigerator (2 °C-8 °C) as this might cause precipitation. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3.  
 
6.5 Nature and contents of container 
 
Trecondi 1 g powder for solution for infusion 
Colourless type III glass vial, with rubber stopper and aluminium cap containing 1 g of treosulfan. 
 
Trecondi 5 g powder for solution for infusion 
Colourless type III glass vial, with rubber stopper and aluminium cap containing 5 g of treosulfan. 
 
Trecondi is available in packs of 1 or 5 vials. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
As with all cytotoxic substances, appropriate precautions should be taken when handling treosulfan. 



19 

 
Trained personnel should reconstitute the medicinal product. When handling treosulfan, inhalation, 
skin contact or contact with mucous membranes should be avoided (the use of adequate protective 
disposable gloves, goggles, gown and mask is recommended). Contaminated body parts should be 
carefully rinsed with water and soap, the eyes should be rinsed with sodium chloride 9 mg/mL (0.9%) 
solution. If possible it is recommended to work on a special safety workbench, equipped with laminar 
flow, with liquid-impermeable, absorbent disposable foil. Adequate care and precautions should be 
taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic medicinal 
products. Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended to 
minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of 
a venting needle.  
Pregnant personnel should be excluded from handling cytotoxics. 
 
Instructions for reconstitution of treosulfan: 
1. Treosulfan is reconstituted in its original glass container. Reconstituted solutions of treosulfan 

may be combined into a larger glass vial, PVC bag or PE bag. 
2. To avoid solubility problems, warm the solvent, sodium chloride 4.5 mg/mL (0.45%) solution, 

to 25 °C - 30 °C (not higher), for example by using a water bath. 
3. Remove the treosulfan powder carefully from the inner surface of the vial by shaking. This 

procedure is very important, because moistening of powder that sticks to the surface results in 
caking. If this happens, vigorously shake the vial to redissolve the cake. 

4. Reconstitute each vial of Trecondi containing 1 g treosulfan in 20 mL of pre-warmed 
(maximum 30 °C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking. 
Reconstitute each vial of Trecondi containing 5 g treosulfan in 100 mL of pre-warmed 
(maximum 30 °C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking. 

 
For preparation of sodium chloride 4.5 mg/mL (0.45%) solution equivalent volumes of sodium 
chloride 9 mg/mL (0.9%) solution and water for injections can be mixed. 
 
The reconstituted solution contains 50 mg treosulfan per mL and appears as a clear colourless solution. 
Solutions showing any sign of precipitation should not be used. 
 
Treosulfan has mutagenic and carcinogenic potential. Remnants of the medicinal product as well as all 
materials that have been used for reconstitution and administration must be destroyed according to 
standard procedures applicable to antineoplastic agents, with due regard to current laws related to the 
disposal of hazardous waste. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1351/001 (1 g, 1 vial) 
EU/1/18/1351/002 (1 g, 5 vials) 
EU/1/18/1351/003 (5 g, 1 vial) 
EU/1/18/1351/004 (5 g, 5 vials) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 



20 

 
Date of first authorisation: 20 June 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  

  

http://www.ema.europa.eu/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



22 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
medac Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

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

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

  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Trecondi 1 g powder for solution for infusion 
Trecondi 5 g powder for solution for infusion 
treosulfan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 g treosulfan. 
Each vial contains 5 g treosulfan. 
 
After reconstitution 1 mL of solution contains 50 mg treosulfan. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
1 g 
5 g 
 
1 vial  
5 vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
 
 
8. EXPIRY DATE 
 
EXP 
 



26 

 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Guidelines for the safe disposal of antineoplastic agents must be observed. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1351/001 (1 g, 1 vial) 
EU/1/18/1351/002 (1 g, 5 vials) 
EU/1/18/1351/003 (5 g, 1 vial) 
EU/1/18/1351/004 (5 g, 5 vials) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  



27 

NN:   



28 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
Vial label 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Trecondi 1 g powder for solution for infusion 
Trecondi 5 g powder for solution for infusion 
treosulfan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 g treosulfan. 
Each vial contains 5 g treosulfan. 
 
After reconstitution 1 mL of solution contains 50 mg treosulfan. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion. 
 
1 g 
5 g 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after reconstitution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



29 

9. SPECIAL STORAGE CONDITIONS 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1351/001 (1 g, 1 vial) 
EU/1/18/1351/002 (1 g, 5 vials) 
EU/1/18/1351/003 (5 g, 1 vial) 
EU/1/18/1351/004 (5 g, 5 vials) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



31 

Package leaflet: Information for the user 
 

Trecondi 1 g powder for solution for infusion 
Trecondi 5 g powder for solution for infusion 

treosulfan 
 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again.  
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Trecondi is and what it is used for  
2. What you need to know before you are given Trecondi 
3. How to use Trecondi  
4. Possible side effects  
5. How to store Trecondi 
6. Contents of the pack and other information 
 
 
1. What Trecondi is and what it is used for 
 
Trecondi contains the active substance treosulfan, which belongs to a group of medicines called 
alkylating agents. Treosulfan is used to prepare patients for bone marrow transplant (haematopoietic 
stem cell transplantation). Treosulfan destroys the bone marrow cells and enables the transplant of new 
bone marrow cells which leads to the production of healthy blood cells. 
 
Trecondi is used as a treatment before blood stem cell transplantation in adults with cancer and 
non-cancerous disorders, and in adolescents and children older than one month with cancer.  
 
 
2. What you need to know before you are given Trecondi  
 
Do not use Trecondi 
 if you are allergic to treosulfan, 
 if you suffer from an active uncontrolled infection, 
 if you suffer from severe heart, lung, liver or kidney diseases, 
 if you suffer from hereditary DNA repair disorder, a condition that reduces the ability to repair 

DNA (which carries your genetic information), 
 if you are pregnant, or think you may be pregnant. 
 
Warnings and precautions  
Trecondi is a cell-killing (cytotoxic) medicine that is used to decrease the number of blood cells. At 
the recommended dose, this is the desired effect. You will have regular blood tests during treatment to 
check your blood cell counts do not fall too low. 
 
In order to prevent and treat infections, you will be given medicines, such as antibiotics, antifungals or 
antivirals. 
 
Trecondi may increase the risk of having another cancer in the future. 
 



32 

Since inflammation of the oral mucosa is a common side effect of this medicine, you should pay 
attention to adequate oral hygiene. Prophylactic use of mouthwashes (e.g. with barrier protectants, 
antimicrobials) or application of ice within the oral cavity (lessens blood flow to the oral mucosa and 
reduces the amount of treosulfan reaching the cell) is recommended. 
 
You must not receive live vaccines during treatment with treosulfan. 
 
Trecondi may cause symptoms of the menopause (absence of menstrual periods).  
 
Children and adolescents 
Fits (seizures) may occur very rarely in infants of less than 4 months of age. Children younger than 
1 year may have more severe side effects that affect breathing than older ones. Your child will be 
monitored for signs of side effects affecting nerves and breathing problems.  
 
Nappy rash with ulceration of the area around the anus (perianal) may occur in infants, toddlers and 
children wearing nappies because treosulfan passed out in the urine can damage the skin. Therefore, 
nappies should be changed frequently during 6–8 hours after each dose of this medicine.  
 
There is not sufficient information on the use of treosulfan in children aged less than 1 month. 
 
Other medicines and Trecondi 
Tell your doctor if you are taking, have recently taken or might take any other medicines, including 
medicines obtained without a prescription. 
 
Pregnancy, breast-feeding and fertility 
You must not get pregnant during treatment with this medicine and up to 6 months after treatment. 
Use an effective method of contraception when either you or your partner is receiving this medicine. 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before you receive this medicine. 
 
You should stop breast-feeding before starting treatment with this medicine. 
 
If you are a man treated with this medicine, you should not father a child during and up to 6 months 
after treatment.  
 
This medicine may make you infertile and it may not be possible for you to get pregnant after 
treatment with it. If you are concerned about having children, you should discuss this with your doctor 
before treatment. Men should seek advice about the possibility of sperm preservation before starting 
therapy. 
  
Driving and using machines 
This medicine can cause nausea, vomiting and dizziness which may reduce your ability to drive or use 
machines. If you are affected, do not drive or use machines. 
 
 
3. How to use Trecondi 
 
Use in adults 
This medicine is used in combination with fludarabine. 
The recommended dose is 10–14 g/m² body surface area (calculated using your height and weight).  
 
Use in children and adolescents 
This medicine is used in combination with fludarabine and in most cases also with thiotepa. The 
recommended dose is 10–14 g/m² body surface area.  
 



33 

How Trecondi is given 
This medicine will be given to you by your doctor. It is given by drip (infusion) into a vein over 
2 hours for 3 days before blood stem cell infusion. 
 
If you were given more Trecondi than you should 
Because this medicine is given by a doctor, you will be given the correct dose. However, if you think 
you have received more of this medicine than you should, tell your doctor or nurse as soon as possible. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
The most serious side effects of treosulfan therapy or the transplant procedure include:  
• decrease in blood cell counts which is the intended effect of the medicine to prepare you for 

your transplant infusion (all patients: very common)  
• infections caused by bacteria, viruses and fungi (all patients: very common)  
• blocking of a vein into the liver (adults: uncommon; children and adolescents: not known) 
• inflammation of the lung (pneumonitis) (adults: uncommon)  
 
Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these 
events. 
 
Adults 
 
A list of all other side effects is set out below according to how common they are. 
 
Very common (may affect more than 1 in 10 people) 
• decreased counts of white blood cells with fever (febrile neutropenia) 
• inflammation of the lining of various parts of the body, especially in the mouth (which can 

cause ulcers), diarrhoea, nausea, vomiting, belly (abdominal) pain  
• tiredness  
• increased blood level of bilirubin (a liver pigment, often a sign of liver problems) 
 
Common (may affect up to 1 in 10 people) 
• bloodstream infection (sepsis) 
• allergic reactions  
• decreased appetite 
• problems sleeping (insomnia)  
• headache, dizziness 
• changes and abnormalities in heart rhythm (heartbeat is irregular, too fast or too slow) 
• high blood pressure, flushing  
• difficulty breathing, nosebleeds  
• mouth pain, inflammation of the stomach, upset stomach, constipation, difficulty in swallowing 
• a type of rash with flat or raised red bumps on the skin (maculopapular rash), red spots on the 

skin (purpura), redness of skin (erythema), hand and foot syndrome (palms of the hands or soles 
of the feet tingle, become numb, painfully swollen, or red), itching, hair loss 

• pain in arms or legs, back pain, bone pain, joint pain, muscle pain 
• sudden decrease of kidney function, blood in the urine  
• retention of fluid in the body causing swelling (oedema), fever, chills 
• increased liver enzymes, increased C-reactive protein (a marker of inflammation in the body), 

weight gain, weight loss 
 



34 

Uncommon (may affect up to 1 in 100 people) 
• high blood sugar level  
• confusion 
• problems in the nerves of the arms or legs with symptoms such as numbness, reduced or  

increased sensitivity, tingling, burning pain (peripheral sensory neuropathy) 
• bruising, low blood pressure 
• fluid around the lung (pleural effusion), inflammation of throat, inflammation of or pain in voice 

box, cough, hiccups 
• bleeding in the mouth, feeling bloated, gullet or stomach pain, dry mouth 
• liver damage 
• a type of rash with red spots and sometimes with purple or blistered areas in the centre 

(erythema multiforme), acne, rash, excessive sweating 
• chest pain, pain 
 
Not known (frequency cannot be estimated from the available data) 
• life-threatening condition after bloodstream infection (septic shock) 
• different cancer caused by chemotherapeutic treatment (second malignancy) 
• increased acidity in the blood, abnormal control of blood sugar level, abnormal blood level of 

electrolytes (salts in the blood) 
• restlessness 
• abnormal brain function (encephalopathy), bleeding in the brain, restless, repetitive, or 

involuntary movements and rapid speech (extrapyramidal disorder), fainting, sensation of 
tingling, pricking or numbness (paraesthesia) 

• dry eye 
• heart not pumping enough blood for the body’s needs (heart failure), heart attack, fluid in the 

sac around the heart (pericardial effusion) 
• blockage of a blood vessel (embolism), bleeding 
• throat pain, decrease in the oxygen supply to a tissue (hypoxia), hoarseness 
• gastrointestinal bleeding, inflammation of the colon, inflammation of the gullet, inflammation of 

the anus, mouth ulcer 
• liver failure, enlarged liver, liver pain 
• reddening of the skin(generalised erythema), inflammation of skin (dermatitis), death of skin 

tissue, skin ulcer, bronze pigmentation of skin, dry skin 
• muscle weakness 
• kidney failure, inflammation of the urinary bladder (cystitis), pain on passing urine (dysuria) 
• pain or inflammation at the injection site, feeling cold 
• increased blood level of creatinine (a substance normally removed by the kidneys into the 

urine), increased blood level of lactate dehydrogenase (a substance that indicates tissue or 
cellular damage) 

 
Children and adolescents 
 
A list of all other side effects is set out below according to how common they are. 
 
Very common (may affect more than 1 in 10 people) 
• inflammation of the mucosa especially in the mouth (with ulcers), diarrhoea, nausea, vomiting, 

abdominal pain  
• itching 
• fever 
 
Common (may affect up to 1 in 10 people) 
• throat pain, nosebleeds  
• difficulty in swallowing, mouth pain 



35 

• reddening and flaking of most of the skin of the body (dermatitis exfoliative), a type of rash 
with flat or raised red bumps on the skin (maculopapular rash), rash, redness of skin (erythema), 
skin pain, bronze pigmentation of skin, hair loss 

• increased liver enzymes, increased blood level of bilirubin (a liver pigment, often a sign of liver 
problems) 

 
Not known (frequency cannot be estimated from the available data) 
• different cancer caused by chemotherapeutic treatment (second malignancy) 
• decreased counts of white blood cells with fever (febrile neutropenia) 
• less acid than normal in the blood (alkalosis), abnormal blood level of electrolytes, decreased 

blood level of magnesium 
• headache, sensation of tingling, pricking or numbness (paraesthesia), seizure 
• bleeding in the eye, dry eye 
• leakage of fluid from the capillaries (small blood vessels), high blood pressure, low blood 

pressure 
• decrease in the oxygen supply to parts of the body (hypoxia) 
• inflammation of the colon, inflammation of anus, upset stomach, inflammation of the lining of 

the rectum, gastrointestinal pain, constipation 
• enlarged liver, liver damage 
• skin ulcer, a type of rash with red spots and sometimes with purple or blistered areas in the 

centre (erythema multiforme), hives, skin condition with fluid-filled blisters (dermatitis 
bullous), acne, hand and foot syndrome (palms of the hands or soles of the feet tingle, become 
numb, painfully swollen, or red), nappy rash with ulceration in the area surrounding the anus 

• pain in arms or legs 
• decrease of kidney function, kidney failure, inflammation of the urinary bladder (cystitis) 
• redness of scrotal skin 
• chills, tiredness, pain 
• increased blood level of a liver enzyme (gamma-glutamyl transferase) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Trecondi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after “EXP”. The 
expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
For storage conditions after reconstitution of the medicine, see the information below for healthcare 
professionals. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Trecondi contains  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

The active substance is treosulfan. This medicine contains no other ingredients. 
 
Trecondi 1 g powder for solution for infusion 
1 vial contains 1 g of treosulfan. 
 
Trecondi 5 g powder for solution for infusion 
1 vial contains 5 g of treosulfan. 
 
After reconstitution 1 mL of the solution contains 50 mg treosulfan. 
 
What Trecondi looks like and contents of the pack 
White crystalline powder in a glass vial with a rubber stopper and aluminium cap. 
Trecondi is available in packs containing 1 or 5 vials (type III glass). 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
Tel.:  +49 4103 8006-0 
Fax:  +49 4103 8006-100 
E-mail: contact@medac.de 
 
This leaflet was last revised in <{MM/YYYY}><{month YYYY}>. 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.  
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
As with all cytotoxic substances, appropriate precautions should be taken when handling treosulfan. 
 
Trained personnel should reconstitute the medicinal product. When handling treosulfan, inhalation, 
skin contact or contact with mucous membranes should be avoided (the use of adequate protective 
disposable gloves, goggles, gown and mask is recommended). Contaminated body parts should be 
carefully rinsed with water and soap, the eyes should be rinsed with sodium chloride 9 mg/mL (0.9%) 
solution. If possible it is recommended to work on a special safety workbench, equipped with laminar 
flow, with liquid-impermeable, absorbent disposable foil. Adequate care and precautions should be 
taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic medicinal 
products. Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended to 
minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of 
a venting needle.  
Pregnant personnel should be excluded from handling cytotoxics. 
 



37 

Instructions for reconstitution of treosulfan: 
1. Treosulfan is reconstituted in its original glass container. Reconstituted solutions of treosulfan 

may be combined into a larger glass vial, PVC bag or PE bag. 
2. To avoid solubility problems, warm the solvent, sodium chloride 4.5 mg/mL (0.45%) solution, 

to 25 °C - 30 °C (not higher), for example by using a water bath. 
3. Remove the treosulfan powder carefully from the inner surface of the vial by shaking. This 

procedure is very important, because moistening of powder that sticks to the surface results in 
caking. If this happens, vigorously shake the vial to redissolve the cake. 

4. Reconstitute each vial of Trecondi containing 1 g treosulfan in 20 mL of pre-warmed 
(maximum 30 °C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking. 
Reconstitute each vial of Trecondi containing 5 g treosulfan in 100 mL of pre-warmed 
(maximum 30 °C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking. 

 
For preparation of sodium chloride 4.5 mg/mL (0.45%) solution equivalent volumes of sodium 
chloride 9 mg/mL (0.9%) solution and water for injections can be mixed. 
 
Reconstituted solution for infusion 
The reconstituted solution contains 50 mg treosulfan per mL and appears as a clear colourless solution.  
Solutions showing any sign of precipitation should not be used. 
 
After reconstitution with sodium chloride 4.5 mg/mL (0.45%) solution, chemical and physical stability 
has been demonstrated for 2 days at 25 °C. 
 
From a microbiological point of view, unless the method of reconstitution precludes the risk of 
microbial contamination, the product should be used immediately. If not used immediately, in-use 
storage times and conditions are the responsibility of the user.  
Do not store the reconstituted solution in a refrigerator (2 °C - 8 °C) as this might cause precipitation. 
 
Treosulfan has mutagenic and carcinogenic potential. Remnants of the medicinal product as well as all 
materials that have been used for reconstitution and administration must be destroyed according to 
standard procedures applicable to antineoplastic agents, with due regard to current laws related to the 
disposal of hazardous waste. 
 


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