Fertility warning
This medicine may affect fertility.
Leaflet TRECONDI 5g powder for solution for infusion
- Product code:
- W72167001
- Quantity:
- 1
- Indicated for:
- cancer
- Route of administration:
- infusion
- Substance:
- treosulfan (antineoplastic agent)
- ATC
- L01AB02 — Antineoplastic and immunomodulating agents | Alkylating agents | Alkyl sulfonates
Treosulfan is an alkylating agent primarily used as part of conditioning regimens for hematopoietic stem cell transplantation. It works by forming covalent bonds with DNA, leading to the inhibition of cellular replication and the destruction of malignant or existing hematopoietic cells.
Treosulfan is administered intravenously, usually in combination with other drugs such as fludarabine, to prepare patients for transplantation. It is particularly used in patients who cannot tolerate more intensive conditioning regimens due to its lower toxicity profile.
Common side effects include myelosuppression, nausea, vomiting, diarrhea, and fatigue. In rare cases, severe adverse reactions such as hepatotoxicity, pulmonary function impairment, or serious infections may occur. Careful monitoring of hematological parameters and organ function is essential during treatment.
Treosulfan is an important therapeutic option for patients requiring stem cell transplantation, contributing to increased success rates and reduced associated risks.
Treosulfan is administered intravenously, usually in combination with other drugs such as fludarabine, to prepare patients for transplantation. It is particularly used in patients who cannot tolerate more intensive conditioning regimens due to its lower toxicity profile.
Common side effects include myelosuppression, nausea, vomiting, diarrhea, and fatigue. In rare cases, severe adverse reactions such as hepatotoxicity, pulmonary function impairment, or serious infections may occur. Careful monitoring of hematological parameters and organ function is essential during treatment.
Treosulfan is an important therapeutic option for patients requiring stem cell transplantation, contributing to increased success rates and reduced associated risks.
General data about TRECONDI 5g
- Substance:
- treosulfan
- Date of latest medicines list:
- 01-09-2026
- Product code:
- W72167001
- Concentration:
- 5g
- Pharmaceutical form:
- powder for solution for infusion
- Quantity:
- 1
- Product type:
- Original
- Prescription status:
- P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Concentrations available for treosulfan
- 1g
- 5000mg
- 5g
Official documents
- Added to database:
- 22/07/2019
- Source record updated:
- 12/06/2026
Precautions:
Dose adjustment in hepatic impairment
Dose adjustment may be needed in liver disease.
Cytotoxic / special handling
Handle with special care.
Contraception required
Effective contraception is required during treatment.
Contraindicated during breastfeeding
Do not use this medicine while breastfeeding.
Contraindicated during pregnancy
Do not use this medicine during pregnancy.
Hepatotoxicity
This medicine may affect the liver.
Major drug interactions
This medicine may have important interactions with other medicines.
Myelosuppression / agranulocytosis
This medicine may lower blood cell counts.
Additional monitoring
This medicine is subject to additional monitoring.
Requires periodic laboratory tests
Periodic laboratory tests may be required during treatment.
Severe skin reactions
Stop taking the medicine and seek urgent medical help if a severe rash occurs.
Contents of the package leaflet for the medicine TRECONDI 5g powder for solution for infusion
Find in leaflet
Leaflet TRECONDI 5g
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 of powder contains 1 g of treosulfan.
Trecondi 5 g powder for solution for infusion
One vial of powder contains 5 g of treosulfan.
When reconstituted according to section 6.6, 1 mL of the solution for infusion contains 50 mgtreosulfan.
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 toallogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients and in paediatricpatients older than one month with malignant and non-malignant diseases.
4.2 Posology and method of administration
Administration of treosulfan should be supervised by a physician experienced in conditioningtreatment followed by alloHSCT.
PosologyAdults 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, givenon three consecutive days (day -4, -3, -2) before stem cell infusion (day 0). The total treosulfandose is 30 g/m²;
* Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on fiveconsecutive days (day -6, -5, -4, -3, -2) before stem cell infusion (day 0). The total fludarabinedose 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:
* Treosulfan 14 g/m² body surface area (BSA) per day as a two-hour intravenous infusion, givenon three consecutive days (day -6, -5, -4) before stem cell infusion (day 0). The total treosulfandose is 42 g/m²;
* Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on fiveconsecutive days (day -7, -6, -5, -4, -3) before stem cell infusion (day 0). The total fludarabinedose 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 -2before stem cell infusion (day 0).
Special populationsPaediatric population older than 1 month
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 totaltreosulfan 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)< 0.4 10.0≥ 0.4 to < 0.9 12.0≥ 0.9 14.0
* Fludarabine 30 mg/m² BSA per day as a 0.5-hour intravenous infusion, given on fiveconsecutive days (day -7, -6, -5, -4, -3) before stem cell infusion (day 0). The total fludarabinedose 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.
ElderlyNo dose adjustment is necessary in any subset of the elderly population.
Renal and hepatic impairmentNo dose adjustment is necessary for mild or moderate impairment, but treosulfan is contraindicated inpatients with severe impairment (see section 4.3).
Method of administrationTreosulfan is for intravenous use as a two-hour infusion.
Precautions to be taken before handling or administering the medicinal productWhen handling treosulfan, inhalation, skin contact or contact with mucous membranes should beavoided. Pregnant personnel should be excluded from handling cytotoxics.
Intravenous administration should be performed using a safe technique to avoid extravasation (seesection 4.4).
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
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
Seizures
Profound myelosuppression with pancytopenia is the desired therapeutic effect of treosulfan-basedconditioning treatment, occurring in all patients. It is therefore recommended to monitor blood cellcounts frequently until recovery of the haematopoietic system.
During phases of severe neutropenia (median duration of neutropenic period is 14-17.5 days in adultsand 20-22 days in paediatric patients) the risk of infection is increased. Prophylactic or empiricanti-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 secondmalignancy should be explained to the patient. On the basis of human data, treosulfan has beenclassified 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 oftreosulfan-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.
FertilityTreosulfan can impair fertility. Therefore, men treated with treosulfan are advised not to father a childduring and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior totreatment because of the possibility of irreversible infertility due to therapy with treosulfan.
Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur inpre-menopausal patients (see section 4.6).
Paediatric populationSeizures
There have been isolated reports of seizures in infants (≤ 4 months of age) with primaryimmunodeficiencies after conditioning treatment with treosulfan in combination with fludarabine orcyclophosphamide. Therefore, infants ≤ 4 months of age should be monitored for signs of neurologicaladverse reactions. Although it cannot be proved that treosulfan was the cause, the use of clonazepamprophylaxis for children younger than 1 year might be considered.
Respiratory, thoracic and mediastinal disordersThere was a significant association between age and respiratory toxicity in paediatric patients treatedwith 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 alreadyexisting 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.
ExtravasationTreosulfan is considered an irritant. Intravenous application should be performed using a safetechnique. If extravasation is suspected, general safety measures should be implemented. No specificmeasure 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 plasmaconcentrations of treosulfan and CYP3A4, CYP2C19, or P-glycoprotein (P-gp) substrates.
Physiologically-based pharmacokinetic modelling predicted a weak (AUC ratio ≥ 1.25 and < 2) tomoderate (AUC ratio ≥ 2 and < 5) interaction for CYP3A4, a weak interaction for CYP2C19, and anegligible (AUC ratio < 1.25) interaction for P-gp. Therefore, medicinal products with a narrowtherapeutic index (e.g. tacrolimus) that are substrates for CYP3A4 or CYP2C19 should not be givenduring treatment with treosulfan.
Considering overall timing of treatments and the respective pharmacokinetic properties ofconcomitantly used medicinal products (e.g. half-life), the interaction potential can be reduced to “nointeraction” (AUC ratio < 1.25), if all concomitantly used medicinal products are dosed 2 hours beforeor 8 hours after the 2-hour intravenous infusion of 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 contraceptionduring and up to 6 months after treatment.
PregnancyThere are no data from the use of treosulfan in pregnant women. Animal studies are insufficient withrespect to reproductive toxicity (see section 5.3). Treosulfan is contraindicated during pregnancy (seesection 4.3).
Breast-feedingIt is unknown whether treosulfan is excreted in human milk. Breast-feeding should be discontinuedduring treatment with treosulfan.
FertilityTreosulfan might impair fertility in men and women (see section 4.4). Men should seek advice oncryo-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 andamenorrhoea with menopausal symptoms in pre-menopausal women.
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 certainadverse reactions of treosulfan like nausea, vomiting or dizziness could affect these functions.
4.8 Undesirable effects
Summary of the safety profile
Tabulated list of adverse reactions
Overall infections
Tabulated list of adverse reactions
Infections
Profound myelosuppression/pancytopenia is the desired therapeutic effect of conditioning therapy andoccurs in all patients. Blood cell counts usually recover after HSCT.
The most commonly observed adverse reactions (adults/paediatric patients) after treosulfan-basedconditioning followed by alloHSCT include overall infections (10.1%/11.6%), gastrointestinaldisorders (nausea [38.0%/26.4%], stomatitis [36.4%/66.1%], vomiting [22.5%/42.1%], diarrhoea[14.4%/33.1%], abdominal pain [9.6%/17.4%]), fatigue (14.4%/1.7%), hepatotoxicity (0.3%/26.4%),febrile neutropenia (10.1%/1.7%), decreased appetite (8.0%/0.8%), maculopapular rash (5.2%/7.4%),pruritus (2.8%/10.7%), alopecia (1.5%/9.9%), pyrexia (4.1%/13.2%), oedema (6.2%/0.8%), rash(0.7%/5.8%), and increases of alanine transaminase (ALT [4.9%/10.7%]), aspartate transaminase(AST [4.1%/6.6%]), and bilirubin (17.1%/6.6%).
AdultsTabulated list of adverse reactions
The frequencies of adverse reactions reported in the table below are derived from 5 clinical trials(including a total of 613 patients) where treosulfan combined with fludarabine was investigated asconditioning treatment prior to alloHSCT in adult patients. Treosulfan was administered in a doserange 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), veryrare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequencygroup, undesirable effects are presented in order of decreasing seriousness.
System organ class All adverse reactions/frequency Grade 3-4 adverse reactions /(SOC) frequency
Infections and Common Commoninfestations* Infections (bacterial, viral, fungal), Infections (bacterial, viral, fungal),sepsisa sepsisa
Not known Not known
Septic shockc Septic shockc
Neoplasms benign, Not known Not knownmalignant and Treatment-related second Treatment-related secondunspecified malignancy malignancy(including cysts andpolyps)*
Blood and lymphatic Very common Very commonsystem disorders* Myelosuppression, pancytopenia, Myelosuppression, pancytopenia,febrile neutropenia febrile neutropenia
Immune system Commondisorders Hypersensitivity
Metabolism and Common Commonnutrition disorders Decreased appetite Decreased appetite
Uncommon Uncommon
Glucose tolerance impaired Glucose tolerance impaired,including hyperglycaemia and including hyperglycaemia andhypoglycaemia hypoglycaemia
Not known Not known
Acidosisb Acidosisb
Psychiatric disorders Common Not known
Insomnia Confusional state
Uncommon
Confusional state
Nervous system Common Uncommondisorders Headache, dizziness Headache
Uncommon Not known
Intracranial haemorrhage, peripheral Encephalopathy, intracranialsensory neuropathy haemorrhage, syncope, peripheralsensory neuropathy
Not known
Encephalopathy, extrapyramidaldisorder, syncope, paraesthesia
Eye disorders Not known
Dry eye
Ear and labyrinth Uncommondisorders Vertigo
System organ class All adverse reactions/frequency Grade 3-4 adverse reactions /(SOC) frequency
Cardiac disorders* Common Uncommon
Cardiac arrhythmias (e.g. atrial Cardiac arrhythmias (e.g. atrialfibrillation, sinus arrhythmia) fibrillation, sinus arrhythmia)
Not known Not known
Cardiac arrest, cardiac failure, Cardiac arrest, myocardial infarctionmyocardial infarction, pericardialeffusion
Vascular disorders Common Uncommon
Hypertension, hypotension, flushing Hypertension
Uncommon Not known
Haematoma Embolism
Not known
Embolism
Respiratory, Common Uncommonthoracic and Dyspnoea, epistaxis Dyspnoeamediastinaldisorders Uncommon Not known
Pneumonitis, pleural effusion, Pneumonitis, pleural effusion,pharyngeal or laryngeal pharyngeal inflammation, epistaxisinflammation, oropharyngeal pain,hiccups
Not known
Laryngeal pain, cough, dysphonia
Gastrointestinal Very common Commondisorders* Stomatitis/mucositis, diarrhoea, Stomatitis/mucositis, diarrhoea,nausea, vomiting nausea, abdominal pain
Common Uncommon
Oral pain, gastritis, dyspepsia, Vomiting, oral pain, dysphagia,constipation, dysphagia, abdominal oesophageal or gastrointestinal painpain, oesophageal or gastrointestinalpain Not known
Gastric or mouth haemorrhage,
Uncommon neutropenic colitis
Mouth haemorrhage, abdominaldistension, dry mouth
Not known
Gastric haemorrhage, neutropeniccolitis, oesophagitis, analinflammation
Hepatobiliary Uncommon Not knowndisorders* Veno-occlusive liver disease Veno-occlusive liver disease,hepatotoxicity
Not known
Hepatotoxicity, hepatomegaly
System organ class All adverse reactions/frequency Grade 3-4 adverse reactions /(SOC) frequency
Skin and Common Uncommonsubcutaneous tissue Maculo-papular rash, purpura, Maculo-papular rashdisorders erythema, palmar-plantarerythrodysaesthesia syndrome, Not knownpruritus, alopecia Skin necrosis, purpura, erythema
Uncommon
Erythema multiforme, dermatitisacneiform, rash, dry skin
Not known
Skin necrosis or ulcer, dermatitis,skin hyperpigmentationd
Musculoskeletal and Common Not knownconnective tissue Pain in extremity, back pain, bone Pain in extremity, bone paindisorders pain, arthralgia
Uncommon
Myalgia
Renal and urinary Common Uncommondisorders Acute kidney injury, haematuria Acute kidney injury
Uncommon Not known
Urinary tract pain Haematuria
Not known
Renal failure, haemorrhagic cystitisc,dysuria
General disorders Very common Commonand administration Asthenic conditions (fatigue, Fatiguesite conditions asthenia, lethargy)
Common Not known
Oedema, pyrexiae, chills Non-cardiac chest pain, pyrexiae
Uncommon
Non-cardiac chest pain, pain
Investigations Very common Common
Blood bilirubin increased Blood bilirubin increased,transaminases (ALT/AST) increased,
Common γGT increased
Transaminases (ALT/AST)increased, γGT increased, C-reactive Uncommonprotein increased, weight decreased, C-reactive protein increasedweight increased
Not known
Uncommon Blood alkaline phosphatase
Blood alkaline phosphatase increasedincreased
Not known
Blood lactate dehydrogenase (LDH)increased
* See detailed sections belowa Clinically or microbiologically documented infection with grade 3 or 4 neutropenia (absoluteneutrophil count [ANC] < 1.0 x 109/L) and sepsisb Acidosis might be a consequence of the release of methanesulfonic acid through treosulfanactivation/cleavage in the plasmac Case reports (> 2) after treosulfan-based conditioning obtained from other sourcesd Bronze pigmentatione Fever in the absence of neutropenia where neutropenia is defined as ANC < 1.0 x 109/L
Description of selected adverse reactionsOverall infections
The overall incidence of infections was 10.1% (62/613). This includes the incidence for bacterial, viraland fungal infections (50/613; 8.1%) and for overall sepsis (12/613; 2%). The most frequent type ofinfection was lung infection (10/62 [16.1%]). Pathogens included bacteria (e.g. Staphylococcus,
Enterococcus, Corynebacterium), viruses (e.g. cytomegalovirus [CMV], Epstein-Barr virus [EBV]) aswell as fungi (e.g. candida). Overall sepsis includes sepsis (9/613; 1.5%), staphylococcal sepsis(2/613; 0.3%) and enterococcal sepsis (1/613; 0.2%). The infection rate was lowest in patients treatedwith the dose regimen of 10 g/m² of treosulfan per day, from day -4 to -2 (8.1%).
Neoplasms benign, malignant and unspecified (including cysts and polyps)
One of 613 adult patients (0.2%) developed a second malignancy (breast cancer). A few further casesof 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 acutemyeloid leukaemia was observed in 1.4% of 553 patients.
Blood and lymphatic system disordersBlood disorders were observed in 62 of 613 adult patients (10.1%). The most frequent adverse reactionwas febrile neutropenia (10.1%). The lowest incidence was noted with the dose regimen of10 g/m²/day, day -4 to -2 (4.4%).
The median (25%/75% percentiles) duration of neutropenia was 14 (12, 20) days with the 10 g/m²treosulfan dose and 17.5 (14, 21) days with the 14 g/m² treosulfan dose.
Cardiac disordersCardiac disorders were observed in 21 patients (3.4%). The most frequent adverse reactions werecardiac arrhythmias, e.g. atrial fibrillation (1.0%), sinus tachycardia (0.8%), supraventriculartachycardia (0.3%), and ventricular extrasystole (0.3%). Isolated cases of cardiac arrest, cardiacfailure, and myocardial infarction occurred. The lowest frequency of cardiac disorders was seen withthe dose regimen of 10 g/m²/day, day -4 to -2 (2.6%).
Gastrointestinal disordersGastrointestinal disorders were observed in 379 patients (61.8%). The most frequent adverse reactionsreported were nausea (38.0%), stomatitis (36.4%), vomiting (22.5%), diarrhoea (14.4%), andabdominal pain (9.6%). The lowest frequencies of these adverse reactions were seen with the doseregimen of 10 g/m² per day, day -4 to -2 (21.5%, 32.2%, 14.8%, 5.9%, and 6.7% respectively).
Hepatobiliary disordersThe overall incidence of veno-occlusive liver disease (VOD) was 0.8% (5/613). VOD occurred onlywith the dose regimen of 14 g/m²/day treosulfan. None of these cases were fatal or life-threatening.
Paediatric populationTabulated list of adverse reactions
The adverse reactions reported in the table below are derived from two clinical trials (including a totalof 121 patients; median age 7 years [range 0-17 years]) where treosulfan combined with fludarabine(and mostly with additional thiotepa) was administered as conditioning treatment prior to alloHSCT inpaediatric patients with malignant or non-malignant diseases. Treosulfan was administered in a doserange 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), veryrare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequencygroup, undesirable effects are presented in order of decreasing seriousness.
System organ class (SOC) All adverse reactions/Grade 3-4 adverse reactions /frequency frequency
Infections and infestations* Very common Common
Infections (bacterial, viral, Infections (bacterial, viral,fungal) fungal)
Neoplasms benign, malignant Not known Not knownand unspecified (including Treatment-related second Treatment-related secondcysts and polyps)* malignancya malignancya
Blood and lymphatic system Very common Very commondisorders* Myelosuppression, Myelosuppression,pancytopenia pancytopenia
Not known Not known
Febrile neutropenia Febrile neutropenia
Metabolism and nutrition Not known Not knowndisorders Alkalosis, electrolyte imbalance, Alkalosishypomagnesaemia, decreasedappetite
Nervous system disorders* Common Not known
Headache Paraesthesia
Not known
Seizure, paraesthesia
Eye disorders Not known
Conjunctival haemorrhage, dryeye
Vascular disorders Not known Not known
Capillary leak syndrome, Capillary leak syndrome,hypertension, hypotension hypertension, hypotension
Respiratory, thoracic and Common Not knownmediastinal disorders Oropharyngeal pain, epistaxis Hypoxia
Not known
Hypoxia, cough
System organ class (SOC) All adverse reactions/Grade 3-4 adverse reactions /frequency frequency
Gastrointestinal disorders Very common Very common
Stomatitis/mucositis, diarrhoea, Stomatitis/mucositisnausea, vomiting, abdominalpain Common
Dysphagia, diarrhoea, nausea,
Common vomiting
Dysphagia, anal inflammation,oral pain Not known
Neutropenic colitis, abdominal
Not known pain, oesophageal pain
Neutropenic colitis, dyspepsia,proctitis, gingival pain,oesophageal pain, constipation
Hepatobiliary disorders Very common
HepatotoxicityNot known
Veno-occlusive liver disease,hepatomegaly
Skin and subcutaneous tissue Very common Commondisorders Pruritus, alopecia Dermatitis exfoliative,maculo-papular rash
Common
Dermatitis exfoliative, Not knownmaculo-papular rash, rash, Erythemaerythema, urticaria, pain of skin,skin hyperpigmentationb
Not known
Skin ulcer, erythemamultiforme, dermatitis bullous,dermatitis acneiform,palmar-plantarerythrodysaesthesia syndrome,dermatitis diapera
Musculoskeletal and Not knownconnective tissue disorders Pain in extremity
Renal and urinary disorders Not known Not known
Acute kidney injury, renal Acute kidney injury, renalfailure, noninfective cystitis, failure, noninfective cystitishaematuria
Reproductive system and Not knownbreast disorders Scrotal erythema, penile pain
General disorders and Very commonadministration site conditions Pyrexiac
Common
Chills
Not known
Face oedema, fatigue, pain
System organ class (SOC) All adverse reactions/Grade 3-4 adverse reactions /frequency frequency
Investigations Very common Common
ALT increased ALT increased, blood bilirubinincreased
Common
AST increased, blood bilirubin Not knownincreased, C-reactive protein AST increased, γGT increased,increased C-reactive protein increased
Not knownγGT increased
* See detailed sections belowa Case reports (> 1) after treosulfan-based conditioning obtained from other sourcesb Bronze pigmentationc Fever in the absence of neutropenia where neutropenia is defined as ANC < 1.0 x 109/L
Description of selected adverse reactionsInfections
The overall incidence of infections in 121 paediatric patients was 11.6% (14/121) and thus comparableto that seen in adults. The frequency was higher in the paediatric age group 12-17 years (6/39[15.4%]) compared to younger children (7/59 [11.9%]).
Neoplasms benign, malignant and unspecified (including cysts and polyps)
One case of a second malignancy (myelodysplastic syndrome) was reported in a child about 12 monthsafter treosulfan-based conditioning for sickle cell disease.
Six cases of a second malignancy were reported by other investigators after treosulfan-basedconditioning. Five paediatric patients received alloHSCT for primary immunodeficiencies, i.e.diseases with an increased risk for neoplasias per se. They developed myelodysplastic syndrome, acutelymphoblastic leukaemia, and Ewing’s sarcoma. One patient with haemophagocyticlymphohistiocytosis developed secondary juvenile chronic myeloid leukaemia.
Blood and lymphatic system disordersThe median (25%/75% percentiles) duration of neutropenia was 22 (17, 26) days in paediatric patientswith malignant diseases and 20 (15, 25) days in patients with non-malignant disorders.
Nervous system disordersSeizure in the context of an encephalitis infection was reported in one of 121 paediatric patients. Areport from an investigator-initiated trial performed in children with primary immunodeficiencies listsfive cases of seizures occurring after other treosulfan-based conditioning regimens (see section 4.4).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted 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 haematopoieticstem cell transplantation, the recommended dose of treosulfan would constitute an overdose. Nospecific antidote of treosulfan overdose is known. The haematologic status should be closelymonitored 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 actionTreosulfan is a pro-drug of a bifunctional alkylating agent with cytotoxic activity to haematopoieticprecursor cells. The activity of treosulfan is due to the spontaneous conversion into a mono-epoxideintermediate and L-diepoxybutan (see section 5.2).
The epoxides formed alkylate nucleophilic centres of deoxyribonucleic acid (DNA) and are able toinduce DNA cross-links which are considered responsible for the stem cell depleting andantineoplastic effects.
Pharmacodynamic effectsTreosulfan has a broad antineoplastic and antileukaemic activity. This was demonstrated againsttransplanted mouse and rat lymphomas/leukaemias, sarcomas and hepatomas, human tumourxenografts, human tumour biopsies and cell lines.
The immunosuppressive effects of treosulfan are attributed to its toxicity against primitive andcommitted progenitor cells, T and NK cells, reduction of cellularity of primary and secondarylymphatic 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 safetyIn the pivotal phase III trial, adult patients with acute myeloid leukaemia (AML) or myelodysplasticsyndrome (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 withfludarabine (FT10; n = 268) or a regimen of intravenous busulfan (total dose 6.4 mg/kg) combined withfludarabine (FB2; n = 283), followed by alloHSCT. 64% of patients had AML and 36% MDS. Themedian 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 asrelapse of disease, graft failure or death (whatever occurred first). Non-inferiority of FT10 versus thereference FB2 was statistically proven. The p-value of 0.0005787 indicates superiority of treosulfancompared to busulfan (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, agegroup, 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 oneexception (risk group II of matched related donor [MRD] patients; HR 1.18 [95% CI 0.61, 2.26]).
Further results are shown in Table 1.
Table 1: Treatment results at 24 months (full analysis set)
Parameter Treosulfan Busulfan Hazard ratiob P valueb(95% CI)
Number of patients 268 283
Overall survivala; % (95% CI) 72.7 (66.8, 60.2 (54.0, 0.64 (0.48, 0.003777.8) 65.8) 0.87)
Cumulative incidence ofrelapse/progression; % (95% 22.0 (16.9, 25.2 (20.0, 0.82 (0.59,
CI) 27.1) 30.3) 1.16) 0.2631
Cumulative incidence oftransplant-related mortality; % 12.8 (9.2, 17.7) 24.1 (19.1, 0.52 (0.34, 0.0043(95% CI) 30.2) 0.82)a Based on Kaplan-Meier estimates; b adjusted for donor type, risk group and centre using Coxregression 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 268 283
Acute GvHD, all grades; % (95% CI) 52.8 (46.8, 58.8) 57.2 (51.5, 63.0) 0.2038
Acute GvHD, grades III/IV; % (95%
CI) 6.4 (3.4, 9.3) 8.1 (4.9, 11.3) 0.4267
Chronic GvHDa; % (95% CI) 61.7 (55.1, 68.3 60.3 (53.8, 66.7) 0.9964
Extensive chronic GvHDa; % (95%
CI) 19.8 (14.5, 25.1) 28.6 (22.5, 34.7) 0.0750a Up to 2 years after alloHSCT
There is limited information available on treosulfan-based conditioning (FT14 regimen ± thiotepa; seesection 4.2) in adult patients with non-malignant disorders (NMD). The main indications for analloHSCT with treosulfan conditioning in adult NMD patients are haemoglobinopathies (e.g. sicklecell disease, thalassaemia major [TM]), primary immune deficiency, haemophagocytic disorder,immune dysregulatory disorder and bone marrow failure).
In one study, 31 NMD patients were treated with the FT14 regimen plus anti-thymocyte globulin. Theage of the patients ranged from 0.4 to 30.5 years, and 29% had HCT-CI scores > 2. All patientsengrafted, with a median time to neutrophil engraftment of 21 (range, 12-46) days. The two-yearprojected 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 plusthiotepa regimen. All patients engrafted except one, who died on day +11; the median time toneutrophil 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 outcomewas 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) conditioningin adult patients revealed quite comparable survival rates (70.3 ± 15.1% vs. 69.3 ± 5.5%), while riskfor 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 populationThe efficacy and safety of treosulfan-based conditioning was evaluated in 70 patients with acutelymphoblastic leukaemia (ALL), AML, MDS, or juvenile myelomonocytic leukaemia (JMML) whoreceived a conditioning regimen with treosulfan and fludarabine with (n = 65) or without (n = 5)thiotepa. Treosulfan dose was adapted to the patient’s BSA and 10, 12, or 14 g/m² body surface areaper day was administered as a two-hour intravenous infusion on day -6, -5, and -4 prior to stem cellinfusion (day 0). 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 graftfailure. The incidence of complete donor-type chimerism was 94.2% (90% CI 87.2-98.0%) at day +28visit, 91.3% (90% CI 83.6-96.1%) at day +100 visit and 91.2% (90% CI 82.4-96.5%) at month 12visit.
The overall survival at 24 months was 85.7% (90% CI 77.1-91.2%). Overall, 12 of the 70 patients(17.1%) died, 8 patients because of relapse/progression and 4 patients transplant-related. Freedomfrom transplant-related mortality until day +100 after HSCT (primary endpoint) was 98.6% (90% CI93.4-99.9%). One transplant-/treatment-related death was noted until day +100 after HSCT.
Transplant-related mortality at 24 months was 4.6% (90% CI 1.8-11.4%). Sixteen patients sufferedfrom relapse/progression. The cumulative incidence of relapse/progression was 23.0% (90% CI 14.7-31.3%) at month +24.
The efficacy and safety of treosulfan/fludarabine ± thiotepa-based conditioning was further evaluatedin 51 patients with non-malignant diseases (primary immunodeficiency, haemoglobinopathy, inbornerror of metabolism and bone marrow failure syndromes). Treosulfan dose was adapted to the patient’s
BSA and 10, 12, or 14 g/m² body surface area per day was administered as a two-hour intravenousinfusion on day -6, -5, and -4 prior to stem cell infusion (day 0). The dosing scheme was adaptedduring the trial in terms of the BSA categories applied for the different doses, as a consequence2 patients received a higher dose compared to the initial dosing scheme. Fifty evaluable patientstreated with the reference conditioning regimen busulfan/fludarabine ± thiotepa served asactive-control group. Busulfan dose was adapted to the patient’s body weight and 3.2 to 4.8 mg/kg/daywere administered on days -7, -6, -5, and -4. Most trial subjects (84% in both arms) received theintensified regimen with thiotepa given in 2 single doses of 5 mg/kg/body weight on day -2. Mostpatients were 28 days to 11 years of age (88.2% in the treosulfan arm and 80% in the busulfan arm).
Alpha was not controlled for multiple testing in this trial. The incidence of freedom fromtransplantation (treatment)-related mortality until day +100 (primary endpoint) was 100.0% (90% CI94.3%-100.0%) in the treosulfan arm and 90.0% (90% CI 80.1%-96.0%) in the busulfan arm. Overallsurvival at 1 year was 96.1% (90% CI 88.0%-98.8%) with treosulfan and 88.0% with busulfan(90% CI 77.9%-93.7%). In total, 2 patients (3.9%) in the treosulfan arm and 2 patients (4.0%) in thebusulfan arm experienced primary graft failure, while secondary graft failures were reported for9 patients (18.4%) receiving treosulfan-based conditioning. The incidence of complete donor typechimerism was comparable between the groups.
5.2 Pharmacokinetic properties
Treosulfan is a pro-drug 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.
AbsorptionAfter 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, or14 g/m² treosulfan were 306 ± 94 µg/mL, 461 ± 102 µg/mL, and 494 ± 126 µg/mL, respectively.
DistributionTreosulfan is rapidly distributed in the body; however, its penetration through the blood-brain barrieris quite limited (see section 5.3). The volume of distribution in adult patients is about 20-30 litres. Nodose accumulation with the recommended daily treatment on three consecutive days was observed.
Treosulfan does not bind to plasma proteins.
BiotransformationUnder physiological conditions (pH 7.4, temperature 37 °C), the pharmacologically inactive treosulfanis 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).
Treosulfan does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2D6, or CYP3A4 using testosterone assubstrate. However, treosulfan was a reversible inhibitor for CYP2C19, and of CYP3A4 usingmidazolam as the substrate. Treosulfan does not inhibit substrate transport via various transportproteins with the exception of P-gp and MATE2 at very high concentrations.
EliminationPlasma concentrations of treosulfan decline exponentially and are best described by a first orderelimination process fitted by a two-compartment model.
The terminal half-life (T1/2ß) of intravenously administered treosulfan (up to 47 g/m²) is approximately2 hours. Approximately 25-40% of the treosulfan dose is excreted unchanged with the urine within24 hours, nearly 90% of which within the first 6 hours after administration.
Linearity/non-linearityRegression analysis of the area under the curve (AUC0-∞) versus treosulfan dose indicated a linearcorrelation.
Renal and hepatic impairmentNo pharmacokinetic studies with treosulfan were done in patients with severe renal or hepaticimpairment, because such patients are generally excluded from alloHSCT. About 25-40% oftreosulfan is excreted in urine; however, an influence of renal function on renal clearance of treosulfanwas not observed.
Paediatric populationConventional 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 oftreosulfan in paediatric patients should be adapted to the BSA (see section 4.2), which results in acomparable treosulfan exposure in children of all age groups, corresponding to an exposure of a3 x 14 g/m² dose in adults.
Mean apparent terminal half-life of treosulfan was comparable between the different age groups andranged between 1.3 and 1.6 hours.
PK/PD evaluation did not show a significant change of time to engraftment as function of AUC.
5.3 Preclinical safety data
Four-week subchronic, intravenous treatment of rats resulted in haematological changes in form ofdecreased levels of leucocytes and neutrophilic granulocytes; decreased relative spleen and thymusweights in the context of a lymphoid atrophy, and bone marrow depression. Lymphohistiocyticinfiltration in the skeletal musculature and histopathological changes in the urinary bladder wereobserved. Signs of haematuria were seen preferentially in male animals.
Due to its alkylating mechanism of action treosulfan is characterised as a genotoxic compound withcarcinogenic potential. Specific reproductive and developmental toxicity studies on treosulfan inanimals were not conducted. However, during chronic toxicity tests in rats spermatogenesis andovarian function were significantly affected. Published literature data report on gonadotoxicity oftreosulfan in pre-pubertal and pubertal male and female mice.
Published data concerning treatment of mice and rats with L-diepoxibutane (the alkylatingtransformation product of treosulfan) revealed impairment of fertility, uterine-ovarian and spermdevelopment.
Juvenile animal studiesIn juvenile rat toxicity studies treosulfan induced slight retardation of physical development and aslightly delayed time-point of vaginal opening in females. A very low penetration of blood-brainbarrier 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 ofjuvenile 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 medicinalproducts.
6.3 Shelf life
Unopened vial5 years
Reconstituted solution for infusion
After reconstitution with sodium chloride 4.5 mg/mL (0.45%) solution, chemical and physical stabilityhas been demonstrated for 3 days at 25 °C.
From a microbiological point of view, unless the method of reconstitution precludes the risk ofmicrobial contamination, the product should be used immediately. If not used immediately, in-usestorage 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 I glass vial, with rubber stopper and aluminium cap containing 1 g of treosulfan.
Trecondi 5 g powder for solution for infusion
Colourless type I 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.
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 protectivedisposable gloves, goggles, gown and mask is recommended). Contaminated body parts should becarefully 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 laminarflow, with liquid-impermeable, absorbent disposable foil. Adequate care and precautions should betaken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic medicinalproducts. Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended tominimise pressure and the possible formation of aerosols. The latter may also be reduced by the use ofa 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 treosulfanmay 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. Thisprocedure is very important, because moistening of powder that sticks to the surface results incaking. 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 sodiumchloride 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 asall materials that have been used for reconstitution and administration must be destroyed according tostandard procedures applicable to antineoplastic agents, with due regard to current laws related to thedisposal of hazardous waste.
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.