Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880, Wedel, Germany
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 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.
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.
Concomitant use of live attenuated vaccines is not recommended.
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).
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.
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 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.
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.
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.
Both sexually active men and women of childbearing potential have to use effective contraception during and up to 6 months after treatment.
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).
It is unknown whether treosulfan is excreted in human milk. Breast-feeding should be discontinued during treatment with treosulfan.
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.
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.
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%).
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.
All Adverse Reactions:
Very common: Infections (bacterial, viral, fungal)
Common: Sepsisa
Not known: Septic shockc
Not known: Treatment-related second malignancy
Very common: Myelosuppression, pancytopenia, febrile neutropenia
Common: Hypersensitivity
Common: Decreased appetite
Uncommon: Hyperglycaemia
Not known: Acidosisb, glucose tolerance impaired, electrolyte imbalance
Common: Insomnia
Uncommon: Confusional state
Not known: Agitation
Common: Headache, dizziness
Uncommon: Peripheral sensory neuropathy
Not known: Encephalopathy, intracranial haemorrhage, extrapyramidal disorder, syncope, paraesthesia
Not known: Dry eye
Common: Cardiac arrhythmias (e.g. atrial fibrillation, sinus arrhythmia)
Not known: Cardiac arrest, cardiac failure, myocardial infarction, pericardial effusion
Common: Hypertension, flushing
Uncommon: Haematoma, hypotension
Not known: Embolism, haemorrhage
Common: Dyspnoea, epistaxis
Uncommon: Pneumonitis, pleural effusion, pharyngeal or laryngeal inflammation, cough, laryngeal pain, hiccups
Not known: Oropharyngeal pain, hypoxia, dysphonia
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
Uncommon: Veno-occlusive liver disease, hepatotoxicity
Not known: Hepatic failure, hepatomegaly, hepatic pain
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
Common: Pain in extremities, back pain, bone pain, arthralgia, myalgia
Not known: Muscular weakness
Common: Acute kidney injury, haematuria
Not known: Renal failure, cystitisc, dysuria
Very common: Asthenic conditions (fatigue, asthenia, lethargy)
Common: Oedema, pyrexiae, chills
Uncommon: Non-cardiac chest pain, pain
Not known: Injection site reaction, feeling cold
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
Grade 3-4 Adverse Reactions:
Common: Infections (bacterial, viral, fungal), sepsisa
Not known: Septic shockc
Not known: Treatment-related second malignancy
Very common: Myelosuppression, pancytopenia, febrile neutropenia
Common: Decreased appetite
Uncommon: Hyperglycaemia
Not known: Acidosisb , glucose tolerance impaired, electrolyte imbalance
Rare: Confusional state
Rare: Headache, peripheral sensory neuropathy
Not known: Encephalopathy, intracranial haemorrhage, syncope
Common: Cardiac arrhythmias (e.g. atrial fibrillation, sinus arrhythmia)
Not known: Cardiac arrest, myocardial infarction
Uncommon: Hypertension
Not known: Embolism, haemorrhage
Uncommon: Dyspnoea, pleural effusion, pharyngeal or laryngeal inflammation
Rare: Epistaxis, pneumonitis
Not known: Hypoxia
Common: Stomatitis/mucositis, diarrhoea, nausea, abdominal pain
Uncommon: Vomiting, oral pain, dysphagia, mouth haemorrhage, oesophageal or gastrointestinal pain
Not known: Gastrointestinal haemorrhage, neutropenic colitis
Rare: Veno-occlusive liver disease, hepatotoxicity
Not known: Hepatic failure
Uncommon: Maculo-papular rash, purpura, erythema
Not known: Skin necrosis
Rare: Pain in extremities, bone pain
Uncommon: Acute kidney injury, haematuria
Common: Fatigue
Rare: Non-cardiac chest pain, oedema pyrexiae
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 × 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 × 109/L.
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%).
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 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 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 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).
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.
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 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.
All Adverse Reactions:
Very common: Infections (bacterial, viral, fungal)
Not known: Treatment-related second malignancya
Very common: Myelosuppression, pancytopenia
Not known: Febrile neutropenia
Not known: Alkalosis, electrolyte imbalance, hypomagnesaemia
Not known: Headache, paraesthesia, seizure
Not known: Conjunctival haemorrhage, dry eye
Not known: Capillary leak syndrome, hypertension, hypotension
Common: Oropharyngeal pain, epistaxis
Not known: Hypoxia
Very common: Stomatitis/mucositis, diarrhoea, nausea, vomiting, abdominal pain
Common: Dysphagia, oral pain
Not known: Neutropenic colitis, anal inflammation, dyspepsia, proctitis, gastrointestinal pain, constipation
Not known: Veno-occlusive liver disease, hepatomegaly, hepatotoxicity
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
Not known: Pain in extremities
Not known: Acute kidney injury, renal failure, noninfective cystitis
Not known: Scrotal erythema
Very common: Pyrexiac
Not known: Chills, fatigue, pain
Common: Transaminases (ALT/AST) increased, bilirubin increased
Not known: γGT increased
Grade 3-4 Adverse Reactions:
Common: Infections (bacterial, viral, fungal)
Not known: Treatment-related second malignancya
Very common: Myelosuppression, pancytopenia
Not known: Febrile neutropenia
Not known: Alkalosis
Not known: Paraesthesia
Not known: Capillary leak syndrome, hypertension, hypotension
Not known: Hypoxia
Very common: Stomatitis/mucositis, nausea
Common: Dysphagia, diarrhoea, vomiting, abdominal pain
Not known: Neutropenic colitis
Not known: Veno-occlusive liver disease
Common: Dermatitis exfoliative, maculo-papular rash, erythema
Not known: Acute kidney injury, renal failure
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 × 109/L.
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%]).
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.
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.
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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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