TRECONDI

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).

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: • 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).

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). Special populations Paediatric 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).

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. Elderly No dose adjustment is necessary in any subset of the elderly population. 3). Method of administration Treosulfan is for intravenous use as a two-hour infusion.

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. 6%). 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 613 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. g. g. atrial fibrillation, sinus arrhythmia) Not known Cardiac arrest, myocardial infarction Vascular disorders Common Hypertension, hypotension, flushing Uncommon Haematoma Not known Embolism Uncommon Hypertension Not known Embolism Respiratory, thoracic and mediastinal disorders Common Dyspnoea, epistaxis Uncommon Pneumonitis, pleural effusion, pharyngeal or laryngeal inflammation, oropharyngeal pain, hiccups Not known Laryngeal pain, cough, dysphonia Uncommon Dyspnoea Not known Pneumonitis, pleural effusion, pharyngeal inflammation, epistaxis System organ class (SOC) All adverse reactions /fFrequency Grade 3-4 adverse reactions / frequency Gastrointestinal disorders* Very common Stomatitis/mucositis, diarrhoea, nausea, vomiting Common Oral pain, gastritis, dyspepsia, constipation, dysphagia, abdominal pain, oesophageal or gastrointestinal pain Uncommon Mouth haemorrhage, abdominal distension, dry mouth Not known Gastric haemorrhage, neutropenic colitis, oesophagitis, anal inflammation Common Stomatitis/mucositis, diarrhoea, nausea, abdominal pain Uncommon Vomiting, oral pain, dysphagia, oesophageal or gastrointestinal pain Not known Gastric or mouth haemorrhage, neutropenic colitis Hepatobiliary disorders* Uncommon Veno-occlusive liver disease Not known Hepatotoxicity hepatomegaly Not known Veno-occlusive liver disease, hepatotoxicity System organ class (SOC) All adverse reactions /fFrequency Grade 3-4 adverse reactions / frequency Skin and subcutaneous tissue disorders Common Maculo-papular rash, purpura, erythema, palmar-plantar erythrodysaesthesia syndrome, pruritus, alopecia Uncommon Erythema multiforme, dermatitis acneiform, rash, dry skin Not known Skin necrosis or ulcer, dermatitis, skin hyperpigmentationd Uncommon Maculo-papular rash Not known Skin necrosis, purpura, erythema Musculoskeletal and connective tissue disorders Common Pain in extremity, back pain, bone pain, arthralgia Uncommon Myalgia Not known Pain in extremity, bone pain Renal and urinary disorders Common Acute kidney injury, haematuria Uncommon Urinary tract pain Not known Renal failure, haemorrhagic cystitisc, dysuria Uncommon Acute kidney injury Not known Haematuria System organ class (SOC) All adverse reactions /fFrequency Grade 3-4 adverse reactions / frequency General disorders and administration site conditions Very common Asthenic conditions (fatigue, asthenia, lethargy) Common Oedema, pyrexiae, chills Uncommon Non-cardiac chest pain, pain Common Fatigue Not known Non-cardiac […]

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.

5 days in adults and 20–22 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. 8). 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.

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.

6) • Administration of live vaccine