Special Warning : אזהרת שימוש

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 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.

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.

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.

Effects on Driving

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.