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HOS-098641 · has-adverse-reaction-information · PDF-Seite 6

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 overall infections (10.1%/11.6%), gastrointestinal disorders (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%). 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 6 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 All adverse reactions / frequency Grade 3-4 adverse reactions / (SOC) frequency Infections and Common Common infestations* Infections (bacterial, viral, fungal), Infections (bacterial, viral, fungal), sepsisa sepsisa Not known Not known Septic shockc Septic shockc Neoplasms benign, Not known Not known malignant and Treatment-related second Treatment-related second unspecified

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HOS-098637 · has-contraindication-information · PDF-Seite 4

• 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

HOS-098636 · has-indication-information · PDF-Seite 2

Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients and in paediatric patients older than one month with malignant and non-malignant diseases.

HOS-098639 · has-interaction-information · PDF-Seite 5

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-glycoprotein (P-gp) substrates. Physiologically-based pharmacokinetic modelling predicted a weak (AUC ratio ≥ 1.25 and < 2) to moderate (AUC ratio ≥ 2 and < 5) interaction for CYP3A4, a weak interaction for CYP2C19, and a negligible (AUC ratio < 1.25) interaction for P-gp. Therefore, medicinal products with a narrow therapeutic index (e.g. tacrolimus) that are substrates for CYP3A4 or CYP2C19 should not be given during treatment with treosulfan. Considering overall timing of treatments and the respective pharmacokinetic properties of concomitantly used medicinal products (e.g. half-life), the interaction potential can be reduced to “no interaction” (AUC ratio < 1.25), if all concomitantly used medicinal products are dosed 2 hours before or 8 hours after the 2-hour intravenous infusion of treosulfan. The effect of treosulfan on the pharmacokinetics of fludarabine is not known.

HOS-098640 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential/Contraception in males and females 5 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 (see section 4.4). 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.

HOS-098638 · has-warning-information · PDF-Seite 4

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 4 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 asso

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