TREOSULFAN

Posology The dosage of treosulfan as monotherapy is 8 g/m² in patients who have not undergone previous chemotherapy. The dose should be reduced to 6 g/m² or less in patients with risk factors such as pre- treatment with myelosuppressive agents or radiotherapy and reduced performance status.

The therapy should be repeated every three to four weeks. In combination with cisplatin, treosulfan should be dosed at 5 g/m², with cycles repeated every 3-4 weeks. Duration of treatment In general, 6 courses of treatment with treosulfan are given.

In the case of progressive disease and/or occurrence of non-tolerable adverse events, the treatment must be stopped. Dose modification If, following administration of treosulfan, the white cell count falls below 1,000/μl and/or the platelet count falls below 25,000/μl, the following dose must be reduced by 1 g/m².

Treatment should not be given if the white blood cell count is less than 3,500/μl or the thrombocyte count less than 100,000/μl after three weeks. A repeat blood count should be made after a week’s interval, when treatment may be restarted if haematological parameters are satisfactory.

If the values after this are still unchanged, the treosulfan dose must be reduced to 6 g/m² in case of monotherapy and to 3 g/m² in combination with cisplatin. If during treatment the white cell count does not fall below 3,500/μl and/or the platelet count does not fall below 100,000/μl, the dose in the following course of treatment may be increased by 1 g/m².

Elderly patients and patients with renal impairment Treosulfan is renally excreted. Blood counts should be carefully monitored in elderly and renally impaired patients and the dose adjusted accordingly. Paediatric population Treosulfan Injection is not recommended for use in children.

Method of administration Treosulfan should be administered by intravenous infusion over 15 to 30 minutes. 6.

Summary of the safety profile The most commonly reported undesirable effects are myelosuppression and gastrointestinal complaints. They are usually mild and resolve after therapy with treosulfan. Bone marrow suppression is the dose-limiting side effect of treosulfan.

Tabulated list of adverse reactions 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), not known (cannot be estimated from the available data) Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Organ class Frequency Infections and Common: infestations Infections (mycotic, viral, bacterial) Very rare: Sepsis Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: Treatment related secondary malignancies (acute non-lymphocytic leukaemia, myelodysplastic syndrome, myeloma, myeloproliferative disorder) Blood and lymphatic system disorders Very common: Myelosuppression (leukocytopenia, thrombocytopenia, anaemia) Rare: Pancytopenia Immune system disorders Rare: Allergic reactions Endocrine disorders Very rare: Addison’s disease Metabolism and nutrition disorders Very rare: Hypoglycaemia Nervous system disorders Very rare: Paraesthesia Cardiac disorders Very rare: Cardiomyopathy Respiratory, thoracic and mediastinal disorders Very rare: Pulmonary fibrosis, alveolitis, pneumonia Gastrointestinal disorders Very common: Vomiting, nausea Hepatobiliary disorders: Very rare: Hepatic enzyme increased, blood bilirubin increased Skin and subcutaneous tissue disorders Very common: Alopecia (usually mild), bronze skin pigmentation Very rare: Scleroderma, triggering of psoriasis, erythema, urticaria Renal and urinary disorders Very rare: Haemorrhagic cystitis General disorders and administration site Very rare: Flu-like complaints, local painful conditions inflammatory reactions (in case of extravasation) Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

Risk of infections The risk of infections (mycotic, viral, bacterial) is increased. Haematological effects and monitoring of blood count The dose-limiting side effect of treosulfan is myelosuppression, which is usually reversible. It is manifested by a reduction in leukocytes and platelets and a decrease in haemoglobin.

The leukocytes and platelets usually reach their baseline level after 28 days. As the inhibition of bone marrow function is cumulative, the blood count should be monitored at shorter intervals starting with the third course of treatment.

This is especially important if treosulfan is combined with other forms of therapy that suppress bone marrow function such as radiotherapy. 4 % of 553 patients) developed an acute non-lymphocytic leukaemia. The risk was depending on the cumulative dose of treosulfan.

Single cases of myeloma, myeloproliferative disorder and myelodysplastic syndrome have additionally been reported. Cardiac toxicity It cannot be totally ruled out that one case of cardiomyopathy was related to treosulfan. Pulmonary toxicity If allergic alveolitis or pulmonary fibrosis develop, treosulfan should be permanently discontinued.

Risk of cystitis Due to the possible development of a haemorrhagic cystitis, patients are advised to drink more fluids for up to 24 hours after intravenous infusion. 2). Use with live vaccines Cytostatic therapy may increase the risk of generalised infection after immunisation using live vaccines.

Therefore live vaccines should not be used in patients receiving treosulfan. Extravasation During infusion, care must be taken to use a flawless technique, since painful inflammatory reactions may occur as a result of extravasation of treosulfan solution into surrounding tissue.

Hypersensitivity to the active substance. Severe and lasting bone marrow depression.