4.1 Therapeutic indications
For the treatment of all types of ovarian cancer, either supplementary to surgery or palliatively. Some uncontrolled studies have suggested activity in a wider range of neoplasms.

Because of a lack of cross-resistance reported between treosulfan and other cytotoxic agents treosulfan may be useful in any neoplasm refractive to conventional therapy. Treosulfan has been used in combination regimens in conjunction with vincristine, methotrexate, 5-FU and procarbazine.

4.2 Posology and method of administration
3 - 8 g/m2 i.v. every 1-3 weeks depending on blood count and concurrent chemotherapy. Single injections of up to 8 g/m2have been given with no serious adverse effects. Doses up to 1.5 g/m2 have been given intraperitoneally. Doses up to 3 g/m2 treosulfan may be given as a bolus injection. Larger doses should be administered as an i.v. infusion at a rate of 3 g/m2 every 5-10 minutes (8 g/m2 as a 30 minutes infusion).

Treatment should not be given if the white blood cell count is less than 3.000/microlitre or the thrombocyte count less than 100.000/microlitre. A repeat blood count should be made after a weeks interval, when treatment may be restarted if haematological parameters are satisfactory. Lower doses of treosulfan should be used if other cytotoxic drugs or radiotherapy are being given concurrently. Treatment is initiated as soon as possible after diagnosis.

Care should be taken in administration of the injection to avoid extravasation into tissues since this will cause local pain and tissue damage. If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should be introduced into another vein.

Dosage in the elderly - Treosulfan is renally excreted. Blood counts should be carefully monitored in the elderly and the dosage adjusted accordingly.

Children - Treosulfan Injection is not recommended for use in children.

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

4.4 Special warnings and precautions for use

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 a 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.

Because 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 combined with other forms of therapy that suppress bone marrow function such as radiotherapy.

Risk of malignancy
During long term therapy with oral treosulfan doses eight patients (1.4% 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
Because of the possible development of a haemorrhagic cystitis patients are advised to drink more fluids for up to 24 hours after infusion.

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.

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.