TRECONDI Powder for solution for infusion Ref.[9055] Active ingredients: Treosulfan

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). The total treosulfan dose is 30 g/m²;
• Fludarabine 30 mg/m² BSA per day as a 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 (FT 10 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). The total treosulfan dose is 42 g/m²;
• Fludarabine 30 mg/m² BSA per day as a 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).

Elderly

No dose adjustment is necessary in any subset of the elderly population.

Renal and hepatic impairment

No dose adjustment is necessary for mild or moderate impairment, but treosulfan is contraindicated in patients with severe impairment (see section 4.3).

Paediatric population

Treosulfan is given in combination with fludarabine, with thiotepa (intensified regimen; FT_10-14 TT regimen) or without thiotepa (FT_10-14 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). The total treosulfan dose is 30-42 g/m²;

The dose of treosulfan should be adapted to the patient’s BSA as follows (see section 5.2):

• Fludarabine 30 mg/m² BSA per day as a 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.

Method of administration

Treosulfan is for intravenous use as a two-hour infusion.

Precautions to be taken before handling or administering the medicinal product

When handling treosulfan, inhalation, skin contact or contact with mucous membranes should be avoided. Pregnant personnel should be excluded from handling cytotoxics.

Intravenous administration should be performed using a safe technique to avoid extravasation (see section 4.4).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

The principal toxic effect of treosulfan is profound myeloablation and pancytopenia. In addition, acidosis, skin toxicity, nausea, vomiting and gastritis may occur. In the absence of haematopoietic stem cell transplantation, the recommended dose of treosulfan would constitute an overdose. No specific antidote of treosulfan overdose is known. The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated.

Unopened vial: 5 years.

Reconstituted solution for infusion: After reconstitution with sodium chloride 4.5 mg/mL (0.45%) solution, chemical and physical stability has been demonstrated for 2 days at 25°C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Do not store in a refrigerator (2°C-8°C) as this might cause precipitation.

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Trecondi 1 g powder for solution for infusion: Colourless type III glass vial, with rubber stopper and aluminium cap containing 1 g of treosulfan.

Trecondi 5 g powder for solution for infusion: Colourless type III glass vial, with rubber stopper and aluminium cap containing 5 g of treosulfan.

Trecondi is available in packs of 1 or 5 vials.

Not all pack sizes may be marketed.

As with all cytotoxic substances, appropriate precautions should be taken when handling treosulfan.

Trained personnel should reconstitute the medicinal product. When handling treosulfan, inhalation, skin contact or contact with mucous membranes should be avoided (the use of adequate protective disposable gloves, goggles, gown and mask is recommended). Contaminated body parts should be carefully rinsed with water and soap, the eyes should be rinsed with sodium chloride 9 mg/mL (0.9%) solution. If possible it is recommended to work on a special safety workbench, equipped with laminar flow, with liquid-impermeable, absorbent disposable foil. Adequate care and precautions should be taken in the disposal of items (syringes, needles, etc.) used to reconstitute cytotoxic medicinal products. Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Pregnant personnel should be excluded from handling cytotoxics.

Instructions for reconstitution of treosulfan:

1. Treosulfan is reconstituted in its original glass container. Reconstituted solutions of treosulfan may be combined into a larger glass vial, PVC bag or PE bag.
2. To avoid solubility problems, warm the solvent, sodium chloride 4.5 mg/mL (0.45%) solution, to 25°C-30°C (not higher), for example by using a water bath.
3. Remove the treosulfan powder carefully from the inner surface of the vial by shaking. This procedure is very important, because moistening of powder that sticks to the surface results in caking. If this happens, vigorously shake the vial to redissolve the cake.

Reconstitute each vial of Trecondi containing 1 g treosulfan in 20 mL of pre-warmed (maximum 30°C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking. Reconstitute each vial of Trecondi containing 5 g treosulfan in 100 mL of pre-warmed (maximum 30°C) sodium chloride 4.5 mg/mL (0.45%) solution by shaking.

For preparation of sodium chloride 4.5 mg/mL (0.45%) solution equivalent volumes of sodium chloride 9 mg/mL (0.9%) solution and water for injections can be mixed.

The reconstituted solution contains 50 mg treosulfan per mL and appears as a clear colourless solution. Solutions showing any sign of precipitation should not be used.

Treosulfan has mutagenic and carcinogenic potential. Remnants of the medicinal product as well as all materials that have been used for reconstitution and administration must be destroyed according to standard procedures applicable to antineoplastic agents, with due regard to current laws related to the disposal of hazardous waste.