Treosulfan IV Infusion

Treosulfan is indicated in combination with fludarabine as part of conditioning treatment prior to allogeneic hematopoietic stem cell transplantation (alloHSCT).

• in adult patients with AML or MDS at increased risk for standard conditioning therapies,
• in pediatric patients older than 1 year old with AML or MDS.

Administration of Treosulfan should be supervised by a physician experienced in conditioning treatment followed by alloHSCT.

Treosulfan is a prodrug of a bifunctional alkylating agent with cytotoxic activity to hematopoietic stem cells. The activity of treosulfan is due to the spontaneous, pH-dependent conversion into a mono-epoxide intermediate and di-epoxybutan. These epoxides alkylate and cross-link nucleophilic centers of deoxyribonucleic acid (DNA) and other biological molecules involved in various physiological functions and are considered responsible for the stem cell depleting, immune-suppressive and antineoplastic effects.

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).

Health Canada has not authorized the use of Treosulfan in children less than 1 year of age.

No dose adjustment is necessary for mild or moderate liver or renal impairment, but treosulfan is contraindicated in patients with severe impairment.

Pediatrics (>1 year to 18 years): The use of Treosulfan has not been fully investigated in the pediatric population.

Geriatrics: Eighty-one (13.2%) of the 613 adult patients treated within the clinical trial program for Treosulfan were above the age of 65 years.

Hepatic Insufficiency: No pharmacokinetic studies with treosulfan were conducted in patients with severe hepatic impairment, because such patients are generally excluded from alloHSCT.

Renal Insufficiency: No pharmacokinetic studies with treosulfan were conducted in patients with severe renal impairment.

Drug interactions with Treosulfan were not studied in vivo. Detailed in vitro studies did not completely exclude potential interactions between high plasma concentrations of Treosulfan and CYP3A4, CYP2C19, or P-gp substrates. Physiologically-based pharmacokinetic (PBPK) modeling with the sensitive index substrates midazolam, omeprazole, and digoxin for CYP3A4, CYP2C19, and P-gp predicted a weak interaction (AUC ratio ≥1.25 and <2) for CYP3A4, and CYP2C19, and a negligible (AUC ratio <1.25) interaction for P-gp. Therefore, medicinal products with a narrow therapeutic index that are substrates for CYP3A4 or CYP2C19 should not be given during treatment with Treosulfan.

Treosulfan is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

• Active non-controlled infectious disease
• Severe concomitant cardiac, lung, liver, and renal impairment
• Fanconi anemia and other DNA breakage repair disorders
• Pregnancy
• Administration of live vaccine

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 common (>10%) adverse reactions observed in 5 clinical studies in 613 adults with Treosulfan-based conditioning followed by alloHSCT include gastrointestinal disorders (nausea 38.5%, stomatitis 36.4%, vomiting 22.5%, diarrhea 15.2%), increases of bilirubin 17.9%, fatigue 14.8%, infections 12.9%, and febrile neutropenia 10.9%.

The most common (>10%) adverse reactions observed in two clinical studies in 115 pediatric patients with Treosulfan-based conditioning followed by alloHSCT include gastrointestinal disorders (stomatitis 67.0%, vomiting 41.7%, diarrhea 34.8%, nausea 27.8%, abdominal pain 17.4%), hepatotoxicity 26.1%, pyrexia 13.0%, infections 12.2%, increased alanine aminotransferase 11.3%, alopecia 10.4%, and pruritus 10.4%.

There is no experience from the use of treosulfan in pregnant women. Treosulfan is contraindicated during pregnancy. It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human
milk precaution should be exercised. Breastfeeding should be discontinued during treatment with treosulfan.

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. During a phase 3 clinical trial (MC-FludT.14/L Trial II) treatment emergent adverse events (TEAEs) were reported by 92.6% of patients in the Treosulfan treatment group. TEAEs were most commonly reported in the SOCs "Gastrointestinal disorders", "General disorders and administration site conditions", and "Musculoskeletal and connective tissue disorders" (TEAEs reported by 68.1%, 56.3%, and 37.8% of patients, respectively). TEAEs of at least CTCAE Grade III were reported by 54.8% of patients in the Treosulfan treatment group. Severe Adverse Events (SAEs) were reported by 8.5% of patients in the Treosulfan treatment group.

Cytotoxic Chemotherapy

Unopened vials of Treosulfan should be stored at room temperature 15°C to 30°C. Treosulfan dissolved in 0.45% or 0.9% Sodium Chloride Injection or 5% Glucose Injection or Water for Injection is stable for 3 days if stored at 15°C to 30°C. Do not store under refrigeration (2°C-8°C) as this might result in the formation of precipitate. Do not use if the solution contains a precipitate.