TRECONDYV

1 Dosing Considerations Administration of Trecondyv® should be supervised by a physician experienced in conditioning treatment followed by alloHSCT. 2 Recommended Dose and Dosage Adjustment Trecondyv® 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). 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 (FT10 regimen). Health Canada has not authorized the use of Trecondyv® 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 (see section CONTRAINDICATION).

3 Administration Trecondyv® is for intravenous use as a two-hour infusion. Intravenous administration should be performed using a safe technique to avoid extravasation. When handling treosulfan, inhalation, skin contact or contact with mucous membranes should be avoided.

Pregnant personnel should be excluded from handling cytotoxics. Consider providing prophylactic anti-emetic therapy during Trecondyv® treatment. 9% Sodium Chloride Injection or 5% Glucose Injection or Water for Injection. Trecondyv® is dissolved in its original glass container by shaking with solvent.

Reconstituted Serious Warnings and Precautions:  Myelosuppression  Causes severe and prolonged myelosuppression.  Hematopoietic stem cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression Trecondyv® Page 6 of 27 solutions of Trecondyv® may be combined into a larger glass vial, EVA bag or PE bag.

In case solubility issues are observed when shaking, prolonged standing time or slight warming of the reconstituted solution (hand warm) are useful to improve solubility. Table 1 - Reconstitution Vial Size Volume of Diluent to be Added to Vial Approximate Vial Capacity Nominal Concentration per mL 1 g 20 mL 38 mL 50 mg/mL 5 g 100 mL 119 mL 50 mg/mL The reconstituted solution of Trecondyv® is stable for 3 days if stored at 15°C to 30°C.

1 Adverse Reaction Overview Profound myelosuppression/pancytopenia is the desired therapeutic effect of conditioning therapy and occurs in all patients. Blood cell counts usually recover after HSCT. 9%. 4%. 2 Clinical Trial Adverse Reactions (Adults) Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. 14/L Trial II) in a total of 551 adult patients where a conditioning regimen of treosulfan plus fludarabine was compared to a reduced intensity conditioning regimen consisting of busulfan plus fludarabine (NCT00822393).

Median age of patients in the whole group was 60 years (range 31-70); 61% of patients were male; the underlying diseases were acute myeloid leukemia (64%) and myelodysplastic syndromes (36%). 2 mg/kg on 2 consecutive days. Fludarabine was added in both groups at a dose of 30 mg/m² on 5 consecutive days.

3 Less Common Clinical Trial Adverse Reactions (Adults) Additional Adverse Reactions observed with treosulfan-based conditioning followed by Trecondyv® Page 13 of 27 alloHSCT in 5 clinical trials in adult patients by System Organ Class and Preferred Term.

g. atrial fibrillation, sinus arrhythmia), cardiac arrest, cardiac failure, myocardial infarction, pericardial effusion Eye disorders: Dry eye Gastrointestinal disorders: Oral pain, gastritis, dyspepsia, dysphagia, gastrointestinal hemorrhage, mouth hemorrhage, abdominal distension, esophageal or gastrointestinal pain, dry mouth, neutropenic colitis, esophagitis, anal inflammation, mouth ulceration General disorders and administration site conditions: Edema, non-cardiac chest pain, injection site reaction, feeling cold Hepatobiliary disorders: Veno-occlusive liver disease, hepatotoxicity, hepatic failure, hepatomegaly, hepatic pain Immune system disorders: Hypersensitivity Infections and infestations: Sepsis, septic shock Investigations: Alkaline phosphatase increased, C reactive protein increased, weight decreased, blood creatinine increased, blood lactate dehydrogenase increased Metabolism and nutrition disorders: Hyperglycemia, acidosis, impaired glucose tolerance, electrolyte imbalance Musculoskeletal and connective tissue disorders: Myalgia, muscular weakness Neoplasms benign, malignant and unspecified (including cysts and polyps) : Treatment related second malignancy Nervous system disorders: Peripheral sensory neuropathy, intracranial hemorrhage, encephalopathy, extrapyramidal disorder, […]

Please see the Serious Warnings and Precautions Box at the beginning of Part I:

Health Professional Information [Section 3]. The following warnings pertain to different physiologic effects of Trecondyv® in the setting of allo HSCT. General 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. 6% of patients in the treosulfan treatment group. 8% of patients, respectively). 8% of patients in the treosulfan treatment group.

5% of patients in the treosulfan treatment group. Carcinogenesis and Mutagenesis Secondary malignancies are well-established complications in long-term survivors after alloHSCT. 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 Group 1. Cardiovascular Patients with severe cardiac impairment diagnosed by ECG and left ventricular ejection fraction (LVEF) < 40% or with severe pulmonary impairment were excluded from the pivotal clinical study and therefore the safety and efficacy of TRECONDYV in these patients have not been established.

g. 0% of the adult patients treated with treosulfan-based conditioning regimen, respectively. 14/L Trial II), although none was considered related to treosulfan. No thorough clinical QT/QTc study was performed to rule out the effect of TRECONDYV on in vivo QT prolongation.

In vitro studies on electrophysiological activity of treosulfan on key cardiac ion channels and tests of proarrhythmic potential in human induced pluripotent stem cell (iPS) derived cardiomyocytes, using a microelectrode array (MEA) assay, did not reveal dose -limiting functional or structural changes.

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. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.

 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 Trecondyv® Page 5 of 27