XOSPATA

1 Dosing Considerations  Treatment with Xospata should be initiated and supervised by a physician experienced in the use of anticancer therapies.  Prior to initiation of treatment with Xospata, patients must have confirmation of FLT3 mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.

XOSPATA (gilteritinib) Page 5 of 30  Assess blood counts and chemistries, including creatine phosphokinase, prior to the initiation of treatment with Xospata, once weekly for the first month, once every other week for the second month, and monthly for the duration of therapy.

 Perform electrocardiogram (ECG) prior to initiation of treatment with Xospata, on days 8 and 15 of the first month, prior to the start of the next two months of treatment, and then as clinically indicated. 2 Recommended Dose and Dosage Adjustment The recommended dose of Xospata is 120 mg (three 40 mg tablets) orally once daily with or without food (see DRUG INTERACTIONS, Drug-Food Interactions).

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Clinical response can be delayed (see CLINICAL TRIALS). In the absence of disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response.

Health Canada has not authorized an indication for pediatric use (see WARNINGS AND PRECAUTIONS, Special Populations). No dose adjustment is required in geriatric patients (≥ 65 years of age) (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

No dose adjustment is required in patients with mild or moderate renal impairment (creatinine clearance [CLCr] ≥30 mL/min). Clinical experience in patients with severe renal impairment (CLCr < 30 mL/min) is limited (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh Class C) (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

XOSPATA (gilteritinib) Page 6 of 30 Table 1 – Xospata Dose Modification Recommendations in Patients with Relapsed or Refractory AML Criteria Xospata Dosing Symptoms of Differentiation Syndrome  If differentiation syndrome is suspected, administer corticosteroids and initiate hemodynamic monitoring until symptom resolution.

1 Adverse Reaction Overview The safety of Xospata was evaluated in 319 adult patients with relapsed or refractory AML having a FLT3 mutation, who received at least one dose of 120 mg Xospata in clinical trials including pivotal ADMIRAL study (see CLINICAL TRIALS).

4 months). 0%). 0%). 3%) required a dose reduction due to an adverse reaction. 9%) discontinued Xospata treatment permanently due to an adverse reaction. 6%). 2%). Fatal adverse reactions included two cases with clinical symptoms consistent with differentiation syndrome and one case of cardiac failure congestive.

2 Clinical Trial Adverse Reactions 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 may be useful for identifying and approximating rates of adverse drug reactions in real-world use. The ADMIRAL study is a Phase 3, open-label, multicentre, randomized clinical trial of adult patients with relapsed or refractory AML having a FLT3 mutation.

The trial compared safety and efficacy of Xospata to protocol-defined salvage chemotherapies (see CLINICAL TRIALS). Adverse reactions are reported for the duration of exposure (Table 3). 1 months) for chemotherapy. 8) a. 1 b. Adverse reactions are based on MedDRA preferred terms (PTs).

c. Based on Common Terminology Criteria for Adverse Events (CTCAE). d. 1 months) for chemotherapy. 1 Less Common Clinical Trial Adverse Reactions - Pediatrics Not applicable. 5 Post-Market Adverse Reactions Not applicable.

Please see the SERIOUS WARNINGS AND PRECAUTIONS Box at the beginning of the PART 1: HEALTH PROFESSIONAL INFORMATION. Cardiovascular QTc Interval Prolongation Xospata has been associated with prolonged cardiac ventricular repolarization (QT interval).

6% of patients had an increase from baseline QTcF greater than 60 msec. 2 mg gilteritinib fumarate). hydroxypropyl cellulose, hypromellose, low- substituted hydroxypropyl cellulose, magnesium stearate, mannitol, polyethylene glycol, talc, titanium dioxide, ferric oxide XOSPATA (gilteritinib) Page 8 of 30 the start of the next two months of treatment, and then as clinically indicated.

Interrupt and/or reduce Xospata dosage in patients who have a QTcF >500 msec (see DOSAGE AND ADMINISTRATION; ADVERSE REACTIONS; ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics). Hypokalemia or hypomagnesemia may increase the QT prolongation risk.

Monitor and correct hypokalemia or hypomagnesemia prior to and during Xospata administration. Driving and Operating Machinery Xospata has the potential to influence the ability to drive and use machines. Dizziness and syncope have been reported in patients taking Xospata and should be considered when assessing a patient’s ability to drive or use machines.

9% of 319 patients treated with Xospata monotherapy in clinical trials. Evaluate and monitor patients who develop signs and symptoms suggestive of pancreatitis. Xospata should be interrupted and can be resumed at a reduced dose when the signs and symptoms of pancreatitis have resolved (see DOSAGE AND ADMINISTRATION; ADVERSE REACTIONS).

Neurologic Posterior Reversible Encephalopathy Syndrome Uncommon events of posterior reversible encephalopathy syndrome (PRES) have been reported with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of Xospata.

A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue Xospata in patients who develop PRES (see DOSAGE AND ADMINISTRATION; ADVERSE REACTIONS).

Xospata 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.