Xospata

XOSPATA- gilteritinib fumarate tablet
Astellas Pharma US, Inc.

WARNING: DIFFERENTIATION SYNDROME

Patients treated with XOSPATA have experienced symptoms of differentiation syndrome, which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

1 INDICATIONS AND USAGE

1.1 Relapsed or Refractory Acute Myeloid Leukemia

XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for the treatment of AML with XOSPATA based on the presence of FLT3 mutations in the blood or bone marrow [see Clinical Studies (14)]. Information on FDA-approved tests for the detection of a FLT3 mutation in AML is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended starting dose of XOSPATA is 120 mg orally once daily with or without food. Response may be delayed. 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.

Do not break or crush XOSPATA tablets. Administer XOSPATA tablets orally about the same time each day. If a dose of XOSPATA is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

2.3 Dosage Modifications

Assess blood counts and blood chemistries, including creatine phosphokinase, prior to the initiation of XOSPATA, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Perform electrocardiogram (ECG) prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles.

Interrupt dosing or reduce dose for toxicities as per Table 1.

Table 1: Dosage Modifications for XOSPATA-Related Toxicities *
*
Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.

Adverse Reaction

Recommended Action

Differentiation Syndrome

If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days [see Warnings and Precautions (5.1)].
Interrupt XOSPATA if severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids [see Warnings and Precautions (5.1)].
Resume XOSPATA when signs and symptoms improve to Grade 2* or lower.

Posterior Reversible Encephalopathy Syndrome

Discontinue XOSPATA.

QTc interval greater than 500 msec

Interrupt XOSPATA.
Resume XOSPATA at 80 mg when QTc interval returns to within 30 msec of baseline or less than or equal to 480 msec.

QTc interval increased by >30 msec on ECG on day 8 of cycle 1

Confirm with ECG on day 9.
If confirmed, consider dose reduction to 80 mg.

Pancreatitis

Interrupt XOSPATA until pancreatitis is resolved.
Resume XOSPATA at 80 mg.

Other Grade 3* or higher toxicity considered related to treatment.

Interrupt XOSPATA until toxicity resolves or improves to Grade 1*.
Resume XOSPATA at 80 mg.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 40 mg as light yellow, round-shaped, film-coated tablets debossed with the Astellas logo and ‘235’ on the same side.

4 CONTRAINDICATIONS

XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials [see Adverse Reactions (6) and Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Differentiation Syndrome

Of 319 patients treated with XOSPATA in the clinical trials, 3% experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and other clinical findings of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 1 day and up to 82 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of XOSPATA.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe [see Dosage and Administration (2.3)].

5.2 Posterior Reversible Encephalopathy Syndrome

Of 319 patients treated with XOSPATA in the clinical trials, 1% experienced posterior reversible encephalopathy syndrome (PRES) 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 (2.3) and Adverse Reactions (6.1)].

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