XOSPATA

Gilteritinib is a kinase inhibitor.

The chemical name is 2-Pyrazinecarboxamide, 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl] amino]-5-[(tetrahydro-2 H -pyran-4-yl) amino]-, (2 E )-2-butenedioate (2:1).

The molecular weight is 1221.50 and the molecular formula is (C 29 H 44 N 8 O 3 ) 2 ·C 4 H 4 O 4.

The structural formula is

Gilteritinib fumarate is a light yellow to yellow powder or crystals that is sparingly soluble in water and very slightly soluble in anhydrous ethanol.

XOSPATA (gilteritinib) is provided as a tablet for oral administration.

Each tablet contains 40 mg of gilteritinib active ingredient as free base (corresponding to 44.2 mg gilteritinib fumarate).

The inactive ingredients are ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate, polyethylene glycol, talc, and titanium dioxide.

Structural Formula of

Geltertinep is used to treat adults with acute marrow-white conditions and those who are found to have genetic abnormalities in FLT3 receptors.

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Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3).

Gilteritinib demonstrated the ability to inhibit

FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, tyrosine kinase domain mutations (TKD) FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells expressing FLT3-ITD. 12.2 Pharmacodynamics In patients with relapsed or refractory AML administered gilteritinib 120 mg, substantial (>90%) inhibition of FLT3 phosphorylation was rapid (within 24 hours after first dose) and sustained, as characterized by an ex vivo plasma inhibitory activity (PIA) assay.

Cardiac Electrophysiology The effect of

XOSPATA 120 mg once a day on the QTc interval has been evaluated in patients, which showed an absence of large mean increases (i.e., 20 msec) in the QTc interval.

Of 317 patients with a post-baseline QTc measurement on treatment with gilteritinib at 120 mg in clinical trials, 4 patients (1.3%) experienced a QTcF >500 msec.

Additionally, across all doses 2.3% of patients with relapse/refractory AML had a maximum post-baseline QTcF interval >500 msec. 12.3 Pharmacokinetics The following pharmacokinetic parameters were observed following administration of gilteritinib 120 mg once daily, unless otherwise specified.

Gilteritinib exposure (C max and AUC 24 ) increases proportionally with once daily doses ranging from 20 mg to 450 mg (0.17 to 3.75 times the recommended dosage) in patients with relapsed or refractory AML.

Gilteritinib mean (±SD) steady-state C max is 374 ng/mL (±190) and AUC is 6943 ng•hr/mL (±3221).

Steady-state plasma levels are reached within 15 days of dosing with an approximate 10-fold accumulation.

The time to maximum gilteritinib concentration (t max ) observed is approximately between and 6 hours post dose in the fasted state.

In healthy adults administered a single gilteritinib 40 mg dose (0.3 times the recommended dosage), gilteritinib C max decreased by 26% and AUC decreased by less than 10% when co-administered with a high-fat meal (approximately to 1,000 total calories with to 600 fat calories, 250 carbohydrate calories, 150 protein calories) compared to a fasted state.

Median t max was delayed 2 hours when gilteritinib was administered with a high-fat meal.

The population mean (%CV) estimates of apparent central and peripheral volume of distribution were 1092 L (9.22%) and 1100 L (4.99%), respectively, which may indicate extensive tissue distribution.

In vivo, gilteritinib is approximately 94% bound to human plasma proteins.

In vitro, gilteritinib is primarily bound to human serum albumin.

The estimated half-life of gilteritinib is 113 hours, and the estimated apparent clearance is 14.85 L/h.

Metabolism Gilteritinib is primarily metabolized via

CYP3A4 in vitro.

At steady state, the primary metabolites in humans include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N‑dealkylation).

None of these 3 metabolites exceeded 10% of overall parent exposure.

After a single radiolabeled dose, gilteritinib is excreted in feces with 64.5% of the total administered dose recovered in feces.

Of the total radiolabeled dose of gilteritinib, 16.4% was recovered in urine as unchanged drug and metabolites.

Age (20-87 years), sex, race, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment and mild (creatinine clearance (CLCr) 50-80 mL/min) or moderate (CLCr 30-50 mL/min) renal impairment do not have clinically meaningful effects on the pharmacokinetics of gilteritinib.

The effect of severe hepatic (Child-Pugh Class C) or severe renal impairment (CLCr ≤ 29 mL/min) on gilteritinib pharmacokinetics is unknown.

Drug Interaction Studies Clinical Studies Combined P-gp and Strong CYP3A Inducers: Gilteritinib C max decreased approximately 30% and AUC decreased approximately 70% when co-administered with rifampin (a combined P-gp and strong CYP3A inducer).

CYP3A Inhibitors: Gilteritinib C max increased approximately 20% and AUC increased approximately 120% when co-administered with itraconazole (a strong CYP3A inhibitor).

CYP3A Inhibitors: Gilteritinib C max increased approximately 16% and AUC increased approximately 40% when co-administered with fluconazole (a moderate CYP3A inhibitor).

CYP3A Substrates: Midazolam (a CYP3A substrate) C max and AUC increased approximately 10% when co-administered with gilteritinib.

MATE1 Substrates: Cephalexin (a MATE1 substrate) C max and AUC decreased by less than 10% when co-administered with gilteritinib.

Gilteritinib inhibits human 5HT 2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs that target these receptors such as escitalopram, fluoxetine and sertraline.

Gilteritinib is a substrate of P-gp and BCRP.

Gilteritinib inhibits

BCRP, P-gp and OCT1 at clinically relevant concentrations.

The gelteritenib mechanism, which is a drug used to treat certain cases of leukemia or leukemia, is a drug that is classified as a generitinib inhibitor for casinos of the turus (Tyrosine Kinase Inhibitor), inhibiting the activity of many casinos of turus, as well as receptors known as FMS-like FMS-Like Tyrosine Kinase 3/ FLT3.

• Differentiation syndrome.

• Posterior reversible encephalopathy syndrome.

• Prolonged QT interval.

• Pancreatitis The most common adverse reactions (≥20%) are transaminase increased, myalgia/arthralgia, fatigue/malaise, fever, mucositis, edema, rash, noninfectious diarrhea, dyspnea, nausea, cough, constipation, eye disorders, headache, dizziness, hypotension, vomiting, and renal impairment.

To report SUSPECTED ADVERSE

REACTIONS, contact Astellas Pharma US, Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety profile of

XOSPATA is based on 319 patients with relapsed or refractory AML treated with gilteritinib 120 mg daily in three clinical trials.

The median duration of exposure to

XOSPATA was 3.6 months (range 0.1 to 43.4 months).

Fatal adverse reactions occurred in 2% of patients receiving XOSPATA.

These included cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis.

The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

Of the 319 patients, 91 (29%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were aspartate aminotransferase increased (6%), alanine aminotransferase increased (6%) and fever (4%).

Twenty patients (6%) required a dose reduction due to an adverse reaction.

Twenty-two (7%) discontinued XOSPATA treatment permanently due to an adverse reaction.

The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%).

Overall, for the 319 patients, the most frequent (≥10%) all-grade nonhematological adverse reactions reported in patients were transaminase increased (51%), myalgia/arthralgia (50%), fatigue/malaise (44%), fever (41%), mucositis (41%), edema (40%), rash (36%), noninfectious diarrhea (35%), dyspnea (35%), nausea (30%), cough (28%), constipation (28%), eye disorders (25%), headache (24%), dizziness (22%), hypotension (22%), vomiting (21%), renal impairment (21%), abdominal pain (18%), neuropathy (18%), insomnia (15%) and dysgeusia (11%).

The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

Shifts to grades 3-4 nonhematologic laboratory abnormalities included phosphate decreased 42/309 (14%), alanine aminotransferase increased 41/317 (13%), sodium decreased 37/314 (12%), aspartate aminotransferase increased 33/317 (10%), calcium decreased 19/312 (6%), creatine kinase increased 20/317 (6%), triglycerides increased 18/310 (6%), creatinine increased 10/316 (3%), and alkaline phosphatase increased 5/317 (2%).

Adverse reactions reported in the first 30 days of therapy on the ADMIRAL Study are shown in Tables and 3, according to whether patients were preselected for high intensity or low intensity chemotherapy.

Table 2: Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3-5) Grade 3-5 includes serious, life-threatening and fatal adverse reactions of Patients with Relapsed or Refractory AML in the Pre-selected High Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial Adverse Reaction Any Grade n (%) Grade ≥3 n (%) XOSPATA (120 mg daily) n=149 Chemotherapy n=68 XOSPATA (120 mg daily) n=149 Chemotherapy n=68 Musculoskeletal and connective tissue disorders Myalgia/arthralgia Grouped terms: arthralgia, back pain, bone pain, flank pain, limb discomfort, medial tibial stress syndrome, myalgia, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, muscle spasms, neck pain, non-cardiac chest pain, pain and pain in extremity 56 20 1 3.

Investigations Transaminase increased Grouped terms: aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, hepatic function abnormal, hepatoxicity, liver function test increased and transaminases increased 46 11 15 5 General disorders and administration site conditions Fatigue/malaise Grouped terms: asthenia, fatigue, lethargy and malaise 36 9 1 2 Fever 25 21 2 4 Edema Grouped terms: edema, edema peripheral, face edema, fluid overload, generalized edema, hypervolemia, localized edema, periorbital edema and swelling face 20 13 0 0 Gastrointestinal disorders Constipation 29 10 0 0 Mucositis Grouped terms: aphthous ulcer, colitis, enteritis, esophageal pain, gingival pain, large intestinal ulcer, laryngeal inflammation, lip blister, lip ulceration, mouth hemorrhage, mouth ulceration, mucosal inflammation, oral discomfort, oral pain, oropharyngeal pain, proctalgia, stomatitis, swollen tongue, tongue discomfort and tongue ulceration 18 30 0 5 Nausea 23 26 0 0 Abdominal pain Grouped terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain 16 16 0 0 Blood and lymphatic system disorder Febrile neutropenia 26 30 26 30 Skin and subcutaneous tissue disorders Rash Grouped terms: acne, dermatitis bullous, dermatitis contact, drug eruption, eczema asteatotic, erythema, hyperkeratosis, lichenoid keratosis, palmar-plantar erythrodysesthesia syndrome, rash, rash maculo-papular, rash papular, skin exfoliation, skin lesion and skin hyperpigmentation 23 21 1 2 Respiratory, thoracic and mediastinal disorders Dyspnea Grouped terms: acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, pulmonary edema, respiratory failure, tachypnea and wheezing 20 9 1 6 Cough 18 5 1 0 Nervous system disorders Neuropathy Grouped terms: hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, peripheral sensory neuropathy and paresthesia 19 0 0 0 Dizziness Grouped terms: coordination abnormal and dizziness 17 2 0 0 Headache 17 12 0 0 Table 3: Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3-5) Grade 3-5 includes serious, life-threatening and fatal adverse reactions of Patients with Relapsed or Refractory AML in the Pre-selected Low Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial Adverse Reaction Any Grade n (%) Grade ≥3 n (%) XOSPATA (120 mg daily) n=97 Chemotherapy n=41 XOSPATA (120 mg daily) n=97 Chemotherapy n=41.

Investigations Transaminase increased Grouped terms: aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased and transaminases increased 35 6 9 1 Blood and lymphatic system disorder Febrile neutropenia 26 5 25 5 Musculoskeletal and connective tissue disorders Myalgia/arthralgia Grouped terms: arthralgia, arthritis, back pain, limb discomfort, myalgia, muscle contracture, muscle spasms, myositis, non-cardiac chest pain, pain, pain in extremity and polyarthritis 21 7 2 0 General disorders and administration site conditions Fatigue/malaise Grouped terms: asthenia, fatigue and malaise 20 9 4 1 Edema Grouped terms: edema, face edema, localized edema, edema peripheral, peripheral swelling, periorbital edema, scrotal edema and swelling face 19 5 1 0 Fever 11 7 0 0 Gastrointestinal disorders Mucositis Grouped terms: colitis, mouth hemorrhage, mouth ulceration, mucosal inflammation, oropharyngeal pain, proctalgia, stomatitis, tongue discomfort and tongue ulceration 19 7 1 1 Constipation 13 5 1 0 Diarrhea 12 2 0 0 Nausea 10 7 0 0 Respiratory, thoracic and mediastinal disorders Dyspnea Grouped terms: acute respiratory failure, dyspnea, hypoxia and respiratory failure 11 2 3 2 Skin and subcutaneous tissue disorders Rash Grouped terms: dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, erythema, rash, rash maculo-papular, rash papular, rosacea and skin ulcer 10 2 2 0 Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity (8%), pancreatitis (5%), cardiac failure (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%). *Grouped terms: cardiac failure (cardiac failure, cardiac failure congestive, cardiomegaly, cardiomyopathy, chronic left ventricular failure, and ejection fraction decreased), hypersensitivity (anaphylactic reaction, angioedema, dermatitis allergic, drug hypersensitivity, erythema multiforme, hypersensitivity, and urticaria), pancreatitis (amylase increased, lipase increased, pancreatitis, pancreatitis acute), pericarditis/myocarditis (myocarditis, pericardial hemorrhage, pericardial rub, and pericarditis).

Selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 4.

Table 4: Shifts to Grade 3-4 Laboratory Abnormalities in Patients with Relapsed or Refractory AML by Pre-selected High Intensity and Low Intensity Chemotherapy in the First 30 Days of the ADMIRAL Trial Pre-selected High Intensity Chemotherapy Subgroup Pre-selected Low Intensity Chemotherapy Subgroup XOSPATA (120 mg daily) Chemotherapy XOSPATA (120 mg daily) Chemotherapy Alanine aminotransferase increased 7/149 (5%) 1/66 (2%) 7/95 (7%) 1/41 (2%) Alkaline phosphatase increased 1/149 (1%) 0 0 0 Aspartate aminotransferase increased 8/149 (5%) 2/65 (3%) 5/95 (5%) 0 Calcium decreased 2/149 (1%) 3/65 (5%) 3/94 (3%) 0 Creatine kinase increased 1/149 (1%) 0 1/95 (1%) 0 Phosphatase decreased 4/144 (3%) 6/65 (9%) 4/93 (4%) 3/38 (8%) Sodium decreased 7/148 (5%) 5/65 (8%) 6/93 (6%) 2/41 (5%) Triglycerides increased 1/146 (1%) 0 2/94 (2%) 0.

is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients.

Anaphylactic reactions have been observed in clinical trials.

Hypersensitivity to gilteritinib or any of the excipients.

mg orally once daily. 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.

Information on FDA-approved tests for the detection of a FLT3 mutation in AML is available at. 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 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 is mild, Grade is moderate, Grade is serious, Grade is life-threatening.

Adverse Reaction Recommended Action Differentiation

• If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days.

• Interrupt XOSPATA if severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids.

• Resume XOSPATA when signs and symptoms improve to Grade 2 or lower.

QTc interval greater than 500 msec.

• 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 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.

XOSPATA (gilteritinib) 40 mg tablets are supplied as light yellow, round-shaped, film-coated tablets debossed with the Astellas logo and ‘235’ on the same side.

• Bottles of 90 tablets with Child Resistant Closure (NDC 0469-1425-90) Storage Store XOSPATA tablets at 20ºC to 25ºC (68°F to 77°F); excursions permitted between 15ºC to 30ºC (59°F to 86°F) .

Keep in original container until dispensed.

Protect from light, moisture and humidity.

Based on findings from animal studies and its mechanism of action, XOSPATA can cause fetal harm when administered to a pregnant woman.

There are no available data on

XOSPATA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

In animal reproduction studies, administration of gilteritinib to pregnant rats during organogenesis caused adverse developmental outcomes including embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures (AUC 24 ) approximately 0.4 times the AUC in patients receiving the recommended dose.

Advise pregnant women of the potential risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

In an embryo-fetal development study in rats, pregnant animals received oral doses of gilteritinib of 0, 0.3, 3, 10, and 30 mg/kg/day during the period of organogenesis.

Maternal findings at 30 mg/kg/day (resulting in exposures approximately 0.4 times the AUC in patients receiving the recommended dose) included decreased body weight and food consumption.

Administration of gilteritinib at the dose of 30 mg/kg/day also resulted in embryo-fetal death (postimplantation loss), decreased fetal body and placental weight, and decreased numbers of ossified sternebrae and sacral and caudal vertebrae, and increased incidence of fetal gross external (anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (microphthalmia; atrial and/or ventricular defects; and malformed/absent kidney, and malpositioned adrenal, and ovary), and skeletal (sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities.

Single oral administration of [ 14 C] gilteritinib to pregnant rats resulted in transfer of radioactivity to the fetus similar to that observed in maternal plasma on day of gestation.

In addition, distribution profiles of radioactivity in most maternal tissues and the fetus on day of gestation were similar to that on day of gestation.

Safety and effectiveness in pediatric patients have not been established.

Of the 319 patients in clinical studies of XOSPATA, 43% were age 65 years or older, and 13% were 75 years or older.

No overall differences in effectiveness or safety were observed between patients age 65 years or older and younger patients.