a inhibitors. if the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for xospata adverse reactions. interrupt and reduce xospata dosage in patients with serious or life-threatening toxicity [see dosage and administration ( 2.3 )] . 7.2 effect of xospata on other drugs drugs that target 5ht2b receptor or sigma nonspecific receptor concomitant use of gilteritinib may reduce the effects of drugs that target the 5ht 2b receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). avoid concomitant use of these drugs with xospata unless their use is considered essential for the care of the patient [see clinical pharmacology ( 12.3 )] . p-gp, bcrp, and oct1 substrates based on in vitro data, gilteritinib is a p-gp, breast cancer resistant protein (bcrp), and organic cation transporter 1 (oct1) inhibitor. coadministration of gilteritinib may increase the exposure of p-gp, bcrp, and oct1 substrates, which may increase the incidence and severity of adverse reactions of these substrates [see clinical pharmacology ( 12.3 )]. for p-gp, bcrp, or oct1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information.

ntiation 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 )] . 5.3 prolonged qt interval xospata has been associated with prolonged cardiac ventricular repolarization (qt interval). of the 317 patients with a post-baseline qtc measurement on treatment with xospata in the clinical trial, 1% were found to have a qtc interval greater than 500 msec and 7% of patients had an increase from baseline qtc greater than 60 msec. 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 and reduce xospata dosage in patients who have a qtcf >500 msec [see dosage and administration ( 2.3 ), adverse reactions ( 6.1 ) and clinical pharmacology ( 12.2 )] . hypokalemia or hypomagnesemia may increase the qt prolongation risk. correct hypokalemia or hypomagnesemia prior to and during xospata administration. 5.4 pancreatitis of 319 patients treated with xospata in the clinical trials, 4% experienced pancreatitis. evaluate patients who develop signs and symptoms of pancreatitis. interrupt and reduce the dose of xospata in patients who develop pancreatitis [see dosage and administration ( 2.3 )] . 5.5 embryo-fetal toxicity based on findings in animals and its mechanism of action, xospata can cause embryo-fetal harm when administered to a pregnant woman. in animal reproduction studies, administration of gilteritinib to pregnant rats during organogenesis caused embryo-fetal lethality, suppressed fetal growth and teratogenicity at maternal exposures (auc 24 ) approximately 0.4 times the auc 24 in patients receiving the recommended dose. advise females of reproductive potential to use effective contraception during treatment with xospata and for 6 months after the last dose of xospata. advise males with female partners of reproductive potential to use effective contraception during treatment with xospata and for 4 months after the last dose of xospata. pregnant women, patients becoming pregnant while receiving xospata or male patients with pregnant female partners should be apprised of the potential risk to the fetus [see use in specific populations ( 8.1 , 8.3 ) and clinical pharmacology ( 12.1 )] .

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.

nical 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 [see clinical studies ( 14 )] are shown in tables 2 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 (38) 20 (29) 1 (1) 3 (4) 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 (31) 11 (16) 15 (10) 5 (7) general disorders and administration site conditions fatigue/malaise grouped terms: asthenia, fatigue, lethargy and malaise 36 (24) 9 (13) 1 (1) 2 (3) fever 25 (17) 21 (31) 2 (1) 4 (6) edema grouped terms: edema, edema peripheral, face edema, fluid overload, generalized edema, hypervolemia, localized edema, periorbital edema and swelling face 20 (13) 13 (19) 0 0 gastrointestinal disorders constipation 29 (20) 10 (15) 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 (12) 30 (44) 0 5 (7) nausea 23 (15) 26 (38) 0 0 abdominal pain grouped terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain 16 (11) 16 (24) 0 0 blood and lymphatic system disorder febrile neutropenia 26 (17) 30 (44) 26 (17) 30 (44) 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 (15) 21 (31) 1 (1) 2 (3) respiratory, thoracic and mediastinal disorders dyspnea grouped terms: acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, pulmonary edema, respiratory failure, tachypnea and wheezing 20 (13) 9 (13) 1 (1) 6 (9) cough 18 (12) 5 (7) 1 (1) 0 nervous system disorders neuropathy grouped terms: hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, peripheral sensory neuropathy and paresthesia 19 (13) 0 0 0 dizziness grouped terms: coordination abnormal and dizziness 17 (11) 2 (3) 0 0 headache 17 (11) 12 (18) 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 (36) 6 (15) 9 (9) 1 (2) blood and lymphatic system disorder febrile neutropenia 26 (27) 5 (12) 25 (26) 5 (12) 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 (22) 7 (17) 2 (2) 0 general disorders and administration site conditions fatigue/malaise grouped terms: asthenia, fatigue and malaise 20 (21) 9 (22) 4 (4) 1 (2) edema grouped terms: edema, face edema, localized edema, edema peripheral, peripheral swelling, periorbital edema, scrotal edema and swelling face 19 (20) 5 (12) 1 (1) 0 fever 11 (11) 7 (17) 0 0 gastrointestinal disorders mucositis grouped terms: colitis, mouth hemorrhage, mouth ulceration, mucosal inflammation, oropharyngeal pain, proctalgia, stomatitis, tongue discomfort and tongue ulceration 19 (20) 7 (17) 1 (1) 1 (2) constipation 13 (13) 5 (12) 1 (1) 0 diarrhea 12 (12) 2 (5) 0 0 nausea 10 (10) 7 (17) 0 0 respiratory, thoracic and mediastinal disorders dyspnea grouped terms: acute respiratory failure, dyspnea, hypoxia and respiratory failure 11 (11) 2 (5) 3 (3) 2 (5) 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 (10) 2 (5) 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

a inhibitors. if the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for xospata adverse reactions. interrupt and reduce xospata dosage in patients with serious or life-threatening toxicity [see dosage and administration ( 2.3 )] . 7.2 effect of xospata on other drugs drugs that target 5ht2b receptor or sigma nonspecific receptor concomitant use of gilteritinib may reduce the effects of drugs that target the 5ht 2b receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). avoid concomitant use of these drugs with xospata unless their use is considered essential for the care of the patient [see clinical pharmacology ( 12.3 )] . p-gp, bcrp, and oct1 substrates based on in vitro data, gilteritinib is a p-gp, breast cancer resistant protein (bcrp), and organic cation transporter 1 (oct1) inhibitor. coadministration of gilteritinib may increase the exposure of p-gp, bcrp, and oct1 substrates, which may increase the incidence and severity of adverse reactions of these substrates [see clinical pharmacology ( 12.3 )]. for p-gp, bcrp, or oct1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information.

ulation 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. data animal data 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 24 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 14 of gestation. in addition, distribution profiles of radioactivity in most maternal tissues and the fetus on day 18 of gestation were similar to that on day 14 of gestation. 8.2 lactation risk summary there are no data on the presence of gilteritinib and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. following administration of radiolabeled gilteritinib to lactating rats, milk concentrations of radioactivity were higher than radioactivity in maternal plasma at 4 and 24 hours post-dose. in animal studies, gilteritinib and/or its metabolite(s) were distributed to the tissues in infant rats via the milk. because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with xospata and for 2 months after the last dose. 8.3 females and males of reproductive potential xospata can cause fetal harm when administered to a pregnant woman [see use in specific populations ( 8.1 )] . pregnancy testing pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating xospata treatment [see use in specific populations ( 8.1 )] . contraception females advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of xospata. males advise males of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of xospata. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use 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.

of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. data animal data 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 24 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 14 of gestation. in addition, distribution profiles of radioactivity in most maternal tissues and the fetus on day 18 of gestation were similar to that on day 14 of gestation.

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 [see warnings and precautions ( 5.3 )]. 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 24 is 6943 ng•hr/ml (±3221). steady-state plasma levels are reached within 15 days of dosing with an approximate 10-fold accumulation. absorption the time to maximum gilteritinib concentration (t max ) observed is approximately between 4 and 6 hours post dose in the fasted state. effect of food 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 800 to 1,000 total calories with 500 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. distribution 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. elimination 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. excretion 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. specific populations 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). strong cyp3a inhibitors : gilteritinib c max increased approximately 20% and auc increased approximately 120% when co-administered with itraconazole (a strong cyp3a inhibitor). moderate 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. in vitro studies 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.

calories with 500 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. distribution 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. elimination 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. excretion 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. specific populations 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). strong cyp3a inhibitors : gilteritinib c max increased approximately 20% and auc increased approximately 120% when co-administered with itraconazole (a strong cyp3a inhibitor). moderate 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. in vitro studies 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.

ye and kidney.

response was 3.6 months (range, 0.9 to 9.6 months). the cr/crh rate was 29 of 126 in patients with flt3-itd or flt3-itd/tkd and 0 of 12 in patients with flt3-tkd only. among the 106 patients who were dependent on red blood cell (rbc) and/or platelet transfusions at baseline, 33 (31.1%) became independent of rbc and platelet transfusions during any 56-day post-baseline period. for the 32 patients who were independent of both rbc and platelet transfusions at baseline, 17 (53.1%) remained transfusion-independent during any 56-day post-baseline period. table 5: efficacy results in patients with relapsed or refractory aml treated with xospata in the first interim analysis (admiral trial) remission rate xospata n=138 cr cr was defined as an absolute neutrophil count ≥1.0 x 10 9 /l, platelets ≥100 x 10 9 /l, normal marrow differential with <5% blasts, must have been red blood cells, platelet transfusion independent and no evidence of extramedullary leukemia. /crh crh was defined as marrow blasts <5%, partial hematologic recovery absolute neutrophil count ≥0.5 x 10 9 /l and platelets ≥50 x 10 9 /l, no evidence of extramedullary leukemia and could not have been classified as cr. n/n (%) 29/138 (21) 95% ci the 95% ci rate was calculated using the exact method based on binomial distribution. 14.5, 28.8 median dor dor was defined as the time from the date of either first cr or crh until the date of a documented relapse of any type. deaths were counted as events. (months) 4.6 range (months) 0.1 to 15.8 response was ongoing. cr n/n (%) 16/138 (11.6) 95% ci 6.8, 18.1 median dor (months) 8.6 range (months) 1 to 13.8 crh n/n (%) 13/138 (9.4) 95% ci 5.1, 15.6 median dor (months) 2.9 range (months) 0.1 to 15.8 ci: confidence interval; ne: not estimable; nr: not reached; only responses prior to hsct were included in response rate. final analysis the final analysis of the admiral trial included 371 adult patients randomized 2:1 to receive xospata 120 mg once daily (n=247) over continuous 28-day cycles or a prespecified chemotherapy regimen (n=124). randomization was stratified by response to first-line aml therapy and prespecified chemotherapy. the prespecified chemotherapy regimens included high intensity combinations (mec and flag-ida) and low intensity regimens (ldac and aza). the demographic and disease characteristics of the randomized patients are shown in table 6 . table 6: baseline demographic and disease characteristics in patients with relapsed or refractory aml in the final analysis (admiral trial) demographic and disease characteristics xospata (120 mg daily) n=247 chemotherapy n=124 demographics median age (years) (range) 62 (20, 84) 62 (19, 85) age categories, n (%) <65 years 141 (57) 75 (60) ≥65 years 106 (43) 49 (40) sex, n (%) male 116 (47) 54 (44) female 131 (53) 70 (57) race, n (%) white 145 (59) 75 (60) asian 69 (28) 33 (27) black or african american 14 (6) 7 (6) native hawaiian or other pacific islander 1 (0.4) 0 other 5 (2) 1 (0.8) unknown/missing 13 (5) 8 (6) baseline ecog ps, n (%) 0-1 206 (83) 105 (85) ≥2 41 (17) 19 (15) disease characteristics untreated relapse aml, n (%) 151 (61) 74 (60) primary refractory aml, n (%) 96 (39) 49 (40) refractory relapse aml, n (%) 0 1 (0.8) number of relapses, n (%) 0 96 (39) 49 (40) 1 149 (60) 74 (60) 2 or more 2 (0.8) 1 (0.8) median number of relapses (range) 1 (0, 2) 1 (0, 2) transfusion dependent at baseline, n (%) patients were defined as transfusion dependent at baseline if they were dosed and received any red blood cell or platelet transfusions within the 56-day baseline period. 197 (80) 97 (89) flt3 mutation status, n (%) itd alone 215 (87) 113 (91) tkd alone 21 (9) 10 (8) itd and tkd 7 (3) 0 prior use of flt3 inhibitor prior use of flt3 inhibitor is defined as “yes” if patients received prior aml therapy of midostaurin, sorafenib or quizartinib; otherwise, prior use of flt3 inhibitor was assigned as “no.” , n (%) no 215 (87) 110 (89) yes 32 (13) 14 (11) prespecified chemotherapy high intensity 149 (60) 75 (60) mec mec: mitoxantrone 8 mg/m 2 , etoposide 100 mg/m 2 and cytarabine 1000 mg/m 2 once daily by iv for 5 days - 33 (27) flag-ida flag-ida: granulocyte colony-stimulating factor 300 mcg/m 2 once daily by sc days 1 to 5, fludarabine 30 mg/m 2 once daily by iv days 2 through 6, cytarabine 2000 mg/m 2 once daily by iv for days 2 through 6, idarubicin 10 mg/m 2 once daily by iv days 2 through 4 - 42 (34) low intensity 98 (40) 49 (40) ldac ldac: cytarabine 20 mg twice daily by subcutaneous (sc) or intravenous (iv) for 10 days - 17 (14) aza aza: azacitidine 75 mg/m 2 once daily by sc or iv for 7 days - 32 (26) aml: acute myeloid leukemia; flt3: fms-related tyrosine kinase 3; itd: internal tandem duplication; tkd: d835/i836 tyrosine kinase domain point mutation; ecog ps: eastern cooperative oncology group performance status the final analysis included an assessment of os, measured from the date of randomization until death by any cause. at the time of analysis, median follow-up was 17.8 months (range, 14.9 to 19.1). patients randomized to the xospata arm had significantly longer survival compared to the chemotherapy arm (hr 0.64; 95% ci: 0.49 – 0.83; 1-sided p-value: 0.0004). figure 1 and table 7 show the results of the os analysis. exploratory subgroup analyses demonstrated that the hazard ratio for survival was 0.66 (95% ci: 0.47 – 0.93) for patients in the high intensity chemotherapy stratum and 0.56 (95% ci: 0.38 – 0.84) for patients in the low intensity chemotherapy stratum. the cr rates are shown in table 7 . for patients on xospata and chemotherapy arms, the cr rates were 15.4% (95% ci: 10% – 22.3%) and 16% (95% ci: 8.6% – 26.3%), respectively, for patients in the high intensity chemotherapy stratum, and 12.2% (95% ci: 6.5% – 20.4%) and 2% (95% ci 0.1% – 10.9%), respectively, for patients in the low intensity chemotherapy stratum. table 7: os and cr cr was defined as an absolute neutrophil count ≥1.0 x 10 9 /l, platelets ≥100 x 10 9 /l, normal marrow differential with <5% blasts, must have been red blood cells, platelet transfusion independent and no evidence of extramedullary leukemia. in patients with relapsed or refractory aml in the final analysis (admiral trial) ci: confidence interval; only responses prior to hsct were included in response rate. xospata n=247 chemotherapy n=124 overall survival deaths, n (%) 171 (69.2%) 90 (72.6%) median in months (95% ci) 9.3 (7.7, 10.7) 5.6 (4.7, 7.3) hazard ratio (95% ci) 0.64 (0.49, 0.83) p-value (1-sided) 0.0004 complete remission cr, n (%) 35 (14.2%) 13 (10.5%) (95% ci the 95% ci rate was calculated using the exact method based on binomial distribution. ) (10.1, 19.2) (5.7, 17.3) median dor dor was defined as the time from the date of first remission until the date of a documented relapse. (range) (months) 14.8 (0.6 to 23.1+) 1.8 (<0.1+ to 1.8) figure 1: kaplan-meier plot of overall survival in admiral trial in the final analysis, the cr/crh rate in the gilteritinib arm was 22.6% (55/243) and the dor was 7.4 months (range, <0.1+ to 23.1+). for patients who achieved a cr/crh, the median time to first response was 2 months (range, 0.9 to 9.6 months). the cr/crh rate was 49 of 215 in patients with flt3-itd only, 3 of 7 in patients with flt3-itd/tkd and 3 of 21 in patients with flt3-tkd only. among the 197 patients who were dependent on red blood cell (rbc) and/or platelet transfusions at baseline, 68 (34.5%) became independent of rbc and platelet transfusions during any 56-day post-baseline period. for the 49 patients who were independent of both rbc and platelet transfusions at baseline, 29 (59.2%) remained transfusion-independent during any 56-day post-baseline period figure 1: kaplan-meier plot of overall survival in admiral trial

qt interval advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes [see warnings and precautions ( 5.3 )] . pancreatitis advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis, which include severe and persistent stomach pain, with or without nausea and vomiting [see warnings and precautions ( 5.4 )]. use of contraceptives • advise female patients with reproductive potential to use effective contraceptive methods while receiving xospata and for 6 months after completion of treatment. • advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during xospata treatment. • advise males with female partners of reproductive potential to use effective contraception during treatment with xospata and for 4 months after the last dose of xospata [see use in specific populations ( 8.3 )] . lactation advise women not to breastfeed during treatment with xospata for 2 months after the last dose [see use in specific populations ( 8.2 )]. dosing instructions • advise patients not to break, crush or chew the tablets but to swallow them whole with a cup of water. • instruct patients that, if they miss a dose of xospata, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day. instruct patients to not take 2 doses within 12 hours [see dosage and administration ( 2.2 )] . distributed by: astellas pharma us, inc. northbrook, illinois 60062 xospata is a registered trademark of astellas pharma inc. leukostrat is a registered trademark of invivoscribe, inc. ©2021 astellas pharma us, inc. 312959-glt-usa