XOSPATA is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. ( 1.1 )
1.1Relapsed 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.
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 )] . Hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials. ( 4 , 6.1 )
Warnings and precautions
Posterior reversible encephalopathy syndrome (PRES): Discontinue XOSPATA in patients who develop PRES. ( 2.3 , 5.2 , 6.1 )
Prolonged QT Interval: Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration. ( 2.3 , 5.3 , 12.2 , 6.1 )
Pancreatitis: Interrupt and reduce the dose in patients who develop pancreatitis. ( 2.3 , 5.4 )
Embryo-Fetal Toxicity: XOSPATA can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )
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 )] .
5.3Prolonged 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 )] .
5.5Embryo-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 )] .
Strong CYP3A Inhibitors: Consider alternative therapies. If the concomitant use of strong CYP3A inhibitors cannot be avoided, monitor patients more frequently for XOSPATA adverse reactions. ( 2.3 , 7.1 )
P-gp, BCRP, OCT1 Substrates: Decrease the dose of the substrates when coadministered with gilteritinib and as clinically indicated. ( 7.2 )
7.1Effect of Other Drugs on
XOSPATA Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases gilteritinib exposure which may decrease XOSPATA efficacy [see Clinical Pharmacology ( 12.3 )] . Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers. Strong CYP3A Inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases gilteritinib exposure [see Clinical Pharmacology ( 12.3 )] .
Consider alternative therapies that are not strong CYP3A 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 )] .
7.2Effect 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.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies (see Data) and its mechanism of action, XOSPATA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . 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 24 in patients receiving the recommended dose ( see Data ).
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.
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.
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling:
Differentiation syndrome [see Boxed Warning and Warnings and Precautions ( 5.1 )]
Prolonged QT interval [see Warnings and Precautions ( 5.3 )]
Pancreatitis [see Warnings and Precautions ( 5.4 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 [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 (2
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Composition
Active ingredients
GILTERITINIB FUMARATE EQ 40MG BASE
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA211349.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
