6 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)]
•: Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.2)]
•: Prolonged QT interval [see Warnings and Precautions (5.3)]
•: Pancreatitis [see Warnings and Precautions (5.4)]

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 [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)* of Patients with Relapsed or Refractory AML in the Pre-selected High Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial
* Grade 3-5 includes serious, life-threatening and fatal adverse reactions † 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 ‡ 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 § Grouped terms: asthenia, fatigue, lethargy and malaise ¶ Grouped terms: edema, edema peripheral, face edema, fluid overload, generalized edema, hypervolemia, localized edema, periorbital edema and swelling face # 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 Þ Grouped terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain ß 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 à Grouped terms: acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, pulmonary edema, respiratory failure, tachypnea and wheezing è Grouped terms: hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, peripheral sensory neuropathy and paresthesia ð Grouped terms: coordination abnormal and dizziness
Adverse Reaction	Any Grade n (%)		Grade ≥3 n (%)
Adverse Reaction	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†	56 (38)	20 (29)	1 (1)	3 (4)
Investigations
Transaminase increased‡	46 (31)	11 (16)	15 (10)	5 (7)
General disorders and administration site conditions
Fatigue/malaise§	36 (24)	9 (13)	1 (1)	2 (3)
Fever	25 (17)	21 (31)	2 (1)	4 (6)
Edema¶	20 (13)	13 (19)	0	0
Gastrointestinal disorders
Constipation	29 (20)	10 (15)	0	0
Mucositis#	18 (12)	30 (44)	0	5 (7)
Nausea	23 (15)	26 (38)	0	0
Abdominal painÞ	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
Rashß	23 (15)	21 (31)	1 (1)	2 (3)
Respiratory, thoracic and mediastinal disorders
Dyspneaà	20 (13)	9 (13)	1 (1)	6 (9)
Cough	18 (12)	5 (7)	1 (1)	0
Nervous system disorders
Neuropathyè	19 (13)	0	0	0
Dizzinessð	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)* of Patients with Relapsed or Refractory AML in the Pre-selected Low Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial
* Grade 3-5 includes serious, life-threatening and fatal adverse reactions † Grouped terms: aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased and transaminases increased ‡ Grouped terms: arthralgia, arthritis, back pain, limb discomfort, myalgia, muscle contracture, muscle spasms, myositis, non-cardiac chest pain, pain, pain in extremity and polyarthritis § Grouped terms: asthenia, fatigue and malaise ¶ Grouped terms: edema, face edema, localized edema, edema peripheral, peripheral swelling, periorbital edema, scrotal edema and swelling face # Grouped terms: colitis, mouth hemorrhage, mouth ulceration, mucosal inflammation, oropharyngeal pain, proctalgia, stomatitis, tongue discomfort and tongue ulceration Þ Grouped terms: acute respiratory failure, dyspnea, hypoxia and respiratory failure ß Grouped terms: dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, erythema, rash, rash maculo-papular, rash papular, rosacea and skin ulcer
Adverse Reaction	Any Grade n (%)		Grade ≥3 n (%)
Adverse Reaction	XOSPATA (120 mg daily) n=97	Chemotherapy n=41	XOSPATA (120 mg daily) n=97	Chemotherapy n=41
Investigations
Transaminase 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‡	21 (22)	7 (17)	2 (2)	0
General disorders and administration site conditions
Fatigue/malaise§	20 (21)	9 (22)	4 (4)	1 (2)
Edema¶	19 (20)	5 (12)	1 (1)	0
Fever	11 (11)	7 (17)	0	0
Gastrointestinal disorders
Mucositis#	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
DyspneaÞ	11 (11)	2 (5)	3 (3)	2 (5)
Skin and subcutaneous tissue disorders
Rashß	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