6 ADVERSE REACTIONS

The following clinically-significant adverse reactions are described elsewhere in the labeling:

•: QTc Interval Prolongation [see Warnings and Precautions (5.2)]
•: Musculoskeletal Adverse Reactions [see Warnings and Precautions (5.3)]

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 DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated [see Clinical Studies (14)]. Patients were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41). The median duration of treatment in the DAURISMO with low-dose cytarabine arm was 83 days (range 3 to 972 days), and the median duration of treatment in the low-dose cytarabine alone arm was 47 days (range 6 to 239 days). The median exposure to DAURISMO in the DAURISMO with low-dose cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with DAURISMO with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year.

Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%).

Dose reductions associated with adverse reactions were reported in 26% of patients treated with DAURISMO with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and ECG QT prolonged (2%). Adverse reactions leading to permanent discontinuation were reported in 36% of patients treated with DAURISMO with low-dose cytarabine, and the most common (≥2%) reasons for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%).

Adverse reactions reported in the first 90 days of therapy on the BRIGHT AML 1003 study are shown in Table 3.

Table 3. Adverse Reactions Occurring in ≥10% of Patients*† Within the First 90 Days of Therapy in BRIGHT AML 1003
Body System	Adverse Reactions	DAURISMO With Low-Dose Cytarabine N=84		Low-Dose Cytarabine N=41
		All Grades %	Grade ≥3 %	All Grades %	Grade ≥3 %
Abbreviations: N = number of patients. Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse reactions include events that commenced within 28 days after the last treatment dose.
* Adverse reactions with ≥10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included. † No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm. ‡ Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding, hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye hemorrhage, gastric hemorrhage, gastrointestinal hemorrhage, hematemesis, hemoptysis, hemorrhage, implant site hematoma, injection site bruising, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, tracheal hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, eyelid hematoma, hematochezia, hemorrhage intracranial, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, retinal hemorrhage, and subdural hematoma. § Fatigue includes asthenia and fatigue. ¶ Edema includes edema peripheral, edema, fluid overload, fluid retention, and swelling face. # Mucositis includes mucosal inflammation, oropharyngeal pain, stomatitis, anal ulcer, gingival pain, laryngeal inflammation, esophagitis, oral pain, aphthous ulcer, mouth ulceration, and pharyngeal inflammation. Þ Chest pain includes chest pain and non-cardiac chest pain. ß Musculoskeletal pain includes pain in extremity, arthralgia, back pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, neck pain, and bone pain. à Muscle spasms includes muscle spasms and muscle tightness. è Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower. ð Diarrhea includes diarrhea, colitis, and gastroenteritis. ø Dyspnea includes dyspnea, hypoxia, bronchospasm, and respiratory failure. ý Cough includes cough and productive cough. £ Dysgeusia includes dysgeusia and ageusia. ¥ Rash includes rash, pruritus, erythema, skin ulcer, rash maculo-papular, and rash pruritic. Œ Pneumonia includes pneumonia, pneumonia aspiration, and lung infection. œ Atrial arrhythmia includes atrial fibrillation, bradycardia, tachycardia, and sinus tachycardia. Ɖ Renal insufficiency includes acute kidney injury, blood creatinine increased, oliguria, and renal failure.
Blood and lymphatic system disorder	Anemia	43	41	42	37
	Hemorrhage‡	36	6	42	12
	Febrile neutropenia	31	31	22	22
	Thrombocytopenia	30	30	27	24
General disorders and administration site conditions	Fatigue§	36	14	32	7
	Edema¶	30	0	20	2
	Mucositis#	21	1	12	0
	Pyrexia	18	1	22	2
	Chest painÞ	12	1	2	0
Musculoskeletal and connective tissue disorders	Musculoskeletal painß	30	2	17	2
Musculoskeletal and connective tissue disorders	Muscle spasmà	15	0	5	0
Gastrointestinal disorders	Nausea	29	1	12	2
	Constipation	20	1	12	0
	Abdominal painè	19	0	12	0
	Diarrheað	18	4	22	0
	Vomiting	18	2	10	2
Respiratory thoracic and mediastinal disorders	Dyspneaø	23	11	24	7
Respiratory thoracic and mediastinal disorders	Coughý	18	0	15	2
Metabolism and nutrition disorders	Decrease appetite	21	1	7	2
Nervous system disorders	Dysgeusia£	21	0	2	0
	Dizziness	18	1	7	0
	Headache	12	0	10	2
Skin and subcutaneous tissue disorders	Rash¥	20	2	7	2
Infection and infestations	PneumoniaŒ	19	15	24	22
Investigations	Hyponatremia	11	6	0	0
	Platelet count decreased	15	15	10	10
	Weight decreased	13	0	2	0
	White blood cell count decreased	11	11	5	2
Cardiac disorders	Atrial arrhythmiaœ	13	4	7	2
Renal and urinary disorders	Renal insufficiencyƉ	19	5	10	0

The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened (i.e. progressed from Grades ≤2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003.

Additional clinically-significant adverse reactions occurring in <10% of patients treated with DAURISMO and low-dose cytarabine in BRIGHT AML 1003 include:

•: Dental disorders: loose tooth and toothache
•: Skin and subcutaneous tissue disorders: alopecia
•: Cardiac disorders: QT interval prolonged

Changes in selected post-baseline laboratory values that were observed in patients with newly-diagnosed AML and other conditions for which DAURISMO is not indicated in the clinical trial are shown in Table 4.

Table 4. Selected Laboratory Abnormalities (≥15%)* Within the First 90 Days of Therapy in BRIGHT AML 1003
	DAURISMO with Low-Dose Cytarabine			Low-Dose Cytarabine
Laboratory Abnormality	N	All Grades %	Grade 3 or 4† %	N	All Grades %	Grade 3 or 4† %
Abbreviations: N = number of patients; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatinine phosphokinase. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
* Maximum severity based on the number of patients with available on-study laboratory data. † Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
Creatinine increased	81	96	1	40	80	5
Hyponatremia	81	54	7	39	41	8
Hypomagnesemia	81	33	0	39	23	0
AST increased	80	28	1	40	23	0
Blood bilirubin increased	80	25	4	39	33	3
ALT increased	80	24	0	40	28	3
Alkaline phosphatase increased	80	23	0	40	28	3
Hyperkalemia	81	16	1	40	8	3
CPK increased	38	16	0	17	6	0
Hypokalemia	81	15	0	40	23	0

The following laboratory abnormalities worsened (i.e. progressed from Grades ≤2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003:

•: hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients).