6 ADVERSE REACTIONS

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

Differentiation Syndrome [see Warnings and Precautions (5.1)]
Hepatotoxicity [see Warnings and Precautions (5.2)]

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 ofanother drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience

Relapsed or Refractory AML

The safety of REZLIDHIA 150 mg administered twice daily was evaluated in 153 adults with relapsed or refractory AML with an IDH1 mutation [see Clinical Studies (14.1)]. Among the 153 patients who received REZLIDHIA, 35% were exposed for at least 6 months and 21% were exposed for at least 1 year. The median duration of exposure to REZLIDHIA was 4.7 months (range: 0.1 to 34 months).

Serious adverse reactions occurred in 25% of patients who received REZLIDHIA. Serious adverse reactions in ≥5% included differentiation syndrome (9%) and transaminitis (6%). Fatal adverse reactions occurred in 1% of patients who received REZLIDHIA, due to differentiation syndrome.

Permanent discontinuation of REZLIDHIA due to an adverse reaction occurred in 8% of patients. Adverse reactions leading to permanent discontinuation in ≥1% of patients included transaminitis, differentiation syndrome, and gallbladder disorders.

Dosage interruptions of REZLIDHIA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in >5% of patients included transaminitis and differentiation syndrome.

Dose reductions of REZLIDHIA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dose reductions in ≥2% of patients included transaminitis.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

Table 2 summarizes the adverse reactions in the clinical trial for relapsed or refractory AML.

Table 2: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory AML in the Clinical Trial
* Mucositis includes gingival hypertrophy, gingivitis, gingivitis ulcerative, oral disorder, colitis, mouth ulceration, stomatitis, tongue ulceration, oral pain, oropharyngeal pain, pharyngitis, proctalgia, and colitis ischemic. † Includes multiple similar adverse reaction terms. ‡ Arthralgia grouped term includes arthralgia, bone pain, back pain, neck pain, pain in extremity, arthritis, joint effusion, joint range of motion decreased, and joint swelling. § Includes fatal adverse reaction. ¶ Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. # Dyspnea grouped term includes acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, oxygen saturation decreased, respiratory distress, respiratory failure. Þ Transaminitis grouped term includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasemia, liver function test abnormal, liver function test increased, transaminases increased, hepatitis acute, and blood alkaline phosphatase increased.
	Olutasidenib 150 mg BID N=153
Body System Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal Disorders
Nausea	38	0
Constipation	26	0
Mucositis*	23	3
Diarrhea	20	1
Abdominal pain†	18	1
Vomiting	17	1
General Disorders and Administration Site Conditions
Fatigue/malaise†	36	3
Pyrexia	24	1
Edema†	18	3
Musculoskeletal and Connective Tissue Disorders
Arthralgia‡	28	3
Blood System and Lymphatic Disorders
Leukocytosis	25	9
Differentiation syndrome§'¶	16	8
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea§'#	24	5
Cough†	17	1
Skin and subcutaneous tissue disorders
Rash†	24	1
Investigations
TransaminitisÞ	20	12
Metabolism and Nutrition Disorders
Decreased appetite	16	2
Nervous System Disorders
Headache	13	0
Vascular Disorders
Hypertension†	10	5

Clinically relevant adverse reactions in <10% of patients who received REZLIDHIA include:

Gallbladder disorders: biliary tract disorder, biliary colic, cholangitis, and cholestasis
Electrocardiogram QT prolonged

Table 3 summarizes the laboratory abnormalities in the clinical trial for relapsed or refractory AML.

Table 3: Most Common (≥10%) New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML in the Clinical Trial
* The denominator used to calculate the rate varied from 143 to 152 based on the number of patients with a baseline value and at least one post-treatment value.
	Olutasidenib*
Parameter	All Grades (%)	Grade 3 or 4 (%)
Aspartate aminotransferase increased	47	10
Alanine aminotransferase increased	46	13
Potassium decreased	46	9
Sodium decreased	42	7
Alkaline phosphatase increased	42	7
Creatinine increased	38	2
Lymphocytes increased	26	3
Bilirubin increased	26	2
Uric acid increased	25	3
Lipase increased	24	8