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 of another drug and may not reflect the rates observed in practice.
The most common (≥20%) adverse reactions, including laboratory abnormalities, are 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 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 Mucositis includes gingival hypertrophy, gingivitis, gingivitis ulcerative, oral disorder, colitis, mouth ulceration, stomatitis, tongue ulceration, oral pain, oropharyngeal pain, pharyngitis, proctalgia, and colitis ischemic. 23 3 Diarrhea 20 1 Abdominal pain Includes multiple similar adverse reaction terms. 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 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. 28 3 Blood System and Lymphatic Disorders Leukocytosis 25 9 Differentiation syndrome 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. 16 8 Respiratory, Thoracic and Mediastinal Disorders Dyspnea ' Dyspnea grouped term includes acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, oxygen saturation decreased, respiratory distress, respiratory failure. 24 5 Cough 17 1 Skin and subcutaneous tissue disorders Rash 24 1 Investigations Transaminitis 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. 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 Olutasidenib 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. 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
