OLUTASIDENIB: 210 Adverse Event Reports & Safety Profile

Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor. The chemical name is (S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile. The chemical structure is: The molecular formula is C 18 H 15 ClN 4 O 2 and the molecular weight is 354.79 g/mol. Olutasidenib is a white to off-white to brown powder that is practically insoluble in aqueous solutions between pH 1.2 and 7.4. REZLIDHIA (olutasidenib) is available as hard gelatin capsules for oral administration. Each capsule contains 150 mg olutasidenib and the following ingredients: croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shell contains gelatin and titanium dioxide. Each capsule is printed with black ink containing ferrosoferric oxide, propylene glycol, and shellac. chemical structure

AND USAGE Relapsed or Refractory Acute Myeloid Leukemia REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.1 ), and Clinical Studies ( 14.1 )] . REZLIDHIA is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. ( 1 )

AND ADMINISTRATION Select patients based on presence of IDH1 mutation(s). ( 2.1 ) Recommended dosage: 150 mg orally twice daily, until disease progression or unacceptable toxicity. ( 2.2 ) Take on an empty stomach at least 1 hour before or 2 hours after a meal. ( 2.2 )

2.1 Patient Selection Select patients for the treatment of relapsed or refractory AML with REZLIDHIA based on the presence of IDH1 mutations in blood or bone marrow <span class="opacity-50 text-xs">[see Clinical Trials ( 14.1 )]</span> . Information on FDA- approved tests for the detection of IDH1 mutations in AML is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage The recommended dosage of REZLIDHIA is 150 mg taken orally twice daily until disease progression or unacceptable toxicity. Administer REZLIDHIA capsules orally about the same time each day. Do not administer 2 doses within 8 hours. Take on an empty stomach at least 1 hour before or 2 hours after a meal <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Swallow REZLIDHIA capsules whole. Do not break, open, or chew the capsules. If a dose of REZLIDHIA is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of REZLIDHIA is missed or not taken at the usual time, administer the dose as soon as possible and at least 8 hours prior to the next scheduled dose. Return to the normal schedule the following day.

2.3 Monitoring and Dosage Modifications for Adverse Reactions Assess blood counts, and blood chemistries including liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months; once every other week for the third month; once in the fourth month, and once every other month for the duration of therapy. Manage any abnormalities promptly <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 and 5.2 ) and Adverse Reactions ( 6.1 )]</span> . Interrupt dosing or reduce dose for toxicities.

See Table

1 for dosage modification guidelines.

Table

1: Recommended Dosage Modifications for REZLIDHIA Adverse Reactions Recommended Action Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] If differentiation syndrome is suspected, withhold REZLIDHIA until signs and symptoms improve. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days. Resume REZLIDHIA at 150 mg twice daily after resolution of differentiation syndrome. If a recurrence of differentiation syndrome is suspected, withhold REZLIDHIA and institute treatment per above guidance. After resolution of symptoms, REZLIDHIA may be resumed at a reduced dose of 150 mg once daily for a minimum of 7 days, after which it can be increased to 150 mg twice daily. Noninfectious leukocytosis [see Adverse Reactions ( 6.1 )] Initiate treatment with hydroxyurea, as per standard practices. Taper hydroxyurea only after leukocytosis improves or resolves.

Grade

3 Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03). hepatotoxicity [see Warnings and Precautions ( 5.2 )] Withhold REZLIDHIA and monitor liver function tests, twice per week, until laboratory values have returned to baseline or Grade 1 toxicity. Resume REZLIDHIA at a reduced dose of 150 mg once daily and continue monitoring; may increase to 150 mg twice daily if hepatotoxicity resolves to baseline for at least 28 days. If hepatotoxicity (Grade 3) recurs at 150 mg once daily, discontinue REZLIDHIA.

Grade

4 hepatotoxicity or AST or ALT >3x ULN and total bilirubin >2x ULN and alkaline phosphatase <2x ULN in the absence of a clear alternative explanation [see Warnings and Precautions ( 5.2 )] Permanently discontinue REZLIDHIA Other Grade 3 or higher toxicity considered related to treatment [see Adverse Reactions ( 6.1 )] Interrupt REZLIDHIA until toxicity resolves to Grade 2 or lower. Resume REZLIDHIA at 150 mg once daily; may increase to 150 mg twice daily if toxicities resolve to Grade 1 or lower for at least 1 week.

If Grade

3 or higher toxicity recurs at 150 mg once daily, discontinue REZLIDHIA.

None. None. ( 4 )

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 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 .

6.1 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . 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 &gt;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

AND PRECAUTIONS Hepatotoxicity : Monitor liver function tests during treatment with REZLIDHIA. If hepatotoxicity occurs, interrupt and reduce or discontinue REZLIDHIA. ( 2.3 , 5.2 )

5.1 Differentiation Syndrome REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% (25/153) of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dosage interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.2 Hepatotoxicity REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin.

Of

153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity [see Adverse Reactions ( 6.1 )] . One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin. Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity [see Dosage and Administration ( 2.3 )] .

INTERACTIONS Strong or moderate CYP3A Inducers: Avoid concomitant use. ( 7.1 ) Sensitive CYP3A Substrates: Avoid concomitant use. Monitor if unavoidable. ( 7.1 )

7.1 Effect of Other Drugs on Olutasidenib Strong or Moderate CYP3A4 Inducers Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers. Olutasidenib is a CYP3A substrate. Concomitant use of REZLIDHIA with a strong CYP3A inducer decreases olutasidenib Cmax and AUC, which may reduce REZLIDHIA efficacy <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Concomitant use of REZLIDHIA with a moderate CYP3A inducer may also decrease olutasidenib Cmax and AUC, which may also reduce REZLIDHIA efficacy, based on observations from concomitant use with a strong CYP3A inducer.

7.2 Effect of Olutasidenib on Other Drugs Sensitive CYP3A Substrates Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Olutasidenib induces CYP3A. Concomitant use of REZLIDHIA may decrease plasma concentrations of sensitive CYP3A substrates, which may reduce the substrate’s efficacy <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .