olutasidenib 150 MG Oral Capsule

INDICATIONS 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 )

DOSAGE 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 [see Clinical Trials ( 14.1 )] . 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 [see Clinical Pharmacology ( 12.3 )] . 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 [see Warnings and Precautions ( 5.1 and 5.2 ) and Adverse Reactions ( 6.1 )] . 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.

WARNINGS 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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration ( 2.3 )] . 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 )] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Olutasidenib is a small-molecule inhibitor of mutated isocitrate dehydrogenase-1 (IDH1). In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of olutasidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of olutasidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions. In vitro, olutasidenib inhibited mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins were not inhibited. Olutasidenib inhibition of mutant IDH1 led to decreased 2-HG levels in vitro and in in vivo xenograft models.