Enasidenib Mesylate

1 INDICATIONS AND USAGE IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test ( 1.1 ). 1.1 Acute Myeloid Leukemia IDHIFA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.

2 DOSAGE AND ADMINISTRATION 100 mg orally once daily until disease progression or unacceptable toxicity ( 2.2 ). 2.1 Patient Selection Select patients for the treatment of AML with IDHIFA based on the presence of IDH2 mutations in the blood or bone marrow [see Indications and Usage (1.1) and Clinical Studies (14.1) ] . Information on FDA-approved tests for the detection of IDH2 mutations in AML is available at http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage The recommended dosage of IDHIFA is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Swallow tablets whole. Do not chew, split, or crush IDHIFA tablets. Administer IDHIFA tablets orally about the same time each day. If a dose of IDHIFA is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day. 2.3 Monitoring and Dosage Modifications for Toxicities Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of IDHIFA and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly [see Adverse Reactions (6.1) ] . Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. Table 1: Dosage Modifications for IDHIFA-Related Toxicities *Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening. Adverse Reaction Recommended Action • Differentiation syndrome • If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring [see Warnings and Precautions (5.1) ] . • Interrupt IDHIFA if severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids [see Warnings and Precautions (5.1) ] . • Resume IDHIFA when signs and symptoms improve to Grade 2* or lower. • Noninfectious leukocytosis (white blood cell [WBC] count greater than 30 × 10 9 /L) • Initiate treatment with hydroxyurea, as per standard institutional practices. • Interrupt IDHIFA if leukocytosis is not improved with hydroxyurea, and then resume IDHIFA at 100 mg daily when WBC is less than 30 × 10 9 /L. • Elevation of bilirubin greater than 3 times the upper limit of normal (ULN) sustained for ≥2 weeks without elevated transaminases or other hepatic disorders • Reduce IDHIFA dose to 50 mg daily. • Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 × ULN. • Other Grade 3* or higher toxicity considered related to treatment including tumor lysis syndrome • Interrupt IDHIFA until toxicity resolves to Grade 2* or lower. • Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade 1* or lower. • If Grade 3* or higher toxicity recurs, discontinue IDHIFA.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Differentiation Syndrome [see Warnings and Precautions (5.1) ] The most common adverse reactions (≥20%) are nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 evaluation of single-agent IDHIFA is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily [see Clinical Studies (14.1) ] . The median duration of exposure to IDHIFA was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with IDHIFA were 4.2% (9/214) and 11.7% (25/214), respectively. Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most frequent adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%) permanently discontinued IDHIFA due to an adverse reaction; the most frequent adverse reaction leading to permanent discontinuation was leukocytosis (1%). The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Adverse reactions reported in the trial are shown in Table 2. Table 2: Adverse Reactions Reported in ≥10% (Any Grade) or ≥3% (Grade 3-5) of Patients with Relapsed or Refractory AML a Gastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased. b Tumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increased. c Differentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency. IDHIFA (100 mg daily) N=214 Body System Adverse Reaction All Grades N=214 n (%) ≥Grade 3 N=214 n (%) Gastrointestinal Disorders a Nausea 107 (50) 11 (5) Diarrhea 91 (43) 17 (8) Vomiting 73 (34) 4 (2) Metabolism and Nutrition Disorders Decreased appetite 73 (34) 9 (4) Tumor lysis syndrome b 13 (6) 12 (6) Blood and Lymphatic System Disorders Differentiation syndrome c 29 (14) 15 (7) Noninfectious leukocytosis 26 (12) 12 (6) Nervous System Disorders Dysgeusia 25 (12) 0 (0) Other clinically significant adverse reactions occurring in <10% of patients included: • Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 3. Table 3: Most Common (≥20%) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML IDHIFA (100 mg daily) N=214 Parameter a All Grades (%) Grade ≥3 (%) a Includes abnormalities occurring up to 28 days after last IDHIFA dose, if new or worsened by at least one grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N=213 except phosphorous N=209). Total bilirubin increased 81 15 Calcium decreased 74 8 Potassium decreased 41 15 Phosphorus decreased 27 8 Elevated Bilirubin IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1 [see Clinical Pharmacology (12.3) ] . Thirty-seven percent of patients (80/214) experienced total bilirubin elevations ≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders. No patients required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days. Three patients (1.4%) discontinued IDHIFA permanently due to hyperbilirubinemia. Noninfectious Leukocytosis IDHIFA can induce myeloid proliferation resulting in a rapid increase in white blood cell count. Tumor Lysis Syndrome IDHIFA can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome. Other Clinical Trials Experience The following adverse reactions occurred in other clinical trials of IDHIFA at the recommended dosage: neutropenia, thrombocytopenia, anemia, stomatitis, renal failure, fatigue, dyspnea, and QT prolongation.

12.3 Pharmacokinetics The peak plasma concentration (C max ) is 1.4 mcg/mL [coefficient of variation (CV%) 50%] after a single dose of 100 mg, and 13.1 mcg/mL (CV% 45%) at steady state for 100 mg daily. The area under concentration time curve (AUC) of enasidenib increases in an approximately dose proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. Absorption The absolute bioavailability after 100 mg oral dose of enasidenib is approximately 57%. After a single oral dose, the median time to C max (T max ) is 4 hours. Distribution The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). Human plasma protein binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro. Elimination Enasidenib has a terminal half-life of 7.9 days and a mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5). Metabolism Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. Metabolism of enasidenib is mediated by multiple cytochrome P450 (CYP) enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UDP glucuronosyl transferases (UGTs) (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15) in vitro. Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9) in vitro. Excretion Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. Specific Populations No clinically meaningful effect on the pharmacokinetics of enasidenib was observed for the following covariates: age (19 years to 100 years), race (White, Black, or Asian), mild (Child-Pugh A or total bilirubin ≤upper limit of normal (ULN) and aspartate transaminase (AST) >ULN or total bilirubin 1 to 1.5 times ULN and any AST), moderate (Child-Pugh B or total bilirubin >1.5 to 3 times ULN and any AST), and severe (Child-Pugh C or total bilirubin >3 to 10 times ULN and any AST) hepatic impairment, renal impairment (defined as creatinine clearance ≥30 mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area. Drug Interaction Studies Clinical Studies CYP1A2 Substrates: Caffeine (a sensitive CYP1A2 substrate) AUC 0-INF and C max increased by 655% and 18%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of 100 mg caffeine. CYP2C19 substrates: Omeprazole (a sensitive CYP2C19 substrate) AUC 0-INF and C max increased by 86% and 47%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of omeprazole 40 mg. CYP2D6 substrates: Dextromethorphan (a sensitive CYP2D6 substrate) AUC 0-INF and C max increased by 37% and 24% respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of dextromethorphan 30 mg. CYP3A substrates: Midazolam (a sensitive CYP3A substrate) AUC 0‑INF and C max decreased by 43% and 23%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single intravenous dose of midazolam 0.03 mg/kg. The decrease in midazolam exposure following oral administration of midazolam is expected to be larger than that following intravenous administration of midazolam. This is due to induction of CYP3A4 first pass metabolism by enasidenib and the reduced bioavailability of the midazolam oral formulation compared to the midazolam intravenous formulation. CYP2C9 and CYP2C8 substrates: Coadministration of multiple doses of IDHIFA 100 mg did not have clinically significant effect on the exposure of flurbiprofen (a CYP2C9 substrate) or pioglitazone (a CYP2C8 substrate). OATP1B1, OATP1B3, and BCRP Substrates: Rosuvastatin (an OATP1B1, OATP1B3, and BCRP substrate) AUC 0-INF and C max increased by 244% and 366%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of rosuvastatin 10 mg. P-gp Substrates: Digoxin (a P-gp Substrate) AUC 0-30h and C max increased by 20% and 26%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of digoxin 0.25 mg. In Vitro Studies CYP and UGT Enzymes: Enasidenib inhibits CYP2B6 and UGT1A1. The metabolite AGI-16903 inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Enasidenib induces CYP2B6. Transporter Systems: Enasidenib is not a substrate for P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). AGI-16903 is a substrate of both P-gp and BCRP. Enasidenib and AGI-16903 are not substrates of multidrug resistance-associated protein 2 (MRP2), organic anion transporter 1 (OAT1), OAT3, organic anion transporter family member 1B1 (OATP1B1), OATP1B3, and organic cation transporter 2 (OCT2). Enasidenib inhibits OAT1 and OCT2, but not MRP2 or OAT3. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3.