ere small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such a p-gp substrate and monitor for adverse reactions as recommended in the respective prescribing information.

been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after idhifa initiation. if differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. taper corticosteroids only after resolution of symptoms. symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. if severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt idhifa until signs and symptoms are no longer severe [see dosage and administration (2.3) ] . hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. 5.2 embryo-fetal toxicity based on animal embryo-fetal toxicity studies, idhifa can cause embryo-fetal harm when administered to a pregnant woman. in animal embryo-fetal toxicity studies, enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (auc) at the recommended human dose. advise pregnant women of the potential risk to the fetus. advise females of reproductive potential to use effective contraception during treatment with idhifa and for at least 2 months after the last dose. advise males with female partners of reproductive potential to use effective contraception during treatment with idhifa and for at least 2 months after the last dose [see use in specific populations (8.1 , 8.3) ] .

he 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.

. 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.

ere small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such a p-gp substrate and monitor for adverse reactions as recommended in the respective prescribing information.

and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. data animal data enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. these effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day. in pregnant rabbits treated during organogenesis (gestation days 7-19), enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose). 8.2 lactation risk summary there are no data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with idhifa and for at least 2 months after the last dose. 8.3 females and males of reproductive potential based on animal embryo-fetal toxicity studies, idhifa can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . pregnancy testing verify pregnancy status in females of reproductive potential prior to starting idhifa. contraception females advise females of reproductive potential to use effective contraception during treatment with idhifa and for at least 2 months after the last dose. coadministration of idhifa may increase or decrease the concentrations of combined hormonal contraceptives. the clinical significance of this potential drug interaction is unknown at this time. males advise males with female partners of reproductive potential to use effective contraception during treatment with idhifa and for at least 2 months after the last dose of idhifa. infertility based on findings in animals, idhifa may impair fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see nonclinical toxicology (13.1) ] . 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use no dosage adjustment is required for idhifa based on age. in the clinical study, 61% of 214 patients were aged 65 years or older, while 24% were older than 75 years. no overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients.

respectively. data animal data enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. these effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day. in pregnant rabbits treated during organogenesis (gestation days 7-19), enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).

ak 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 hepatic impairment [defined as total bilirubin ≤ upper limit of normal (uln) and aspartate transaminase (ast) >uln or total bilirubin 1 to 1.5 times uln and any ast], 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 oatp1b1, oatp1b3, and bcrp substrates: coadministration of rosuvastatin 10 mg after multiple doses of idhifa 100 mg increased rosuvastatin c max by 366% and auc 0-inf by 244%. p-gp substrates: coadministration of digoxin 0.25 mg after multiple doses of idhifa 100 mg increased digoxin c max by 26% and auc 0-30h by 20%. in vitro studies cyp and ugt enzymes: enasidenib inhibits cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, cyp3a4, and ugt1a1. the metabolite agi-16903 inhibits cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, and cyp2d6. enasidenib induces cyp2b6 and cyp3a4. 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. coadministration of idhifa may increase or decrease the concentrations of combined hormonal contraceptives. the clinical significance of this potential drug interaction is unknown at this time.

ean 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 hepatic impairment [defined as total bilirubin ≤ upper limit of normal (uln) and aspartate transaminase (ast) >uln or total bilirubin 1 to 1.5 times uln and any ast], 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 oatp1b1, oatp1b3, and bcrp substrates: coadministration of rosuvastatin 10 mg after multiple doses of idhifa 100 mg increased rosuvastatin c max by 366% and auc 0-inf by 244%. p-gp substrates: coadministration of digoxin 0.25 mg after multiple doses of idhifa 100 mg increased digoxin c max by 26% and auc 0-30h by 20%. in vitro studies cyp and ugt enzymes: enasidenib inhibits cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, cyp2d6, cyp3a4, and ugt1a1. the metabolite agi-16903 inhibits cyp1a2, cyp2b6, cyp2c8, cyp2c9, cyp2c19, and cyp2d6. enasidenib induces cyp2b6 and cyp3a4. 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. coadministration of idhifa may increase or decrease the concentrations of combined hormonal contraceptives. the clinical significance of this potential drug interaction is unknown at this time.

seline demographic and disease characteristics in patients with relapsed or refractory aml demographic and disease characteristics idhifa (100 mg daily) n=199 demographics ecog ps: eastern cooperative oncology group performance status. a 1 patient had missing baseline ecog ps. b for 3 patients with different mutations detected in bone marrow compared to blood, the result of blood is reported. c patients were defined as transfusion dependent at baseline if they received any red blood cell or platelet transfusions within the 8-week baseline period. d includes intensive and/or nonintensive therapies. age (years) median (min, max) 68 (19, 100) age categories, n (%) <65 years 76 (38) ≥65 years to <75 years 74 (37) ≥75 years 49 (25) sex, n (%) male 103 (52) female 96 (48) race, n (%) white 153 (77) black 10 (5) asian 1 (1) native hawaiian/other pacific islander 1 (1) other / not provided 34 (17) disease characteristics, n (%) ecog ps a , n (%) 0 46 (23) 1 124 (62) 2 28 (14) relapsed aml, n (%) 95 (48) refractory aml, n (%) 104 (52) idh2 mutation b , n (%) r140 155 (78) r172 44 (22) time from initial aml diagnosis (months) median (min, max) (172 patients) 11.3 (1.2, 129.1) cytogenetic risk status, n (%) intermediate 98 (49) poor 54 (27) missing /failure 47 (24) prior stem cell transplantation for aml, n (%) 25 (13) transfusion dependent at baseline c , n (%) 157 (79) number of prior anticancer regimens, n (%) d 1 89 (45) 2 64 (32) ≥3 46 (23) median number of prior therapies (min, max) 2 (1, 6) efficacy was established on the basis of the rate of complete response (cr)/complete response with partial hematologic recovery (crh), the duration of cr/crh, and the rate of conversion from transfusion dependence to transfusion independence. the efficacy results are shown in table 5 and were similar in both cohorts. the median follow-up was 6.6 months (range, 0.4 to 27.7 months). similar cr/crh rates were observed in patients with either r140 or r172 mutation. table 5: efficacy results in patients with relapsed or refractory aml endpoint idhifa (100 mg daily) n=199 ci: confidence interval, na: not available. a cr (complete remission) was defined as <5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [anc] >1,000/microliter). b dor (duration of response) was defined as time since first response of cr or crh to relapse or death, whichever is earlier. c crh (complete remission with partial hematological recovery) was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and anc >500/microliter). cr a n (%) 37 (19) 95% ci (13, 25) median dor b (months) 8.2 95% ci (4.7, 19.4) crh c n (%) 9 (4) 95% ci (2, 8) median dor (months) 9.6 95% ci (0.7, na) cr/crh n (%) 46 (23) 95% ci (18, 30) median dor (months) 8.2 95% ci (4.3, 19.4) for patients who achieved a cr/crh, the median time to first response was 1.9 months (range, 0.5 to 7.5 months) and the median time to best response of cr/crh was 3.7 months (range, 0.6 to 11.2 months). of the 46 patients who achieved a best response of cr/crh, 39 (85%) did so within 6 months of initiating idhifa. among the 157 patients who were dependent on red blood cell (rbc) and/or platelet transfusions at baseline, 53 (34%) became independent of rbc and platelet transfusions during any 56-day post baseline period. of the 42 patients who were independent of both rbc and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period.

, decreased appetite, and changes in their sense of taste. ask patients to report these reactions to their healthcare provider, and advise patients how to manage them [see adverse reactions (6.1) ] . elevated blood bilirubin inform patients that taking idhifa may cause elevated blood bilirubin, which is due to its mechanism of action, and not due to liver damage. advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation [see adverse reactions (6.1) ] . embryo-fetal toxicity advise pregnant women of the potential risk to a fetus. advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy [see warnings and precautions (5.2) , use in specific populations (8.1) ] . advise females of reproductive potential to use effective contraception during treatment with idhifa and for at least 2 months after the last dose. advise males with female partners of reproductive potential to use effective contraception during treatment with idhifa and for at least 2 months after the last dose. coadministration of idhifa may increase or decrease the concentrations of combined hormonal contraceptives. the clinical significance of this potential drug interaction is unknown at this time [see use in specific populations (8.3) ]. lactation advise women not to breastfeed during treatment with idhifa and for at least 2 months after the last dose [see use in specific populations (8.2) ]. drug interactions advise patients to inform their healthcare providers of all concomitant products, including over-the-counter products and supplements [see drug interactions (7.1) ] . dosing and storage instructions • advise patients not to chew or split the tablets but swallow whole with a cup of water. • instruct patients that if they miss a dose or vomit after a dose of idhifa, to take it as soon as possible on the same day and return to normal schedule the following day. advise patients not to take 2 doses to make up for the missed dose [see dosage and administration (2.2) ]. • keep idhifa in the original container. keep the container tightly closed with desiccant canister inside to protect the tablets from moisture [see how supplied/storage and handling (16.2) ]. marketed by: bristol-myers squibb company princeton, nj 08543 usa licensed from: servier pharmaceuticals llc boston, ma 02210 trademarks are the property of their respective owners. idhifa ® is a trademark of celgene corporation, a bristol-myers squibb company. pat. https://www.bms.com/patient-and-caregivers/our-medicines.html idhpi.005/mg.005