CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Enasidenib is small molecule inhibitor of the isocitrate dehydrogenase (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. No large mean changes in the QTc interval (>20 ms) were observed following treatment with enasidenib.. 12.3 Pharmacokinetics. The peak plasma concentration (Cmax) is 1.4 mcg/mL [coefficient of variation (CV%) 50%] after 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.. AbsorptionThe absolute bioavailability after 100 mg oral dose of enasidenib is approximately 57%. After single oral dose, the median time to Cmax (Tmax) is hours.. DistributionThe mean volume of distribution (Vd) of enasidenib is 55.8 (CV% 29). Human plasma protein binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro.. EliminationEnasidenib has terminal half-life of 7.9 days and mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5).. MetabolismEnasidenib 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.. ExcretionEighty-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 PopulationsNo 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 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 Cmax by 366% and AUC0-INF by 244%.. P-gp Substrates: Coadministration of digoxin 0.25 mg after multiple doses of IDHIFA 100 mg increased digoxin Cmax by 26% and AUC0-30h 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 substrate for P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). AGI-16903 is substrate of both P-gp and BCRP. Enasidenib and AGI-16903 are not substrates of multidrug resistance-associated protein (MRP2), organic anion transporter (OAT1), OAT3, organic anion transporter family member 1B1 (OATP1B1), OATP1B3, and organic cation transporter (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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Acute Myeloid Leukemia. The efficacy of IDHIFA was evaluated in an open-label, single-arm, multicenter, two-cohort clinical trial (Study AG221-C-001, NCT01915498) of 199 adult patients with relapsed or refractory AML and an IDH2 mutation, who were assigned to receive 100 mg daily dose. Cohort included 101 patients and Cohort included 98 patients. IDH2 mutations were identified by local diagnostic test and retrospectively confirmed by the Abbott RealTime IDH2 assay, or prospectively identified by the Abbott RealTime IDH2 assay, which is the FDA-approved test for selection of patients with AML for treatment with IDHIFA. IDHIFA was given orally at starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events.The baseline demographic and disease characteristics are shown in Table 4. The baseline demographics and disease characteristics were similar in both study cohorts.Table 4: Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory AMLDemographic and Disease CharacteristicsIDHIFA (100 mg daily)N=199DemographicsECOG PS: Eastern Cooperative Oncology Group Performance Status.Age (Years) Median (Min, Max)68 (19, 100)Age Categories, (%)<65 years76 (38)>=65 years to <75 years74 (37)>=75 years49 (25)Sex, (%)Male103 (52)Female96 (48)Race, (%)White153 (77)Black10 (5)Asian1 (1)Native Hawaiian/Other Pacific Islander1 (1)Other Not Provided34 (17) Disease Characteristics, (%)ECOG PS patient had missing baseline ECOG PS., (%)046 (23)1124 (62)228 (14)Relapsed AML, (%) 95 (48) Refractory AML, (%) 104 (52) IDH2 Mutation For patients with different mutations detected in bone marrow compared to blood, the result of blood is reported., (%)R140155 (78)R17244 (22)Time from Initial AML Diagnosis (months)Median (min, max) (172 patients)11.3 (1.2, 129.1)Cytogenetic Risk Status, (%)Intermediate 98 (49)Poor54 (27)Missing /Failure 47 (24)Prior Stem Cell Transplantation for AML, (%)25 (13)Transfusion Dependent at Baseline Patients were defined as transfusion dependent at baseline if they received any red blood cell or platelet transfusions within the 8-week baseline period., (%)157 (79)Number of Prior Anticancer Regimens, (%) Includes intensive and/or nonintensive therapies. 189 (45)264 (32)>=346 (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 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 AMLEndpointIDHIFA (100 mg daily)N=199CI: confidence interval, NA: not available.CRCR (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). (%)37 (19) 95% CI (13, 25) Median DORDOR (duration of response) was defined as time since first response of CR or CRh to relapse or death, whichever is earlier. (months) 8.2 95% CI (4.7, 19.4)CRhCRh (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). (%)9 (4) 95% CI (2, 8) Median DOR (months) 9.6 95% CI (0.7, NULL)CR/CRh (%)46 (23) 95% CI (18, 30) Median DOR (months) 8.2 95% CI (4.3, 19.4)For patients who achieved 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 best response of CR/CRh, 39 (85%) did so within 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 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 AMLIDHIFA (100 mg daily)N=214Body System Adverse ReactionAll GradesN=214n (%)>=Grade 3N=214n (%)Gastrointestinal Disorders Gastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased.Nausea107 (50)11 (5)Diarrhea91 (43)17 (8)Vomiting73 (34)4 (2)Metabolism and Nutrition DisordersDecreased appetite73 (34)9 (4)Tumor lysis syndrome Tumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increased. 13 (6)12 (6)Blood and Lymphatic System DisordersDifferentiation syndrome Differentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency. 29 (14)15 (7)Noninfectious leukocytosis26 (12)12 (6)Nervous System DisordersDysgeusia25 (12)0 (0)Other clinically significant adverse reactions occurring in <=10% of patients included:Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndromeChanges 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 AMLIDHIFA (100 mg daily)N=214Parameter 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). All Grades(%)Grade >=3(%)Total bilirubin increased8115Calcium decreased748Potassium decreased4115Phosphorus decreased278. Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome. Elevated BilirubinIDHIFA 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 ULN at least one time. Of those patients who experienced total bilirubin elevations >=2 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 dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for median of days. Three patients (1.4%) discontinued IDHIFA permanently due to hyperbilirubinemia.. Noninfectious LeukocytosisIDHIFA can induce myeloid proliferation resulting in rapid increase in white blood cell count.. Tumor Lysis SyndromeIDHIFA can induce myeloid proliferation resulting in rapid reduction in tumor cells which may pose risk for tumor lysis syndrome.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

INDICATIONS & USAGE SECTION.

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).. 1.1Acute 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Differentiation Syndrome [see Warnings and Precautions (5.1)] 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 Celgene Corporation at 1-888-423-5436 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 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 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 dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 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 AMLIDHIFA (100 mg daily)N=214Body System Adverse ReactionAll GradesN=214n (%)>=Grade 3N=214n (%)Gastrointestinal Disorders Gastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased.Nausea107 (50)11 (5)Diarrhea91 (43)17 (8)Vomiting73 (34)4 (2)Metabolism and Nutrition DisordersDecreased appetite73 (34)9 (4)Tumor lysis syndrome Tumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increased. 13 (6)12 (6)Blood and Lymphatic System DisordersDifferentiation syndrome Differentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency. 29 (14)15 (7)Noninfectious leukocytosis26 (12)12 (6)Nervous System DisordersDysgeusia25 (12)0 (0)Other clinically significant adverse reactions occurring in <=10% of patients included:Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndromeChanges 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 AMLIDHIFA (100 mg daily)N=214Parameter 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). All Grades(%)Grade >=3(%)Total bilirubin increased8115Calcium decreased748Potassium decreased4115Phosphorus decreased278. Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome. Elevated BilirubinIDHIFA 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 ULN at least one time. Of those patients who experienced total bilirubin elevations >=2 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 dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for median of days. Three patients (1.4%) discontinued IDHIFA permanently due to hyperbilirubinemia.. Noninfectious LeukocytosisIDHIFA can induce myeloid proliferation resulting in rapid increase in white blood cell count.. Tumor Lysis SyndromeIDHIFA can induce myeloid proliferation resulting in rapid reduction in tumor cells which may pose risk for tumor lysis syndrome.

BOXED WARNING SECTION.

WARNING: DIFFERENTIATION SYNDROME. Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].. WARNING: DIFFERENTIATION SYNDROMESee full prescribing information for complete boxed warning.Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution (5.1, 6.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been performed with enasidenib.Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay.Fertility studies in animals have not been conducted with enasidenib. In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus.

DESCRIPTION SECTION.

11 DESCRIPTION. Enasidenib is an inhibitor of isocitrate dehydrogenase-2 (IDH2) enzyme. Enasidenib is available as the mesylate salt with the chemical name:2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate.Or2-Propanol, 2-methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]amino-1,3,5-triazin-2-yl]amino]-, methanesulfonate (1:1).The chemical structure is:The empirical formula is C19H17F6N7O CH3SO3H (C20H21F6N7O4S), and the molecular weight is 569.48 g/mol. Enasidenib is practically insoluble (solubility <=74 mcg/mL) in aqueous solutions across physiological pH range (pH 1.2 and 7.4).IDHIFA (enasidenib) is available as 50-mg tablet (equivalent to 60 mg enasidenib mesylate) and 100-mg tablet (equivalent to 120 mg enasidenib mesylate) for oral administration. Each tablet contains inactive ingredients of colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose acetate succinate, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium starch glycolate, talc, and titanium dioxide. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 100 mg orally once daily until disease progression or unacceptable toxicity (2.2).. 2.1Patient 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.. 2.2Recommended 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 minimum of months to allow time for clinical response.Do not split or crush IDHIFA tablets. Administer IDHIFA tablets orally about the same time each day. If 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. 2.3Monitoring 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 minimum of every weeks for at least the first months during treatment. Manage any abnormalities promptly [see Adverse Reactions (6.1)].Interrupt dosing or reduce dose for toxicities. See Table for dosage modification guidelines.Table 1: Dosage Modifications for IDHIFA-Related ToxicitiesAdverse ReactionRecommended ActionDifferentiation syndromeIf 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 2Grade is mild, Grade is moderate, Grade is serious, Grade is life-threatening. or lower.Noninfectious leukocytosis (white blood cell [WBC] count greater than 30 109/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 30 109/L.Elevation of bilirubin greater than times the upper limit of normal (ULN) sustained for >=2 weeks without elevated transaminases or other hepatic disordersReduce IDHIFA dose to 50 mg daily.Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than x ULN.Other Grade or higher toxicity considered related to treatment including tumor lysis syndrome Interrupt IDHIFA until toxicity resolves to Grade or lower.Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade or lower.If Grade or higher toxicity recurs, discontinue IDHIFA.. 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 2Grade is mild, Grade is moderate, Grade is serious, Grade is life-threatening. or lower.. Noninfectious leukocytosis (white blood cell [WBC] count greater than 30 109/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 30 109/L.. Elevation of bilirubin greater than 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 x ULN.. Other Grade or higher toxicity considered related to treatment including tumor lysis syndrome. Interrupt IDHIFA until toxicity resolves to Grade or lower.. Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade or lower.. If Grade or higher toxicity recurs, discontinue IDHIFA.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. IDHIFA is available in the following tablet strengths:50-mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed ENA on one side and 50 on the other side.100-mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed ENA on one side and 100 on the other side.. 50-mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed ENA on one side and 50 on the other side.. 100-mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed ENA on one side and 100 on the other side.. Tablets: 50 mg or 100 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. OATP1B1, OATP1B3, BCRP, and P-gp Substrates: Decrease the dosage of these substrates as recommended in its prescribing information when coadministered with IDHIFA, and as clinically indicated (7.1). 7.1Effect of IDHIFA on Other Drugs. OATP1B1, OATP1B3, and BCRP SubstratesIDHIFA is an OATP1B1, OATP1B3, and BCRP inhibitor. Coadministration of IDHIFA increases the exposure of OATP1B1, OATP1B3, and BCRP substrates, which may increase the incidence and severity of adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. Decrease the dosage of OATP1B1, OATP1B3, and BCRP substrate(s) as recommended in the respective prescribing information, and as clinically indicated.. Certain P-glycoprotein (P-gp) Substrates IDHIFA is P-gp inhibitor. Coadministration of IDHIFA increases the exposure of P-gp substrates, which may increase the incidence and severity of adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. For P-gp substrate where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such P-gp substrate and monitor for adverse reactions as recommended in the respective prescribing information.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to starting IDHIFA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 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.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least months after the last dose of IDHIFA.. InfertilityBased 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)].

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. 50-mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed ENA on one side and 50 on the other side.30-count bottles of 50-mg tablets with desiccant canister (NDC 59572-705-30)100-mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed ENA on one side and 100 on the other side.30-count bottles of 100-mg tablets with desiccant canister (NDC 59572-710-30). 30-count bottles of 50-mg tablets with desiccant canister (NDC 59572-705-30). 30-count bottles of 100-mg tablets with desiccant canister (NDC 59572-710-30). 16.2Storage Store at 20C-25C (68F-77F); excursions permitted between 15C-30C (59F-86F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed. Store in the original bottle (with desiccant canister) to protect from moisture.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Differentiation SyndromeAdvise patients on the risks of developing differentiation syndrome as early as day and during the first months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, bone pain, rapid weight gain or swelling of their arms or legs, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].. Tumor Lysis SyndromeAdvise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake and the need for frequent monitoring of blood chemistry values [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].. Gastrointestinal Adverse ReactionsAdvise patients on risk of experiencing gastrointestinal reactions, such as diarrhea, nausea, vomiting, 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 BilirubinInform 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 fetus. Advise females of reproductive potential to notify their healthcare provider of 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 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 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)]. LactationAdvise women not to breastfeed during treatment with IDHIFA and for at least months after the last dose [see Use in Specific Populations (8.2)]. Drug InteractionsAdvise 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 InstructionsAdvise patients not to chew or split the tablets but swallow whole with cup of water.Instruct patients that if they miss dose or vomit after 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 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)]. Advise patients not to chew or split the tablets but swallow whole with cup of water.. Instruct patients that if they miss dose or vomit after 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 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)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 months after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Enasidenib is small molecule inhibitor of the isocitrate dehydrogenase (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been performed with enasidenib.Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay.Fertility studies in animals have not been conducted with enasidenib. In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 50 mg Tablet Bottle Label. NDC 59572-705-30IDHIFA(R) (enasidenib) tablets50 mgDispense in originalcontainer with desiccant.Swallow whole, do notchew or split tablets.Rx only30 Tablets. PRINCIPAL DISPLAY PANEL 50 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. No large mean changes in the QTc interval (>20 ms) were observed following treatment with enasidenib.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The peak plasma concentration (Cmax) is 1.4 mcg/mL [coefficient of variation (CV%) 50%] after 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.. AbsorptionThe absolute bioavailability after 100 mg oral dose of enasidenib is approximately 57%. After single oral dose, the median time to Cmax (Tmax) is hours.. DistributionThe mean volume of distribution (Vd) of enasidenib is 55.8 (CV% 29). Human plasma protein binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro.. EliminationEnasidenib has terminal half-life of 7.9 days and mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5).. MetabolismEnasidenib 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.. ExcretionEighty-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 PopulationsNo 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 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 Cmax by 366% and AUC0-INF by 244%.. P-gp Substrates: Coadministration of digoxin 0.25 mg after multiple doses of IDHIFA 100 mg increased digoxin Cmax by 26% and AUC0-30h 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 substrate for P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). AGI-16903 is substrate of both P-gp and BCRP. Enasidenib and AGI-16903 are not substrates of multidrug resistance-associated protein (MRP2), organic anion transporter (OAT1), OAT3, organic anion transporter family member 1B1 (OATP1B1), OATP1B3, and organic cation transporter (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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to pregnant woman. There are no available data on IDHIFA use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.. Data. Animal DataEnasidenib administered to pregnant rats at 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 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 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: November 2020 MEDICATION GUIDEIDHIFA(R) (eyed-HEE-fuh) (enasidenib) tablets What is the most important information should know about IDHIFAIDHIFA may cause serious side effects, including:Differentiation Syndrome. Differentiation syndrome is condition that affects your blood cells which may be life-threatening or lead to death if not treated. Differentiation syndrome has happened within day and up to months after starting IDHIFA. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome while taking IDHIFA:fevercoughshortness of breathswelling of arms and legsswelling around neck, groin, or underarm areafast weight gain (greater than 10 pounds within week)bone painIf you develop any of these symptoms of differentiation syndrome, your healthcare provider may start you on medicine taken by mouth or given through vein (intravenous) called corticosteroids and may monitor you in the hospital. What is IDHIFAIDHIFA is prescription medicine used to treat people with acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation whose disease has come back or has not improved after previous treatment(s). It is not known if IDHIFA is safe and effective in children.Before taking IDHIFA, tell your healthcare provider about all of your medical conditions, including if you:Are pregnant or plan to become pregnant. IDHIFA can cause harm to your unborn baby if taken during pregnancy.If you are able to become pregnant, your healthcare provider will do pregnancy test before you start taking IDHIFA.Females who are able to become pregnant and who take IDHIFA should use effective birth control (contraception) during treatment with IDHIFA and for at least months after your last dose of IDHIFA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with IDHIFA.Males who have female partners that are able to become pregnant should use effective birth control during treatment with IDHIFA and for at least months after your last dose of IDHIFA.IDHIFA may affect how hormonal contraceptives work and may cause them to not work as well. Talk to your healthcare provider about birth control methods that may be right for you while taking IDHIFA. IDHIFA may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility. Are breastfeeding or plan to breastfeed. It is not known if IDHIFA passes into your breast milk. You should not breastfeed during your treatment with IDHIFA and for at least months after your last dose of IDHIFA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take IDHIFATake IDHIFA exactly as your healthcare provider tells you to. Take IDHIFA time day at the same time each day.Swallow IDHIFA tablets whole. Do not chew or split the tablet.Swallow IDHIFA with ounces (one cup) of water.IDHIFA can be taken with or without food. If you miss dose of IDHIFA or vomit after taking dose of IDHIFA, take the dose of IDHIFA as soon as possible on the same day. Then take your next dose the next day at your regularly scheduled time. Do not take doses at the same time to make up for the missed dose. Your healthcare provider should do blood tests to check your blood counts before you start IDHIFA treatment and at minimum of every weeks for at least the first months during treatment to check for side effects.What are the possible side effects of IDHIFAIDHIFA may cause serious side effects, including:See What is the most important information should know about IDHIFAThe most common side effects of IDHIFA include:nauseavomitingdiarrheajaundicedecreased appetiteTell your healthcare provider if you have any changes to the color of your skin or the whites of your eyes. Your healthcare provider will monitor you for side effects during treatment and may tell you to stop taking IDHIFA if you develop certain side effects. These are not all the possible side effects of IDHIFA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store IDHIFAStore IDHIFA at room temperature from 68F to 77F (20C to 25C).Keep IDHIFA in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture.Keep IDHIFA and all medicines out of the reach of children. General information about the safe and effective use of IDHIFA Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not take IDHIFA for conditions for which it was not prescribed. Do not give IDHIFA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IDHIFA that is written for health professionals. What are the ingredients in IDHIFAActive ingredient: enasidenib Inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose acetate succinate, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium starch glycolate, talc, and titanium dioxideManufactured for and marketed by: Celgene Corporation, Summit, NJ 07901Licensed from: Agios Pharmaceuticals, Cambridge, MA 02139IDHIFA(R) is registered trademark of Celgene Corporation.Pat. http://www.celgene.com/therapies IDHMG.004 (C) 2016-2020 Celgene Corporation All rights reserved.For more information go to www.IDHIFA.com or call 1-888-423-5436.. Differentiation Syndrome. Differentiation syndrome is condition that affects your blood cells which may be life-threatening or lead to death if not treated. Differentiation syndrome has happened within day and up to months after starting IDHIFA. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome while taking IDHIFA:. fever. cough. shortness of breath. swelling of arms and legs. swelling around neck, groin, or underarm area. fast weight gain (greater than 10 pounds within week). bone pain. Are pregnant or plan to become pregnant. IDHIFA can cause harm to your unborn baby if taken during pregnancy.If you are able to become pregnant, your healthcare provider will do pregnancy test before you start taking IDHIFA.Females who are able to become pregnant and who take IDHIFA should use effective birth control (contraception) during treatment with IDHIFA and for at least months after your last dose of IDHIFA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with IDHIFA.Males who have female partners that are able to become pregnant should use effective birth control during treatment with IDHIFA and for at least months after your last dose of IDHIFA.IDHIFA may affect how hormonal contraceptives work and may cause them to not work as well. Talk to your healthcare provider about birth control methods that may be right for you while taking IDHIFA. IDHIFA may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility. If you are able to become pregnant, your healthcare provider will do pregnancy test before you start taking IDHIFA.. Females who are able to become pregnant and who take IDHIFA should use effective birth control (contraception) during treatment with IDHIFA and for at least months after your last dose of IDHIFA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with IDHIFA.. Males who have female partners that are able to become pregnant should use effective birth control during treatment with IDHIFA and for at least months after your last dose of IDHIFA.. IDHIFA may affect how hormonal contraceptives work and may cause them to not work as well. Talk to your healthcare provider about birth control methods that may be right for you while taking IDHIFA. IDHIFA may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.. Are breastfeeding or plan to breastfeed. It is not known if IDHIFA passes into your breast milk. You should not breastfeed during your treatment with IDHIFA and for at least months after your last dose of IDHIFA.. Take IDHIFA exactly as your healthcare provider tells you to. Take IDHIFA time day at the same time each day.. Swallow IDHIFA tablets whole. Do not chew or split the tablet.. Swallow IDHIFA with ounces (one cup) of water.. IDHIFA can be taken with or without food. If you miss dose of IDHIFA or vomit after taking dose of IDHIFA, take the dose of IDHIFA as soon as possible on the same day. Then take your next dose the next day at your regularly scheduled time. Do not take doses at the same time to make up for the missed dose. Your healthcare provider should do blood tests to check your blood counts before you start IDHIFA treatment and at minimum of every weeks for at least the first months during treatment to check for side effects.. nausea. vomiting. diarrhea. jaundice. decreased appetite. Store IDHIFA at room temperature from 68F to 77F (20C to 25C).. Keep IDHIFA in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture.

SPL UNCLASSIFIED SECTION.

1.1Acute 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.

STORAGE AND HANDLING SECTION.

16.2Storage Store at 20C-25C (68F-77F); excursions permitted between 15C-30C (59F-86F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed. Store in the original bottle (with desiccant canister) to protect from moisture.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2).. 8.1 Pregnancy. Risk Summary Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to pregnant woman. There are no available data on IDHIFA use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.. Data. Animal DataEnasidenib administered to pregnant rats at 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 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 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).. 8.2 Lactation. Risk SummaryThere 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 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 pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to starting IDHIFA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 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.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least months after the last dose of IDHIFA.. InfertilityBased 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Embryo-Fetal Toxicity: IDHIFA can cause fetal harm. Advise patients of the potential risk to fetus and use effective contraception (5.2, 8.1, 8.3).. 5.1Differentiation Syndrome. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed.Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as day and up to 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 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 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 months after the last dose [see Use in Specific Populations (8.1, 8.3)].