Fact Sheet. Authorized Distributors. AUTHORIZED DISTRIBUTOR NETWORK Community Practices. Institutions/Hospitals. Puerto Rico Hospitals and Clinics

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1 Fact Sheet Authorized Distributors The following distributors are authorized to sell IDHIFA and are able to service qualified accounts. AUTHORIZED DISTRIBUTOR NETWORK Community Practices Cardinal Specialty Distribution Customers Phone: McKesson Specialty Health Phone: Fax: Oncology Supply Phone: Fax: Institutions/Hospitals AmerisourceBergen Phone: Fax: ASD Healthcare Phone: Fax: Cardinal Full Line Wholesale Customers Phone: Cardinal Specialty Distribution Customers Phone: McKesson Pharma Phone: Fax: Puerto Rico Hospitals and Clinics Cardinal Puerto Rico (Borschow) Phone: Online ordering: Cesar Castillo Inc. Phone: (Hospitals) (Specialty Pharmacy) Fax: Online ordering: Please see full Prescribing Information, including Boxed WARNING.

2 Product Information How Supplied The 50- and 100-mg tablets are supplied in bottles with a desiccant canister Storage Store at 20 C-25 C (68 F-77 F); excursions permitted between 15 C-30 C (59 F-86 F). Keep the bottle tightly closed Store in the original bottle (with the desiccant canister) to protect from moisture. NATIONAL DRUG CODES (NDCs) 10-digit NDC 11-digit NDC a Dosage Strength mg/tablet mg/tablet Description Bottle of 30 pale yellow-to-yellow oval-shaped tablets; each film-coated tablet is debossed ENA on one side and 50 on the other side. Bottle of 30 pale yellow-to-yellow capsuleshaped tablets; each film-coated tablet is debossed ENA on one side and 100 on the other side. a The red zero converts the 10-digit NDC to the 11-digit NDC. Some payers may require each NDC number to be listed on the claim. Payer requirements regarding the use of NDCs may vary. Electronic data exchange generally requires use of the 11-digit NDC. Please see full Prescribing Information, including Boxed WARNING. IDHIFA is a registered trademark of Celgene Corporation. IDHIFA is licensed from Agios Pharmaceuticals, Inc Celgene Corporation 07/17 US-IDH170058

3 Product Monograph Indication IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test. Selected Safety Information 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. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING.

4 Table of Contents Table of Contents Disease Overview Mechanism of Action 10 Clinical Studies 12 Adverse Reactions 19 Dosing 22 Summary 24 Enasidenib (IDHIFA) is recommended by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) as a treatment option for relapsed/refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation.1 References 26 NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING. IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test

5 Disease Overview: Acute Myeloid Leukemia Introduction Acute myeloid leukemia (AML) is an aggressive hematologic cancer caused by the proliferation and accumulation of immature precursor blood cells called blasts. 2,3 In AML, as blasts accumulate in the bone marrow, mature red and white blood cells and platelets decline in the blood. As a result, patients present with bleeding, anemia, neutropenia, and infection. 4 Some of these patients depend upon blood transfusions to sustain their platelet and red blood cell counts. 5 Incidence and Survival Rates In 2017, the estimated number of new US cases of AML was 21,380, representing 1.3% of all new cancer cases. 2 Lifetime risk of developing AML is approximately 0.5% ( ). 2 Estimated overall incidence rate of AML in the United States is 4.2 per 100,000 population ( ) (Figure 1). 6 Incidence is greater among the elderly, and elderly men have an increased risk of AML compared to elderly women (Figure 1). 6 The median age at diagnosis is 68 years; about one-third of patients are diagnosed at age 75 or older. 2 The estimated 5-year survival rate in AML is 26.9% the lowest of any type of leukemia ( ). 2,7-9 Survival is age dependent, with lower rates for older adults. 10 Survival is generally poor in the elderly population, which comprises the majority of patients with AML up to 70% of patients aged 65 years die of AML within 1 year after diagnosis. 3,11 Relapse Among patients with AML, relapsed/refractory disease is a frequent event in the clinical course: 1 year after treatment initiation, 52% of AML patients have relapsed or become refractory. 12 The prognosis following relapse is poor. 13,14 Risk Factors Environmental and occupational risk factors for AML include exposure to petroleum, solvents (eg, benzene), and radiation. 15 Prior anticancer chemotherapy or radiation therapy is also a recognized risk factor. 15 Classes of chemotherapy agents include alkylating agents, platinum agents, and topoisomerase II inhibitors. 15 Some cases of secondary AML progress from myelodysplastic syndromes and are linked to a poor prognosis. 15 Figure 1. Incidence of AML by age and sex in the United States based on SEER data, Incidence rate per 100,000 population Men Women <65 years 65 years Age at diagnosis Abbreviations: AML, acute myeloid leukemia; SEER, Surveillance, Epidemiology, and End Results Overall incidence rate is 4.2 per 100,000 population Disease Overview 4 5

6 Disease Overview: Relapsed/Refractory AML With IDH2 Mutation IDH2 Mutation In the assessment of patients with AML, molecular biomarkers are increasingly used to identify gene mutations that may have clinical utility. 3,16-19 One type of driver mutation of AML is the isocitrate dehydrogenase-2 gene (midh2), which expresses mutant IDH2 enzyme. 16,17 Frequency About 12% of adults with AML have an IDH2 mutation. 20,21 In the United States, the frequency of midh2 translates into about 1400 cases per year of relapsed/refractory AML with an IDH2 mutation (Figure 2). 2,12,20,21 Conventional Management In relapsed/refractory AML, there have been 4 treatment approaches that are selected based on age and whether relapse is early (<12 months) or late ( 12 months) 1 : Clinical trial (strongly preferred) Chemotherapy* followed by allogeneic hematopoietic stem cell transplantation Repeat of successful induction chemotherapy regimen if remission was 12 months Best supportive care The standard of care for induction in AML, which may be repeated in relapsed disease if remission is 12 months, is a type of therapy developed more than 30 years ago. 3,22 Figure 2. Estimated cases per year of relapsed/refractory AML with IDH2 mutation in the United States 2,12,20,21 AML 21,380 estimated new cases in 2017 (1.3% of all new cancer cases) 2 With IDH2 mutation ~2600 patients/year ~12% of patients with AML will have an IDH2 mutation 20,21 midh2 + R/R AML ~1400 patients/year 52% of AML patients are relapsed/refractory 1 year after treatment initiation 12 Abbreviations: AML, acute myeloid leukemia; IDH2, isocitrate dehydrogenase-2; midh2, mutant IDH2; R/R AML, relapsed/refractory AML. * Therapy options for relapsed/refractory disease include aggressive therapy, less aggressive therapy, therapy for AML with FLT3-ITD mutation, therapy for AML with IDH2 mutation, and therapy for CD33-positive AML. 6 7

7 Disease Overview: Relapsed/Refractory AML With IDH2 Mutation (cont d ) A Therapeutic Target in AML: Mutant IDH2 Enzyme The mutant IDH2 enzyme leads to impaired cellular differentiation and results in myeloblast proliferation. 23,24 Expression of midh2 enzyme disrupts the normal activity of α-ketoglutarate (α-kg), metabolizing α-kg to an oncometabolite, 2-hydroxyglutarate (2-HG); 2-HG alters histone and DNA methylation and blocks differentiation of blasts into mature blood cells (Figure 3). 18,23-26 Immature blast cells proliferate, resulting in the signs and symptoms of AML. 3 The IDH2 mutation is proposed as an early event in AML development, which may help drive the disease process This mutation may have prognostic significance as part of multigene panels. 19 NCCN and College of American Pathologists (CAP)-American Society of Hematology (ASH) guidelines recommend molecular testing, including testing for IDH2 mutations, for all patients with AML during diagnostic workup. 1,33 Figure 3. Mutated IDH2 in the pathogenesis of AML 18,23-26 Normal marrow Isocitrate IDH2 α-kg The normal IDH2 enzyme helps myeloblasts differentiate into mature red and white blood cells and platelets by converting isocitrate into α-kg. Differentiation blocked IDH2 Mutated IDH2 Isocitrate α-kg 2-HG Mutated IDH2 converts α-kg to 2-HG, which leads to a block on myeloid differentiation and results in myeloblast proliferation. Key Myeloblast Red blood cell White blood cell Platelet Abbreviations: 2-HG, 2-hydroxyglutarate; α-kg, α-ketoglutarate; AML, acute myeloid leukemia; IDH2, isocitrate dehydrogenase-2. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 8 9

8 Mechanism of Action A Targeted Inhibitor of midh2 Figure 4. H ow IDHIFA releases the block on myeloid differentiation Differentiation blocked18,23-26 IDH2 Mutated IDH2 Isocitrate α-kg Differentiation restored34 IDH2 IDHIFA Mechanism of Action Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase-2 (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. MUTATED IDH2 2-HG Mutated IDH2 converts α-kg to 2-HG, which leads to a block on myeloid differentiation and results in myeloblast proliferation. α-kg Isocitrate 2-HG In preclinical studies, IDHIFA blocked the conversion of α-kg to 2-HG. In patient blood samples, IDHIFA decreased 2-HG levels and induced myeloid differentiation. Selected Safety Information WARNINGS AND PRECAUTIONS Differentiation Syndrome: See Boxed WARNING. 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 has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. 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. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. 10 Key Myeloblast Red blood cell White blood cell Platelet Abbreviations: 2-HG, 2-hydroxyglutarate; α-kg, α-ketoglutarate; IDH2, isocitrate dehydrogenase-2. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING. 11

9 Clinical Studies Acute Myeloid Leukemia The efficacy of IDHIFA was evaluated in an open-label, single-arm, multicenter, 2-cohort clinical trial of 199 adult patients with relapsed or refractory AML and an IDH2 mutation, who were assigned to receive a 100-mg daily dose. Cohort 1 included 101 patients and Cohort 2 included 98 patients. IDH2 mutations were identified by a 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 a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. Figure 5 summarizes the study design. Figure 5. Study design Population: Adult patients with relapsed/refractory AML and an IDH2 mutation who were assigned a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. 199 patients in the efficacy analysis 214 patients in the safety analysis For patients in the efficacy analysis, IDH2 mutations were either prospectively identified or retrospectively confirmed by the Abbott RealTime IDH2 assay. Of the patients enrolled and treated, 93% (199/214) had IDH2 mutations detected by the Abbott RealTime IDH2 assay, and had refractory/relapse status confirmed by FDA. Therefore, the 199 patients were included in the efficacy analysis 34 Clinical Studies Efficacy was established on the basis of: Rate of CR: defined as <5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/μL and ANC >1000/μL). Rate of CRh: defined as CR requirement for blast count, no evidence of disease, but only partial recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/μL). Duration of response: defined as time since first response of CR or CRh to relapse or death, whichever is earlier. Rate of conversion from transfusion dependence to transfusion independence: patients were defined as transfusion independent if they received no red blood cell or platelet transfusions within any 56-day post baseline period. The median follow-up was 6.6 months (range, ). Abbreviations: AML, acute myeloid leukemia; ANC, absolute neutrophil count; CR, complete response; CRh, CR with partial hematologic recovery; IDH2, isocitrate dehydrogenase-2. Selected Safety Information WARNINGS AND PRECAUTIONS (cont d ) Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus. Selected Safety Information ADVERSE REACTIONS The most common adverse reactions ( 20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%) Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

10 Clinical Studies (cont d ) Patient Demographics and Baseline Characteristics The baseline demographic and disease characteristics are shown in Table 1. The baseline demographics and disease characteristics were similar in both study cohorts. Table 1. Baseline demographic and disease characteristics in patients with relapsed or refractory AML Demographic and Disease Characteristics IDHIFA (100 mg daily) N = 199 Demographics Age (years) Median (min, max) 68 (19, 100) Age Categories, n (%) <65 years 76 (38) 65 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) Table 1. Baseline demographic and disease characteristics in patients with relapsed or refractory AML (cont d ) IDHIFA (100 mg daily) Demographic and Disease Characteristics N = 199 Disease Characteristics ECOG PS, a n (%) 0 46 (23) (62) 2 28 (14) Relapsed AML, n (%) 95 (48) Refractory AML, n (%) 104 (52) IDH2 Mutation, b n (%) R (78) R (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) a One 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. Selected Safety Information ADVERSE REACTIONS (cont d ) The most frequently reported Grade 3 adverse reactions ( 5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%) Abbreviations: AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IDH2, isocitrate dehydrogenase-2. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

11 Clinical Studies (cont d ) Additional Outcomes Efficacy 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 Figures 6, 7, and 8 and were similar in both cohorts. The median follow-up was 6.6 months (range, months). Similar CR/CRh rates were observed in patients with either R140 or R172 mutation. Figure 7 depicts the FDA-adjudicated CR/CRh rates and other parameters retrospectively determined by the sponsor using the pivotal data set (N = 199). Figure 7. Best objective response in patients with relapsed/refractory AML treated with IDHIFA 100 mg/day 34,a Figure 6. Efficacy results in patients with relapsed / refractory AML treated with IDHIFA 100 mg / day Complete response (CR) and complete response with partial hematologic recovery (CRh) Median duration of CR/CRh c CR 19% n = 37/199 (95% CI, 13%-25%) CRh 4% n = 9/199 47% Stable disease n = 94/199 CR/CRh 23% n = 46/199 (95% CI, 18%-30%) CR 19% a n = 37/199 (95% CI, 13%-25%) CRh 4% b n = 9/199 (95% CI, 2%-8%) 8.2 months n = 46/ months In patients achieving CR/CRh (95% CI, ) In patients achieving CR (95% CI, ) ORR 33% a,b n = 65/199 (95% CI, 26%-40%) (95% CI, 2%-8%) PR 2% n = 4/199 MLFS 8% n = 15/199 12% 1% Progressive disease n = 23/199 Not evaluable n = 1/199 n = 37/ months n = 9/199 In patients achieving CRh (95% CI, 0.7-NA) a ORR is defined as CR + CRh + PR + MLFS. b Percentages are based on the number of subjects in each group. Abbreviations: AML, acute myeloid leukemia; CI, confidence interval; CR, complete response; CRh, CR with partial hematologic recovery; MLFS, morphologic leukemia-free state for subjects with AML; ORR, overall response rate; PR, partial response. a CR 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 ANC >1000/microliter). b CRh 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). c Time since first response of CR or CRh to relapse or death, whichever is earlier. For patients who achieved a CR/CRh The median time to first response was 1.9 months (range, ) The median time to best response of CR/CRh was 3.7 months (range, ) Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6 months of initiating IDHIFA Selected Safety Information ADVERSE REACTIONS (cont d ) 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 Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

12 Clinical Studies (cont d ) Adverse Reactions Efficacy (cont d ) Among the 157 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 53 (34%) became independent of red blood cell and platelet transfusions during any 56-day post-baseline period. Of the 42 patients who were independent of both red blood cell and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post-baseline period. Figure 8. Transfusion status during treatment with IDHIFA 100 mg / day 34% (n = 53/157) 34% of patients on IDHIFA who were red blood cell and/or platelet transfusion dependent at baseline achieved transfusion independence during any 56-day post-baseline period a Of these 53 patients, 27 had not achieved a CR / CRh at the time of follow-up 34 Clinical Trials Experience 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. The median duration of exposure to IDHIFA was 4.3 months (range, ). The 30- and 60-day mortality rates observed with IDHIFA were 4.2% (9/214) and 11.7% (25/214), respectively. The most common adverse reactions ( 20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. 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. a Patients were defined as transfusion independent if they received no red blood cell or platelet transfusions within any 56-day post-baseline period. Adverse Reactions 43% of patients (85/199) on IDHIFA became or remained transfusion independent during any 56-day post-baseline period. Selected Safety Information LACTATION Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

13 Adverse Reactions (cont d ) Clinical Trials Experience (cont d ) 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 Body System Adverse Reaction Gastrointestinal Disorders a IDHIFA (100 mg daily) N = 214 All grades N = 214 n (%) Grade 3 N = 214 n (%) 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) 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 Parameter a IDHIFA (100 mg daily) N = 214 All grades (%) Grade 3 (%) Total bilirubin increased Calcium decreased 74 8 Potassium decreased Phosphorus decreased 27 8 a Includes abnormalities occurring up to 28 days after last IDHIFA dose, if new or worsened by at least 1 grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N = 213 except phosphorus N = 209). Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most common 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 common adverse reaction leading to permanent discontinuation was leukocytosis (1%). 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. Other clinically significant adverse reactions occurring in 10% of patients included Respiratory, Thoracic, and Mediastinal Disorders (pulmonary edema, acute respiratory distress syndrome). Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

14 Dosing IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test. Dosage and Administration Patient Selection Select patients for the treatment of AML with IDHIFA based on the presence of IDH2 mutations in the blood or bone marrow. Information on FDA-approved tests for the detection of IDH2 mutations in AML is available at Recommended Dosage The recommended starting dose 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. Do not 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. Table 4. Dosage modifications for IDHIFA-related toxicities Adverse Reaction Differentiation syndrome Noninfectious leukocytosis (WBC count greater than 30 x 10 9 /L) Recommended Action If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring 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 Resume IDHIFA when signs and symptoms improve to Grade 2 a or lower Initiate treatment with hydroxyurea 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 x 10 9 /L 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. Interrupt dosing or reduce dose for toxicities. See Table 4 for dosage modification guidelines. Elevation of bilirubin greater than 3x 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 2x ULN Other Grade 3 a or higher toxicity considered related to treatment, including TLS Interrupt IDHIFA until toxicity resolves to Grade 2 a or lower Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade 1 a or lower If Grade 3 a or higher toxicity recurs, discontinue IDHIFA a Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening. Abbreviations: TLS, tumor lysis syndrome; ULN, upper limit of normal; WBC, white blood cell. Dosing Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

15 Summary IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test. IDHIFA Is the First and Only Oral, Targeted Inhibitor of the Mutant IDH2 Enzyme In blood samples from patients with AML with mutated IDH2, IDHIFA reduced blast counts and increased percentages of mature myeloid cells. The efficacy of IDHIFA was evaluated in a clinical trial of 199 adult patients with relapsed or refractory AML and an IDH2 mutation who were assigned to receive a 100-mg daily dose. IDH2 mutations were retrospectively confirmed 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. In the clinical trial, 23% of patients (46/199) achieved CR/CRh (95% CI, 18%-30%), with a median duration of response of 8.2 months (95% CI, ). For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, ) and the median time to best response of CR/CRh was 3.7 months (range, ). 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 and/or platelet transfusions at baseline, 53 (34%) became independent of red blood cell and platelet transfusions during any 56 day post-baseline period. Of the 42 patients who were independent of both red blood cell and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56 day post-baseline period. 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. The most common adverse reactions ( 20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. Enasidenib (IDHIFA) is recommended by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) as a treatment option for relapsed/refractory AML with an IDH2 mutation. 1 Selected Safety Information 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. WARNINGS AND PRECAUTIONS Differentiation Syndrome: See Boxed WARNING. 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 has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multiorgan dysfunction have also been observed. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. 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. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus. Summary NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING

16 References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Acute Myeloid Leukemia. V National Comprehensive Cancer Network, Inc All rights reserved. Accessed February 8, To view the most recent and complete version of the guideline, go online to NCCN.org. 2. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Acute Myeloid Leukemia (AML). Accessed May 1, De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441. doi: /bcj American Cancer Society. Signs and symptoms of acute myeloid leukemia. Accessed May 1, Dawson MA, Avery S, McQuilten ZK, et al. Blood transfusion requirements for patients undergoing chemotherapy for acute myeloid leukemia: how much is enough? Haematologica. 2007;92(7): Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, National Cancer Institute. Bethesda, MD, based on November 2016 SEER data submission, posted to the SEER website, April National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Acute Lymphocytic Leukemia (ALL). Accessed May 1, National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Chronic Myeloid Leukemia (CML). Accessed May 1, National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Chronic Lymphocytic Leukemia (CLL). Accessed May 1, Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol. 2014;32(24): Meyers J, Yu Y, Kaye JA, Davis KL. Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs. Appl Health Econ Health Policy. 2013;11(3): CancerMPact. Kantar Health. Treatment Architecture: United States, Acute Myeloid Leukemia, Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. Blood. 2010;116(26): Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer. 2011;2(2): American Cancer Society. What are the risk factors for acute myeloid leukemia? Accessed May 1, Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23): Roy DM, Walsh LA, Chan TA. Driver mutations of cancer epigenomes. Protein Cell. 2014;5(4): Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20): Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2): Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-idh2 relapsed or refractory acute myeloid leukemia. Blood doi: /blood DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8): Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982;60(2): McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123(9): Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6): Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30: Genetics Home Reference. Your guide to understanding genetic conditions: IDH2. NIH US National Library of Medicine website. Published May Accessed May 30, Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12): Grove CS, Vassiliou GS. Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech. 2014;7(8): Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26): Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2): Krönke J, Bullinger L, Teleanu V, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122(1): Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111(7): Arber DA, Borowitz MJ, Cessna M, et al. Initial Diagnostic Workup of Acute Leukemia: Guideline from the College of American Pathologists and the American Society of Hematology [published online February 22, 2017]. Arch Pathol Lab Med. doi: /arpa cp 34. Data on file, Celgene Corporation. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING. References 26 27

17 Please see additional Important Safety Information throughout and full Prescribing Information, including Boxed WARNING. IDHIFA is a registered trademark of Celgene Corporation. IDHIFA is licensed from Agios Pharmaceuticals, Inc Celgene Corporation 04/18 US-IDH170012c

18 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IDHIFA safely and effectively. See full prescribing information for IDHIFA. IDHIFA (enasidenib) tablets, for oral use Initial U.S. Approval: 2017 WARNING: DIFFERENTIATION SYNDROME See 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) 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 FDAapproved test (1.1) DOSAGE AND ADMINISTRATION mg orally once daily until disease progression or unacceptable toxicity (2.2) DOSAGE FORMS AND STRENGTHS Tablets: 50 mg or 100 mg (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: IDHIFA can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus (5.2, 8.1, 8.3) ADVERSE REACTIONS The most common adverse reactions ( 20%) included nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at or FDA at FDA-1088 or USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed (8.2). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 08/2017 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DIFFERENTIATION SYNDROME 1 INDICATIONS AND USAGE 1.1 Acute Myeloid Leukemia 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Monitoring and Dosage Modifications for Toxicities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Differentiation Syndrome 5.2 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Acute Myeloid Leukemia 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1

19 FULL PRESCRIBING INFORMATION 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)]. 1 INDICATIONS AND USAGE 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 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 Recommended Dosage The recommended starting dose 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. Do not 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.

20 Table 1: Dosage Modifications for IDHIFA-Related Toxicities 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 x 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 x 10 9 /L. Elevation of bilirubin greater than 3 times Reduce IDHIFA dose to 50 mg daily. the upper limit of normal (ULN) sustained for 2 weeks without elevated transaminases or other hepatic disorders Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 x ULN. Other Grade 3* or higher toxicity considered related to treatment including Interrupt IDHIFA until toxicity resolves to Grade 2* or lower. tumor lysis syndrome 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. *Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening. 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. 3

21 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Differentiation 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, and as early as 10 days and at 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 embryofetal 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 females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose of IDHIFA. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose of IDHIFA. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions (5.1)]