`
`
`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).
`
`
`
`09/2019
`
`
`09/2019
`
`
`
`
`
`
`
`
`--------------------------RECENT MAJOR CHANGES----------------------------
`
`
`
`Warnings and Precautions, Differentiation Syndrome (5.1)
`
`
`Warnings and Precautions, Embryo-Fetal Toxicity (5.2)
`
`---------------------------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).
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`100 mg orally once daily until disease progression or unacceptable toxicity
`
`
`(2.2).
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: DIFFERENTIATION SYNDROME
`
`INDICATIONS AND USAGE
`1
`
`1.1 Acute Myeloid Leukemia
`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
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`
`
`
`2
`
`6
`
`8
`
`
`
`
`
`
`
`Reference ID: 4498655
`
`
`
`
`----------------------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 1-888-423-5436 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`
`
`Lactation: Advise women not to breastfeed (8.2).
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`
`
`
`
`Revised: 09/2019
`
`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.
`
` 
`
` 
`
`

`

` 
`
`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)].
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`
`1
`
`Acute Myeloid Leukemia
`1.1
`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
`
`
`2.1
`Patient Selection
`Select patients for the treatment of AML with IDHIFA based on the presence of IDH2 mutations in the
`blood or bone marrow [see Indications and Usage (1.1) and Clinical Studies (14.1)]. Information on
`FDA-approved tests for the detection of IDH2 mutations in AML is available at
`http://www.fda.gov/CompanionDiagnostics.
`
`Recommended Dosage
`2.2
`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.
`
`Reference ID: 4498655
`
`

`

`
`
`
` Noninfectious leukocytosis (white blood
`cell [WBC] count greater than 30 x 109/L)
`
`
`
`
`
` Elevation of bilirubin greater than 3 times
`the upper limit of normal (ULN) sustained
`for ≥2 weeks without elevated
`transaminases or other hepatic disorders
`
` Other Grade 3* or higher toxicity
`considered related to treatment including
`tumor lysis syndrome
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`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 109/L.
`
`
` Reduce IDHIFA dose to 50 mg daily.
`
` Resume IDHIFA at 100 mg daily if
`bilirubin elevation resolves to less than 2 x
`ULN.
`
`Interrupt IDHIFA until toxicity resolves to
`Grade 2* or lower.
`
` Resume IDHIFA at 50 mg daily; may
`increase to 100 mg daily if toxicities
`resolve to Grade 1* or lower.
`If Grade 3* or higher toxicity recurs,
`discontinue IDHIFA.
` *Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.
`
`3
`
`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.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`Reference ID: 4498655
`
`
`
` 
`
`

`

` 
`
`
`
` CONTRAINDICATIONS
`
`
`WARNINGS AND PRECAUTIONS
`
`4
`
`None.
`
`5
`
`Differentiation Syndrome
`5.1
`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 1 day and up to 5 months after IDHIFA initiation.
`
`If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g.,
`dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper
`corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur
`with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring
`intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation
`of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe [see Dosage and
`Administration (2.3)]. Hospitalization for close observation and monitoring of patients with pulmonary
`and/or renal manifestation is recommended.
`
`Embryo-Fetal Toxicity
`5.2
`Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when
`administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused embryo-
`fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the
`concentration-time curve (AUC) at the recommended human dose. Advise females of reproductive
`potential to use effective contraception during treatment with IDHIFA and for at least 2 months 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 2 months 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
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`• Differentiation Syndrome [see Warnings and Precautions (5.1)]
`
`
`
`
`ADVERSE REACTIONS
`
`
`Reference ID: 4498655
`
`

`

`
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
`in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
`and may not reflect the rates observed in practice.
`
`The safety evaluation of single-agent IDHIFA is based on 214 patients with relapsed or refractory
`AML who were assigned to receive 100 mg daily [see Clinical Studies (14.1)]. The median duration of
`exposure to IDHIFA was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates
`observed with IDHIFA were 4.2% (9/214) and 11.7% (25/214), respectively.
`
`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.
`
`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%).
`
`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
`IDHIFA (100 mg daily)
`N=214
`
`
`
`≥Grade 3
`All Grades
`N=214
`N=214
`n (%)
`n (%)
`
`
`
`Body System
`Adverse Reaction
`
`Gastrointestinal Disorders a
`Nausea
` Diarrhea
`
`Vomiting
`Metabolism and Nutrition Disorders
`Decreased appetite
`Tumor lysis syndrome b
`Blood and Lymphatic System Disorders
`Differentiation syndrome c
`Noninfectious leukocytosis
`
`107 (50)
`91 (43)
`73 (34)
`
`73 (34)
`13 (6)
`
`29 (14)
`26 (12)
`
`11 (5)
`17 (8)
`4 (2)
`
`9 (4)
`12 (6)
`
`15 (7)
`12 (6)
`
`Reference ID: 4498655
`
` 
`
`

`

` 
`
`
`
`
`
`Nervous System Disorders
`0 (0)
`25 (12)
`
` Dysgeusia
`
` 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
`
`Changes in selected post-baseline laboratory values that were observed in patients with relapsed or
`refractory AML are shown in Table 3.
`
`
`
`Parameter a
`
`Table 3: Most Common (≥20%) New or Worsening Laboratory
`
`Abnormalities Reported in Patients with Relapsed or Refractory AML
`
`IDHIFA (100 mg daily)
`N=214
`
` All Grades
` Grade ≥3
`
`(%)
`(%)
`Total bilirubin increased
`81
`15
`
` Calcium decreased
`74
`8
` Potassium decreased
`
`41
`15
`Phosphorus decreased
`27
`8
`
` a Includes abnormalities occurring up to 28 days after last IDHIFA dose, if new or
`
`
`
`
` worsened by at least one grade from baseline, or if baseline was unknown. The
`
`denominator varies based on data collected for each parameter (N=213 except
`
`phosphorous N=209).
`
`
`
`
`
`Elevated Bilirubin
`IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1 [see Clinical
`
`
`Pharmacology (12.3)]. Thirty-seven percent of patients (80/214) experienced total bilirubin elevations
`≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN,
`35% had elevations within the first month of treatment, and 89% had no concomitant elevation of
`transaminases or other severe adverse events related to liver disorders. No patients required a dose
`reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days.
`Three patients (1.4%) discontinued IDHIFA permanently due to hyperbilirubinemia.
`
`Noninfectious Leukocytosis
`
`
`IDHIFA can induce myeloid proliferation resulting in a rapid increase in white blood cell count.
`
`
`Tumor Lysis Syndrome
`
`IDHIFA can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose
`a risk for tumor lysis syndrome.
`
`Reference ID: 4498655
`
`

`

`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8
`
`Pregnancy
`8.1
`Risk Summary
`Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a
`
`pregnant woman. There are no available data on IDHIFA use in pregnant women to inform a 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). If this drug is used during pregnancy,
`or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a
`fetus.
`
`Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
`The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Data
`Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis
`(gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including
`post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal
`variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the
`recommended human daily dose of 100 mg/day.
`
`In pregnant rabbits treated during organogenesis (gestation days 7-19), enasidenib was maternally toxic
`at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state
`clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day
`(exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).
`
`
`Lactation
`8.2
`Risk Summary
`There are no data on the presence of enasidenib or its metabolites in human milk, the effects on the
`breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and
`because of the potential for adverse reactions in breastfed children, advise women not to breastfeed
`during treatment with IDHIFA and for at least 2 months after the last dose.
`
`Females and Males of Reproductive Potential
`8.3
`Pregnancy Testing
`Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a
`pregnant woman [see Use in Specific Populations (8.1)].
`
`Obtain a pregnancy test on females of reproductive potential prior to starting treatment with IDHIFA.
`
`
`Reference ID: 4498655
`
` 
`
`

`

` 
`
`Contraception
`Females
`Advise females of reproductive potential to avoid becoming pregnant while receiving IDHIFA. Advise
`females of reproductive potential to use effective contraception during treatment with IDHIFA and for
`at least 2 months after the last dose. Coadministration of IDHIFA may increase or decrease the
`concentrations of combined hormonal contraceptives. The clinical significance of this potential drug
`interaction is unknown at this time.
`Males
`
`Advise males with female partners of reproductive potential to use effective contraception during
`treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA.
`
`Infertility
`
`Based on findings in animals, IDHIFA may impair fertility in females and males of reproductive
`potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology
`(13.1)].
`
`Pediatric Use
`8.4
`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.
`
`11
`
`IDHIFA (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.
`
`
`Or
`
`
`2-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:
`
`
`
`DESCRIPTION
`
`
`
`
`
`
`
`Reference ID: 4498655
`
`

`

`
`
`CLINICAL PHARMACOLOGY
`
`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 a 50-mg tablet (equivalent to 60 mg enasidenib mesylate) and a
`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.
`
`12
`
`
`12.1 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.
`
`12.2 Pharmacodynamics
`Cardiac Electrophysiology
`The potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients
`with advanced hematologic malignancies with an IDH2 mutation. Based on the QTc data for a single
`dose of 30 mg to 650 mg and multiple doses of 100 mg daily in the fasted state, 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%) 50.2] after a
`single dose of 100 mg, and 13.1 mcg/mL (CV% 44.8) at steady state for 100 mg daily. The area under
`concentration time curve (AUC) of enasidenib increases in an approximately dose proportional manner
`from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended
`dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing.
`Accumulation is approximately 10-fold when administered once daily.
`
`
`Absorption
`The absolute bioavailability after 100 mg oral dose of enasidenib is approximately 57%. After a single
`oral dose, the median time to Cmax (Tmax) is 4 hours.
`
`
`Reference ID: 4498655
`
` 
`
`

`

` 
`
` Distribution
`
`The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). Human plasma protein
`binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro.
`
`Enasidenib is not a substrate for P-glycoprotein or BCRP, while AGI-16903 is a substrate of both P-
`glycoprotein and BCRP. Enasidenib and AGI-16903 are not substrates of MRP2, OAT1, OAT3,
`OATP1B1, OATP1B3, and OCT2.
`
`Elimination
`
`Enasidenib has a terminal half-life of 7.9 days and a mean total body clearance (CL/F) of 0.70 L/hour
`(CV% 62.5).
`
`Metabolism
`
`Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated
`metabolite, represented 10% of the circulating radioactivity.
`
`
`In vitro studies suggest that metabolism of enasidenib is mediated by multiple CYP enzymes (e.g.,
`
`CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs
`(e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). Further metabolism of the
`
`metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4,
`UGT1A1, UGT1A3, and UGT1A9).
`
`Excretion
`
`Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of
`unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine.
`
`Specific Populations
`
`No clinically meaningful effect on the pharmacokinetics of enasidenib was observed for the following
`covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment [defined
`as total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) >ULN or total
`bilirubin 1 to 1.5 times ULN and any AST], renal impairment (defined as creatinine clearance ≥30
`mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area.
`
`Drug Interaction Studies
`
`In vitro studies suggest that enasidenib inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9,
`
`CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib inhibits P-gp, BCRP, OAT1, OATP1B1,
`
`OATP1B3, and OCT2, but not MRP2 or OAT3. Enasidenib induces CYP2B6 and CYP3A4.
`
`
`In vitro studies suggest that the metabolite AGI-16903 inhibits the activity of CYP1A2, CYP2B6,
`CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 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.
`
`
`Reference ID: 4498655
`
`

`

`
`
`NONCLINICAL TOXICOLOGY
`
`
`CLINICAL STUDIES
`
`13
`
`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.
`
`14
`
`14.1 Acute 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 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 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 AML
`
`Demographic and Disease Characteristics
`IDHIFA (100 mg daily)
`N=199
`
`Demographics
`Age (Years) Median (Min, Max)
`
` Age Categories, n (%)
`<65 years
`≥65 years to <75 years
`≥75 years
`
`
`Sex, n (%)
`Male
`Female
` Race, n (%)
`White
`
` Black
`
`
`
`68 (19, 100)
`
`76 (38)
`74 (37)
`49 (25)
`
`103 (52)
`96 (48)
`
`153 (77)
`10 (5)
`
`Reference ID: 4498655
`
` 
`
`

`

` 
`
`
`
`
`
`Asian
`Native Hawaiian/Other Pacific Islander
`
` Other / Not Provided
` Disease Characteristics, n (%)
`
` ECOG PS a, n (%)
`0
`1
`2
`Relapsed AML, n (%)
`
`Refractory AML, n (%)
`
`IDH2 Mutation b, n (%)
`
`R140
`R172
`Time from Initial AML Diagnosis (months)
`
`Median (min, max) (172 patients)
`
` Cytogenetic Risk Status, n (%)
`
` Intermediate
`Poor
`Missing /Failure
` Prior Stem Cell Transplantation for AML, n (%)
`Transfusion Dependent at Baseline c, n (%)
` Number of Prior Anticancer Regimens, n (%) d
`
`1
`2
`≥3
`Median number of prior therapies (min, max)
`ECOG PS: Eastern Cooperative Oncology Group Performance Status.
`
`
`
`
`
` a 1 patient had missing baseline ECOG PS.
`
`b For 3 patients with different mutations detected in bone marrow compared to blood, the result of
`
`
`
`
`
`
`
`
`
`blood is reported.
`
`
`
`c Patients were defined as transfusion dependent at baseline if they received any red blood cell or
`
`
`
`
`
`
`platelet transfusions within the 8-week baseline period.
`
`
`d Includes intensive and/or nonintensive therapies.
`
`
`
`
`
`1 (1)
`1 (1)
`34 (17)
`
`
`46 (23)
`124 (62)
`28 (14)
`95 (48)
`104 (52)
`
`155 (78)
`44 (22)
`
`11.3 (1.2, 129.1)
`
`98 (49)
`54 (27)
`47 (24)
`25 (13)
`157 (79)
`
`89 (45)
`64 (32)
`46 (23)
`2 (1, 6)
`
`
`
`
`Efficacy was established on the basis of the rate of complete response (CR)/complete response with
`
` partial hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion from
`transfusion dependence to transfusion independence. The efficacy results are shown in Table 5 and
`
`were similar in both cohorts. The median follow-up was 6.6 months (range, 0.4 to 27.7 months).
`Similar CR/CRh rates were observed in patients with either R140 or R172 mutation.
`
`Reference ID: 4498655
`
`

`

`
`
`
`
`Table 5: Efficacy Results in Patients with Relapsed or Refractory AML
`
`Endpoint
`IDHIFA (100 mg daily)
`N=199
`37 (19)
`(13, 25)
`8.2
`(4.7, 19.4)
`9 (4)
`(2, 8)
`9.6
`(0.7, NA)
`46 (23)
`(18, 30)
`8.2
`(4.3, 19.4)
`
` CRa n (%)
`
`95% CI
`
`
`Median DORb (months)
`95% CI
`
`
` CRhc n (%)
`
`
`
` 95% CI
`Median DOR (months)
`
`
` 95% CI
`CR/CRh n (%)
`
`
`
`95% CI
`Median DOR (months)
`95% CI
`
`
`
`
`
`
` CI: confidence interval, NA: not available.
`a CR (complete remission) was defined as <5% of blasts in the bone marrow, no evidence of
`
`
`
`
`disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and
`
`
`absolute neutrophil counts [ANC] >1,000/microliter).
`
`b DOR (duration of response) was defined as time since first response of CR or CRh to
`
`
`
`
`
`relapse or death, whichever is earlier.
`
`
`c CRh (complete remission with partial hematological recovery) was defined as <5% of
`
`
`blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood
`
`
`counts (platelets >50,000/microliter and ANC >500/microliter).
`
`
`
`
`
`For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to
`7.5 months) and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to
`11.2 months). Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6
`months of initiating IDHIFA.
`
`Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at
`baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day post
`baseline period. Of the 42 patients who were independent of both RBC and platelet transfusions at
`baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period.
`
`16
`
`
`16.1 How 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 a 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 a desiccant canister (NDC 59572-710-30)
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`Reference ID: 4498655
`
` 
`
`

`

` 
`
`PATIENT COUNSELING INFORMATION
`
`16.2 Storage
`Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F) [see USP
`
`
`Controlled Room Temperature]. Keep the bottle tightly closed. Store in the original bottle (with a
`
`desiccant canister) to protect from moisture.
`
`17
`
`
`
`Advise the