`-------------------------------CONTRAINDICATIONS-----------------------------
`
`None (4).
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS----------------------
`
`Embryo-Fetal Toxicity: IDHIFA can cause fetal harm. Advise patients of the
`
`
`potential risk to a fetus and use effective contraception (5.2, 8.1, 8.3).
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------
`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.
`
`
`--------------------------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).
`
`
`
`
`
`
`--------------------------USE IN SPECIFIC POPULATIONS--------------------
`Lactation: Advise not to breastfeed (8.2).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`Revised: 11/2020
`
`
`
`
`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.
`
`
`
`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 FDA-
`
`
`
`approved test (1.1).
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------
`
`100 mg orally once daily until disease progression or unacceptable toxicity
`
`
`
`
`(2.2).
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------
`
`Tablets: 50 mg or 100 mg (3).
`
`
`
`
`
`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
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Differentiation Syndrome
`
`
`
`
`5.2 Embryo-Fetal Toxicity
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`DRUG INTERACTIONS
`
`7.1 Effect of IDHIFA on Other Drugs
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`
`2
`
`
`6
`
`
`7
`
`
`8
`
`
`
`
`
`
`
`
`Reference ID: 4706449
`
`
`
`1
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`Patient Selection
`2.1
`
`
`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 dosage of IDHIFA is 100 mg taken orally once daily with or without food until
`
`
`
`disease progression or unacceptable toxicity. For patients without disease progression or unacceptable
`
`
`
`
`toxicity, treat for a minimum of 6 months to allow time for clinical response.
`
`
`
`
`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: 4706449
`
`
`
`
`
`
`
`
`
`
` • 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
`
` Recommended Action
`
`
` Adverse Reaction
` • 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
`
`
`
`
`
` 4
`
`
`
`
` CONTRAINDICATIONS
`
`
`3
`
`
`
`Reference ID: 4706449
`
`
`
`
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
` 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.
`
` 5.2
`
`
` Embryo-Fetal Toxicity
` Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when
`
`
`
`
`
`
`
` administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused embryo-
` fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the
`
`
`
`
`
`concentration-time curve (AUC) at the recommended human dose.
`
`
`Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to
`
`use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose.
`
`
`Advise males with female partners of reproductive potential to use effective contraception during
`
`
`treatment with IDHIFA and for at least 2 months after the last dose [see Use in Specific Populations
`
`
`
`
`(8.1, 8.3)].
`
`
`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: 4706449
`
`
`
`
`
` 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.
`
`
`
`
` Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse
`
`
`
`
`
`
`
`
` reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased
` appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation
`
`
`
`
` syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory
`
`
`
`
`
`
` failure, and multi-organ failure.
`
`
`
`Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most
`
`
`
`
`
`
`frequent adverse reactions leading to dose interruption were differentiation syndrome (4%) and
`
`
`
`leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no
`
`
`
`
`
`
`
`adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%)
`
`
`
`
`permanently discontinued IDHIFA due to an adverse reaction; the most frequent adverse reaction
`
`
`
`leading to permanent discontinuation was leukocytosis (1%).
`
`
`
`
`
`The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated
`
`bilirubin and decreased appetite.
`
`
`Adverse reactions reported in the trial are shown in Table 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Body System
`
` Adverse Reaction
`
`
`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 (%)
`
`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: 4706449
`
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`Table 3: Most Common (≥20%) New or Worsening Laboratory
`
`
`
`Abnormalities Reported in Patients with Relapsed or Refractory AML
`
`
`
`
` IDHIFA (100 mg daily)
`
` N=214
`
`
`
` Grade ≥3
`
` All Grades
`
` (%)
`
` (%)
`
`
` Total bilirubin increased
`
`
` 81
` 15
` Calcium decreased
`
`
`
` 74
`
` 8
` Potassium decreased
`
`
` 41
` 15
`
` 8
`
` 27
`
`
` Phosphorus decreased
`
`
`
`
`
`
`
`
`
`
`
` 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).
`
`
`
`
` Parameter a
`
`
`
`
`
` 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: 4706449
`
`
`
`
`
`
`
` DRUG INTERACTIONS
`
`
` 7
`
`
`
`Effect of IDHIFA on Other Drugs
`7.1
`
`
`OATP1B1, OATP1B3, and BCRP Substrates
`
`
`
`
`IDHIFA 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 a 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 a P-gp substrate where small concentration changes may lead to serious
`
`
`
`
`
`
`
` adverse reactions, decrease the dose or modify the dosing frequency of such a P-gp substrate and
`
`
`
` monitor for adverse reactions as recommended in the respective prescribing information.
`
`
`
`
`
`
`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). Advise pregnant women of the
`
`potential risk to a fetus.
`
`
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`
`
`
`unknown. All pregnancies have a 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 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).
`
`7
`
`USE IN SPECIFIC POPULATIONS
`
`
`Reference ID: 4706449
`
`
`
`
`
`
`
`
`
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`
`
`
`
` 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 of the potential for adverse reactions in the
`
` breastfed child, advise women not to breastfeed during treatment with IDHIFA and for at least 2
`
`
` months after the last dose.
`
`
`
`
` 8.3
`
`
`
` Females and Males of Reproductive Potential
`
` Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a
`
`
` pregnant woman [see Use in Specific Populations (8.1)].
`
`
`
` Pregnancy Testing
`
`
`
` Verify pregnancy status in females of reproductive potential prior to starting IDHIFA.
`
`
`Contraception
`
`
` Females
` Advise females of reproductive potential to use effective contraception during treatment with IDHIFA
`
`
`
`
`
`
`
`
` and for at least 2 months after the last dose. Coadministration of IDHIFA may increase or decrease the
` concentrations of combined hormonal contraceptives. The clinical significance of this potential drug
`
`
`
` interaction is unknown at this time.
`
`Males
`
`Advise males with female partners of reproductive potential to use effective contraception during
`
`treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA.
`
`
`
`Infertility
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Based on findings in animals, IDHIFA may impair fertility in females and males of reproductive
`
`
`
`
`
`
`
`
`
`
`
`potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology
`
`
`
`
`
`(13.1)].
`
`
`
`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
`
`
`
`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.
`
`
`
`DESCRIPTION
`
`
`
`
`
`Reference ID: 4706449
`
`
`
`
`
`
` 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:
`
`
`
`CF3
`
`CF3
`
`N
`
`N
`
`N
`
`N
`
`CH3SO3H
`
`N
`H
`
`N
`
`N
`H
`
`OH
`
`
`
`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. 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 a
`
`
`
`
`
`single dose of 100 mg, and 13.1 mcg/mL (CV% 45%) at steady state for 100 mg daily. The area under
`
`
`
`
`
`concentration time curve (AUC) of enasidenib increases in an approximately dose proportional manner
`
`
`
`
`from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended
`
`9
`
`Reference ID: 4706449
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`Distribution
`
`
` The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). Human plasma protein
`
` binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro.
`
`
`
`
`
`Elimination
` Enasidenib has a terminal half-life of 7.9 days and a mean total body clearance (CL/F) of 0.70 L/hour
`
` (CV% 62.5).
`
`
`
`
`Metabolism
`
`Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated
`
`
`
`
`metabolite, represented 10% of the circulating radioactivity.
`
`
`
`
`
`
` Metabolism of enasidenib is mediated by multiple cytochrome P450 (CYP) enzymes (e.g., CYP1A2,
`
` CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UDP glucuronosyl
`
`
`
`
`
`
` transferases (UGTs) (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15) in vitro.
` Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2,
`
`
`
`
` CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9) in vitro.
`
`
`
`
`
`Excretion
`
`Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of
`
`
`
`
`
`
`
`unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine.
`
`
`
`
`
`
`
`
`Specific Populations
`
`No clinically meaningful effect on the pharmacokinetics of enasidenib was observed for the following
`
`covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment [defined
`
`
`as total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) >ULN or total
`
`
`
`bilirubin 1 to 1.5 times ULN and any AST], renal impairment (defined as creatinine clearance ≥30
`
`mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area.
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`
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`
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`Reference ID: 4706449
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`
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`
` 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 a substrate for P-glycoprotein (P-gp) or breast cancer resistance
`
`
`
`
`
`
`
` protein (BCRP). AGI-16903 is a substrate of both P-gp and BCRP. Enasidenib and AGI-16903 are not
`
` substrates of multidrug resistance-associated protein 2 (MRP2), organic anion transporter 1 (OAT1),
`
`
`
`
` OAT3, organic anion transporter family member 1B1 (OATP1B1), OATP1B3, and organic cation
`
`
`
` transporter 2 (OCT2).
`
`
`
`
`Enasidenib inhibits OAT1 and OCT2, but not MRP2 or OAT3. AGI-16903 inhibits BCRP, OAT1,
`
`
` OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3.
`
`
`
`
` Coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal
`
`
` contraceptives. The clinical significance of this potential drug interaction is unknown at this time.
`
`
`
`
` 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
`
`
`
`
`
`11
`
`
`
` NONCLINICAL TOXICOLOGY
`
`
`
`CLINICAL STUDIES
`
`
`Reference ID: 4706449
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
` IDHIFA (100 mg daily)
`
` Demographic and Disease Characteristics
` 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
`
` 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 (%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4706449
`
`
`
`
`
`
`
` 68 (19, 100)
`
`
` 76 (38)
`
` 74 (37)
`
` 49 (25)
`
`
`
` 103 (52)
` 96 (48)
`
`
`
` 153 (77)
`
` 10 (5)
` 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)
`
`
`
`
`
`
`
`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 h