IDHIFA
Generic Name: enasidenib mesylate
Dosage Form: tablet, film coated
Medically reviewed by
Drugs.com. Last updated on Oct 1, 2019.
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 for IDHIFAAcute 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.
IDHIFA
Dosage and AdministrationPatient 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
(http://www.fda.gov/CompanionDiagnostics.
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.
Monitoring and Dosage
Modifications for Toxicities
Assess
blood counts and blood chemistries for leukocytosis and tumor lysis syndrome
prior to the initiation of IDHIFA and monitor at a minimum of every 2 weeks for
at least the first 3 months during treatment. Manage any abnormalities promptly [see
Adverse Reactions (6.1)].
Interrupt dosing or reduce
dose for toxicities. See Table
1 for dosage modification guidelines.
Table 1: Dosage Modifications for
IDHIFA-Related Toxicities
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*Grade 1 is
mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.
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Adverse Reaction
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Recommended Action
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· Differentiation
syndrome
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· 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.
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· Noninfectious
leukocytosis (white blood cell [WBC] count greater than 30 x 109/L)
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· 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.
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· Elevation
of bilirubin greater than 3 times the upper limit of normal (ULN) sustained
for ≥2 weeks without elevated transaminases or other hepatic disorders
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· Reduce
IDHIFA dose to 50 mg daily.
· Resume
IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 x ULN.
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· Other
Grade 3* or higher toxicity considered related to treatment including tumor
lysis syndrome
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· 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.
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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.Contraindications
None.
Warnings
and PrecautionsDifferentiation Syndrome
In the clinical trial, 14%
of patients treated with IDHIFA experienced differentiation syndrome, which may
be life-threatening or fatal if not treated. Differentiation syndrome is
associated with rapid proliferation and differentiation of myeloid cells. While
there is no diagnostic test for differentiation syndrome, symptoms in patients
treated with IDHIFA included acute respiratory distress represented by dyspnea
and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary
infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever
(36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid
weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ
dysfunction have also been observed.
Differentiation syndrome has been
observed with and without concomitant hyperleukocytosis, in as early as 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
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)].
Adverse
Reactions
The following clinically
significant adverse reactions are described elsewhere in the labeling:
Differentiation Syndrome
[see Warnings and Precautions (5.1)]Clinical Trials Experience
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
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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.
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IDHIFA (100 mg daily)
N=214
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Body System
Adverse Reaction
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All Grades
N=214
n (%)
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≥Grade 3
N=214
n (%)
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Gastrointestinal Disordersa
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Nausea
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107 (50)
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11 (5)
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Diarrhea
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91 (43)
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17 (8)
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Vomiting
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73 (34)
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4 (2)
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Metabolism and Nutrition Disorders
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Decreased
appetite
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73 (34)
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9 (4)
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Tumor lysis
syndrome b
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13 (6)
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12 (6)
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Blood and Lymphatic System Disorders
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Differentiation
syndrome c
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29 (14)
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15 (7)
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Noninfectious
leukocytosis
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26 (12)
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12 (6)
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Nervous System Disorders
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Dysgeusia
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25 (12)
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0 (0)
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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
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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).
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IDHIFA (100 mg daily)
N=214
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Parameter a
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All Grades
(%)
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Grade ≥3
(%)
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Total bilirubin
increased
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81
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15
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Calcium
decreased
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74
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8
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Potassium
decreased
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41
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15
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Phosphorus
decreased
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27
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8
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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.
USE IN
SPECIFIC POPULATIONSPregnancy
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 theU.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
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
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.
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
Safety and effectiveness in
pediatric patients have not been established.
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.
IDHIFA
Description
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:
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.
IDHIFA -
Clinical PharmacologyMechanism 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.
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.
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.
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.
Nonclinical
ToxicologyCarcinogenesis, 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.
Clinical
StudiesAcute 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
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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.
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Demographic and Disease Characteristics
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IDHIFA (100 mg daily)
N=199
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Demographics
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Age (Years) Median (Min, Max)
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68 (19, 100)
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Age Categories, n (%)
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<65 years
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76 (38)
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≥65 years to
<75 years
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74 (37)
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≥75 years
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49 (25)
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Sex, n (%)
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Male
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103 (52)
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Female
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96 (48)
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Race, n (%)
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White
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153 (77)
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Black
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10 (5)
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Asian
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1 (1)
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Native
Hawaiian/Other Pacific Islander
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1 (1)
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Other / Not
Provided
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34 (17)
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Disease Characteristics, n (%)
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ECOG PS a, n (%)
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0
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46 (23)
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1
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124 (62)
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2
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28 (14)
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Relapsed AML, n (%)
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95 (48)
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Refractory AML, n (%)
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104 (52)
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IDH2 Mutation b, n (%)
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R140
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155 (78)
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R172
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44 (22)
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Time from Initial AML Diagnosis (months)
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Median (min,
max) (172 patients)
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11.3 (1.2, 129.1)
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Cytogenetic Risk Status, n (%)
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Intermediate
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98 (49)
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Poor
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54 (27)
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Missing /Failure
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47 (24)
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Prior Stem Cell Transplantation for AML, n (%)
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25 (13)
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Transfusion Dependent at Baseline c, n (%)
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157 (79)
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Number of Prior Anticancer Regimens, n (%) d
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1
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89 (45)
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2
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64 (32)
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≥3
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46 (23)
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Median number of
prior therapies (min, max)
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2 (1, 6)
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Efficacy was established on
the basis of the rate of complete response (CR)/complete response with partial
hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion
from transfusion dependence to transfusion independence. The efficacy results are
shown in Table 5 and were similar in both
cohorts. The median follow-up was 6.6 months (range, 0.4 to 27.7 months).
Similar CR/CRh rates were observed in patients with either R140 or R172 mutation.
Table 5: Efficacy Results in Patients
with Relapsed or Refractory AML
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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).
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Endpoint
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IDHIFA (100 mg daily)
N=199
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CRa n (%)
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37 (19)
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95% CI
|
(13, 25)
|
|
Median DORb (months)
|
8.2
|
|
95% CI
|
(4.7, 19.4)
|
|
CRhc n (%)
|
9 (4)
|
|
95% CI
|
(2, 8)
|
|
Median DOR (months)
|
9.6
|
|
95% CI
|
(0.7, NA)
|
|
CR/CRh n (%)
|
46 (23)
|
|
95% CI
|
(18, 30)
|
|
Median DOR (months)
|
8.2
|
|
95% CI
|
(4.3, 19.4)
|
For patients who achieved a
CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5
months) and the median time to best response of CR/CRh was 3.7 months (range,
0.6 to 11.2 months). Of the 46 patients who achieved a best response of CR/CRh,
39 (85%) did so within 6 months of initiating IDHIFA.
Among the 157 patients who
were dependent on red blood cell (RBC) and/or platelet transfusions at
baseline, 53 (34%) became independent of RBC and platelet transfusions during
any 56-day post baseline period. Of the 42 patients who were independent of
both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion
independent during any 56-day post baseline period.
How
Supplied/Storage and HandlingHow 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)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.
Patient
Counseling Information
Advise the patient to read
the FDA-approved patient labeling (Medication Guide).
Differentiation
Syndrome
Advise patients on the risks
of developing differentiation syndrome as early as 1 day and during the first 5
months on treatment. Ask patients to immediately report any symptoms suggestive
of differentiation syndrome, such as fever, cough or difficulty breathing, bone
pain, rapid weight gain or swelling of their arms or legs, to their healthcare
provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].
Tumor
Lysis Syndrome
Advise patients on the risks
of developing tumor lysis syndrome. Advise patients on the importance of
maintaining high fluid intake, and the need for frequent monitoring of blood
chemistry values [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Gastrointestinal
Adverse Reactions
Advise patients on risk of
experiencing gastrointestinal reactions such as diarrhea, nausea, vomiting,
decreased appetite, and changes in their sense of taste. Ask patients to report
these events to their healthcare provider, and advise patients how to manage
them [see Adverse Reactions (6.1)].
Elevated
Blood Bilirubin
Inform patients that taking
IDHIFA may cause elevated blood bilirubin, which is due to its mechanism of
action, and not due to liver damage. Advise patients to report any changes to
the color of their skin or the whites of their eyes to their healthcare
provider for further evaluation [see Adverse Reactions
(6.1)].
Embryo-Fetal
Toxicity and Use of Contraceptives
Advise female patients with
reproductive potential to use effective contraceptive methods while receiving
IDHIFA and to avoid pregnancy while on treatment and for 2 months after
completion of treatment. Advise patients to notify their healthcare provider
immediately in the event of a pregnancy or if pregnancy is suspected during
IDHIFA treatment. 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. Coadministration of IDHIFA may increase
or decrease the concentrations of combined hormonal contraceptives. The clinical
significance of this potential drug interaction is unknown at this time [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)].
Lactation
Advise women not to
breastfeed during treatment with IDHIFA and for at least 2 months after the
final dose [see Use in Specific Populations (8.2)].
Dosing
and Storage Instructions
Advise patients not to chew or
split the tablets but swallow whole with a cup of water.Instruct patients that if they
miss a dose or vomit after a dose of IDHIFA, to take it as soon as
possible on the same day and return to normal schedule the following day.
Warn patients not to take 2 doses to make up for the missed dose
[see Dosage and Administration (2.2)].Keep IDHIFA in the original
container. Keep the container tightly closed with desiccant canister
inside to protect the tablets from moisture
[see
How Supplied/Storage and Handling (16.2)].
Manufactured for and
marketed by:
Celgene Corporation
Summit,NJ07901
Licensed from:
Agios Pharmaceuticals
Cambridge,MA02139
Trademarks are the property
of their respective owners.
IDHIFA® is a registered
trademark of Celgene Corporation.
Pat.
www.celgene.com/therapies
© 2016-2019 Celgene
Corporation
All Rights Reserved.
IDHPI.003/MG.003
|
This Medication
Guide has been approved by the U.S. Food and Drug Administration
|
Revised:
September 2019
|
|
MEDICATION GUIDE
IDHIFA® (eyed-HEE-fuh)
(enasidenib) tablets
|
|
What
is the most important information I should know about IDHIFA?
IDHIFA may
cause serious side effects, including:
Differentiation Syndrome. Differentiation syndrome is a
condition that affects your blood cells which may be life-threatening or
lead to death if not treated. Differentiation syndrome has happened within
1 day and up to 5 months after starting IDHIFA. Call your healthcare
provider or go to the nearest hospital emergency room right away if you
develop any of the following symptoms of differentiation syndrome while
taking IDHIFA:fevercoughshortness
of breathswelling
of arms and legsswelling
around neck, groin, or underarm areafast
weight gain (greater than 10 pounds within a week)bone
pain
If you develop any of these
symptoms of differentiation syndrome, your healthcare provider may start you
on a medicine taken by mouth or given through a vein (intravenous) called
corticosteroids and may monitor you in the hospital.
|
|
What
is IDHIFA?
IDHIFA is a prescription
medicine used to treat people with acute myeloid leukemia (AML) with an
isocitrate dehydrogenase-2 (IDH2) mutation whose disease has come back or has
not improved after previous treatment(s). It is not known if IDHIFA is safe
and effective in children.
|
|
Before
taking IDHIFA, tell your healthcare provider about all of your medical
conditions, including if you:
Are
pregnant or plan to become pregnant. IDHIFA can cause harm to your
unborn baby if taken during pregnancy.If you
are able to become pregnant, your healthcare provider will do a
pregnancy test before you start taking IDHIFA.Females who are able to become pregnant and who
take IDHIFA should use effective birth control (contraception) during
treatment with IDHIFA and for at least 2 months after your last dose of
IDHIFA.Males who have female partners that are able
to become pregnant should use effective birth control during treatment
with IDHIFA and for at least 2 months after your last dose of IDHIFA.IDHIFA
may affect how hormonal contraceptives work and may cause them to not
work as well.Talk
to your healthcare provider about birth control methods that may be
right for you while taking IDHIFA.IDHIFA
may cause fertility problems in females and males, which may affect
your ability to have children. Talk to your healthcare provider if you
have concerns about fertility.Are
breastfeeding or plan to breastfeed. It is not known if IDHIFA passes
into your breast milk. You should not breastfeed during your treatment
with IDHIFA and for at least 2 months after your last dose of IDHIFA.
Tell your
healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
|
|
How
should I take IDHIFA?
Take
IDHIFA exactly as your healthcare provider tells you to.Take
IDHIFA 1 time a day at the same time each day.Swallow
IDHIFA tablets whole. Do not chew or split the tablet.Swallow
IDHIFA with 8 ounces (one cup) of water.IDHIFA
can be taken with or without food.If you
miss a dose of IDHIFA or vomit after taking a dose of IDHIFA, take the
dose of IDHIFA as soon as possible on the same day. Then take your next
dose the next day at your regularly scheduled time. Do not take 2 doses at the same time to
make up for the missed dose.Your healthcare provider should do blood tests
to check your blood counts before you start IDHIFA treatment and at a
minimum of every 2 weeks for at least the first 3 months during
treatment to check for side effects.
|
|
What
are the possible side effects of IDHIFA?
IDHIFA may
cause serious side effects, including:
See "What
is the most important information I should know about IDHIFA?"
The most
common side effects of IDHIFA include:
nauseavomitingdiarrheajaundicedecreased
appetite
Tell your healthcare provider if
you have any changes to the color of your skin or the whites of your eyes.
Your healthcare provider will monitor you for side effects during treatment
and may tell you to stop taking IDHIFA if you develop certain side effects.
These are not all the possible
side effects of IDHIFA.
Call your doctor for medical
advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
|
|
How
should I store IDHIFA?
Store
IDHIFA at room temperature from 68°F to 77°F (20°C to 25°C).Keep
IDHIFA in the original container.Keep
the container tightly closed with desiccant canister inside to protect
the tablets from moisture.
Keep IDHIFA
and all medicines out of the reach of children.
|
|
General
information about the safe and effective use of IDHIFA
Medicines are sometimes prescribed
for purposes other than those listed in a Medication Guide. Do not take
IDHIFA for conditions for which it was not prescribed. Do not give IDHIFA to
other people, even if they have the same symptoms you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about
IDHIFA that is written for health professionals.
|
|
What
are the ingredients in IDHIFA?
Active
ingredient: enasidenib
Inactive
ingredients: colloidal
silicon dioxide, hydroxypropyl cellulose, hypromellose acetate succinate,
iron oxide yellow, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium starch
glycolate, talc, and titanium dioxide
Manufactured for and marketed
by: Celgene Corporation,Summit,NJ07901
Licensed from: Agios
Pharmaceuticals,Cambridge,MA02139
IDHIFA® is a registered trademark of Celgene
Corporation.
Pat.
http://www.celgene.com/therapies
IDHMG.003 © 2016-2019 Celgene
Corporation
All rights reserved.
For more information go to
www.IDHIFA.com or call 1-888-423-5436.
|
PRINCIPAL
DISPLAY PANEL - NDC: NDC 59572-705-30 - 50 mg Label
PRINCIPAL
DISPLAY PANEL - NDC: NDC 59572-710-30 - 100 mg Label
|
IDHIFA
enasidenib mesylate tablet, film coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:59572-705
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
ENASIDENIB
MESYLATE (ENASIDENIB)
|
ENASIDENIB
|
50 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
HYDROXYPROPYL
CELLULOSE, UNSPECIFIED
|
|
|
SODIUM
STARCH GLYCOLATE TYPE A POTATO
|
|
|
SODIUM
LAURYL SULFATE
|
|
|
HYPROMELLOSE
ACETATE SUCCINATE 06081224 (3 MM2/S)
|
|
|
SILICON
DIOXIDE
|
|
|
MAGNESIUM
STEARATE
|
|
|
POLYVINYL
ALCOHOL, UNSPECIFIED
|
|
|
TITANIUM
DIOXIDE
|
|
|
POLYETHYLENE
GLYCOL, UNSPECIFIED
|
|
|
TALC
|
|
|
FERRIC
OXIDE YELLOW
|
|
|
|
Product
Characteristics
|
|
Color
|
YELLOW
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
12mm
|
|
Flavor
|
|
Imprint
Code
|
ENA;50
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:59572-705-30
|
30 TABLET,
FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA209606
|
08/01/2017
|
|
|
|
IDHIFA
enasidenib mesylate tablet, film coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:59572-710
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
ENASIDENIB
MESYLATE (ENASIDENIB)
|
ENASIDENIB
|
100 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
HYDROXYPROPYL
CELLULOSE, UNSPECIFIED
|
|
|
SODIUM
STARCH GLYCOLATE TYPE A POTATO
|
|
|
SODIUM
LAURYL SULFATE
|
|
|
HYPROMELLOSE
ACETATE SUCCINATE 06081224 (3 MM2/S)
|
|
|
SILICON
DIOXIDE
|
|
|
MAGNESIUM
STEARATE
|
|
|
POLYVINYL
ALCOHOL, UNSPECIFIED
|
|
|
TITANIUM
DIOXIDE
|
|
|
POLYETHYLENE
GLYCOL, UNSPECIFIED
|
|
|
TALC
|
|
|
FERRIC
OXIDE YELLOW
|
|
|
|
Product
Characteristics
|
|
Color
|
YELLOW
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
15mm
|
|
Flavor
|
|
Imprint
Code
|
ENA;100
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:59572-710-30
|
30 TABLET,
FILM COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA209606
|
08/01/2017
|
|
|
|
Labeler - Celgene Corporation (174201137)
|
Celgene Corporation
