U.S. FDA APPROVED  DRUGS DURING 2017

These highlights do not include all the information needed to use IDHIFA safely and effectively. See full prescribing information for IDHIFA. IDHIFA® (enasidenib) tablets, for oral use

Initial U.S. Approval: 2017

WARNING: DIFFERENTIATION SYNDROME

See full prescribing information for complete boxed warning.

Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution (5.1, 6.1).

INDICATIONS AND USAGE

­ IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDAapproved test 

ADVERSE REACTIONS

The most common adverse reactions (=20%) included

nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite 

CONTRAINDICATIONS

None 

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 

INDICATIONS AND USAGE

IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDAapproved test 

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 

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 10 days 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 evaluatio. 

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 .

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

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 1 month 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 1 month 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 

Lactation

Advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the final dose

 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 

Keep IDHIFA in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture .

Manufactured for and marketed by:Celgene Corporation Summit, NJ 07901

CLINICAL PHARMACOLOGY

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.

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.

3. Pharmacokinetics

The peak plasma concentration (Cmax) is 1.3 mcg/mL [% coefficient of variation (CV%) 56.4] after a single dose of 100 mg, and 13 mcg/mL (CV% 46.3) 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 Pglycoprotein 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 137 hours (CV% 41) and a mean total body clearance (CL/F) of 0.74 L/hour (CV% 71)

 Metabolism

Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity.

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.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy 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 drugassociated 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 

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.

2.Lactation Risk Summary

There are no data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

Lactation: Advise women not to breastfeed .

3. 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 .

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 1 month 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 1 month 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 .

4. Pediatric

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

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.