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Enasidenib Mesylate

Class: Antineoplastic Agents
Chemical Name: methanesulfonic acid;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
Molecular Formula: C20H21F6N7O4S
CAS Number: 1650550-25-6
Brands: Idhifa

Medically reviewed on August 7, 2017

Warning

Warning: Differentiation Syndrome.1

See full prescribing information for complete boxed warning. 1

Patients treated with enasidenib mesylate 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.1

Introduction

Enasidenib mesylate is an isocitrate dehydrogenase-2 inhibitor antineoplastic agent.1

Uses for Enasidenib Mesylate

Enasidenib mesylate has the following uses:

Enasidenib mesylate 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.1

Enasidenib Mesylate Dosage and Administration

General

Enasidenib mesylate is available in the following dosage form(s) and strength(s):

Tablets: 50 mg or 100 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

The recommended dosage is 100 mg orally once daily until disease progression or unacceptable toxicity occurs.1

Cautions for Enasidenib Mesylate

Contraindications

None.1

Warnings/Precautions

Differentiation Syndrome

In the clinical trial, 14% of patients treated with enasidenib mesylate 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 enasidenib mesylate included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and at up to 5 months after enasidenib mesylate initiation.1

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 enasidenib mesylate until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.1

Embryo-fetal Toxicity

Based on animal embryo-fetal toxicity studies, enasidenib mesylate 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 enasidenib mesylate and for at least 1 month after the last dose of enasidenib mesylate. Advise males with female partners of reproductive potential to use effective contraception during treatment with enasidenib mesylate and for at least 1 month after the last dose of the drug. Pregnant women, patients becoming pregnant while receiving enasidenib mesylate, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.1

Specific Populations

Pregnancy

Risk Summary: Based on animal embryo-fetal toxicity studies, enasidenib mesylate can cause fetal harm when administered to a pregnant woman. There are no available data on enasidenib mesylate 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. 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.1

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.1

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.1

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 per day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).1

Lactation

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 enasidenib mesylate and for at least 1 month after the last dose.1

Females And Males Of Reproductive Potential

Based on animal embryo-fetal toxicity studies, enasidenib mesylate can cause fetal harm when administered to a pregnant woman.1

Obtain a pregnancy test on females of reproductive potential prior to starting treatment with enasidenib mesylate.1

Advise females of reproductive potential to avoid becoming pregnant while receiving enasidenib mesylate. Advise females of reproductive potential to use effective contraception during treatment with enasidenib mesylate and for at least 1 month after the last dose. Coadministration of enasidenib mesylate may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with enasidenib mesylate and for at least 1 month after the last dose of the drug.1

Based on findings in animals, enasidenib mesylate may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.1

Geriatric Use

No dosage adjustment is required for enasidenib mesylate 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.1

Common Adverse Effects

The most common adverse reactions (≥20%) included nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

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.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling.1

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 evaluation.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.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.1

Elevated Blood Bilirubin

Inform patients that taking enasidenib mesylate 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.1

Embryo-Fetal Toxicity and Use of Contraceptives

Advise female patients with reproductive potential to use effective contraceptive methods while receiving enasidenib mesylate 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 enasidenib mesylate treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with enasidenib mesylate and for at least 1 month after the last dose of enasidenib mesylate. Coadministration of enasidenib mesylate may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.1

Lactation

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

Dosing and Storage Instructions

Advise patients not to chew or split the tablets, but to swallow them whole with a cup of water.1

Instruct patients that if they miss a dose or vomit after a dose of enasidenib mesylate, 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. 1

Keep enasidenib mesylate in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture. 1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Enasidenib Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg

Idhifa

Celgene

100 mg

Idhifa

Celgene

AHFS Drug Information. © Copyright 2018, Selected Revisions August 7, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Celgene Corporation. Idhifa (enasidenib mesylate) oral prescribing information. 2017 Aug. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a5b4cdf0-3fa8-4c6c-80f6-8d8a00e3a5b6

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