Enasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a confirmed isocitrate dehydrogenase-2 (IDH2) gene mutation, as identified by an FDA-approved diagnostic test.

Enasidenib is a small-molecule inhibitor of the isocitrate dehydrogenase-2 (IDH2) enzyme. It selectively targets mutant forms of the IDH2 enzyme, including R140Q, R172S, and R172K variants, at significantly lower concentrations compared to the normal (wild-type) enzyme. By inhibiting the mutant IDH2 enzyme, enasidenib reduces the production of the abnormal metabolite 2-hydroxyglutarate (2-HG). This reduction promotes the differentiation of immature myeloid cells into mature blood cells, which helps restore normal blood cell development. Preclinical studies in laboratory models and mouse xenograft models of IDH2-mutated AML demonstrated that enasidenib lowered 2-HG levels, reduced leukemia blast cells, and increased the proportion of mature myeloid cells. Similar effects were observed in blood samples from patients with IDH2-mutated AML.

The recommended starting dose of Enasidenib 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 Enasidenib tablets. Administer Enasidenib tablets orally about the same time each day. If a dose of Enasidenib 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.

Recommended Monitoring for Safety: Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of Enasidenib and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly. Interrupt dosing or reduce dose for toxicities.

Laboratory studies suggest that Enasidenib can inhibit several metabolic enzymes including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. It may also inhibit drug transporters such as P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2, but it does not significantly inhibit MRP2 or OAT3. Enasidenib can induce the activity of CYP2B6 and CYP3A4 enzymes. Its metabolite AGI-16903 may also inhibit several enzymes and transporters including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, BCRP, OAT1, OAT3, OATP1B1, and OCT2. Co-administration of Enasidenib with combined hormonal contraceptives may increase or decrease their concentration in the body. However, the clinical significance of this interaction is currently unknown.

One of the most important side effects of Enasidenib is Differentiation Syndrome, a potentially life-threatening condition that affects blood cells if not treated promptly. It may occur within 10 days to 5 months after starting treatment. Patients should immediately contact their healthcare provider or go to the nearest emergency department if they develop symptoms such as:

• Fever
• Cough
• Shortness of breath
• Swelling in the arms or legs
• Swelling around the neck, groin, or underarm area
• Rapid weight gain
• Bone pain

Pregnancy: Based on animal studies, Enasidenib may cause harm to the developing fetus when used during pregnancy. There are no adequate human studies to determine the exact risk of birth defects or miscarriage. Animal studies showed embryo-fetal toxicity when Enasidenib was administered during organ development. If a patient becomes pregnant during treatment, she should be informed about the potential risks to the fetus.

Lactation: There is no available information on whether Enasidenib or its metabolites pass into human breast milk, or its effects on breastfed infants. Due to the potential risk of serious adverse effects in infants, breastfeeding is not recommended during treatment and for at least 1 month after the last dose.

Differentiation Syndrome: In clinical studies, 14% of patients receiving Enasidenib developed differentiation syndrome, which can be life-threatening or fatal if not managed promptly. This syndrome is linked to rapid growth and maturation of myeloid cells. Although there is no specific diagnostic test, reported symptoms in patients treated with Enasidenib included acute respiratory distress such as dyspnea and/or hypoxia (68%) and requirement for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal dysfunction (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 reported. Differentiation syndrome may occur with or without hyperleukocytosis and has been observed as early as 10 days and up to 5 months after starting Enasidenib.

Embryo-Fetal Toxicity: Based on findings from animal embryo-fetal toxicity studies, Enasidenib may cause harm to the developing fetus when administered during pregnancy. In these studies, embryo-fetal toxicity was observed at exposure levels as low as 0.1 times the steady-state clinical exposure (based on AUC) at the recommended human dose. Females of reproductive potential should be advised to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose. Males with female partners of reproductive potential should also use effective contraception during treatment and for at least 1 month after the last dose. Pregnant women, patients who become pregnant during treatment, or male patients with pregnant partners should be informed about the potential risk to the fetus.

Pediatric Use: The safety and effectiveness of Enasidenib in pediatric patients have not been established.

Geriatric Use: No dose adjustment is required based on age. In clinical studies, 61% of patients were aged 65 years or older, and 24% were older than 75 years, with no significant differences in safety or effectiveness compared to younger patients.

Cytotoxic Chemotherapy

Store Enasidenib tablets below 30°C in a cool and dry place. Protect from light and keep out of the reach of children.