Enasidenib

Enasidenib 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.

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.

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.

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. Co-administration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.

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 10 days and up to 5 months after starting Enasidenib. 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 Enasidenib:

• Fever
• Cough
• Shortness of Breath
• Swelling of Arms and Legs
• Swelling Around Neck, Groin, Or Underarm Area
• Fast Weight Gain
• Bone Pain

Pregnancy: Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on Enasidenib 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. 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.

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 and for at least 1 month after the last dose.

Differentiation Syndrome: In the clinical trial, 14% of patients treated with Enasidenib 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 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 initiation.

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

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

Geriatric Use: No dosage adjustment is required for Enasidenib 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.

Cytotoxic Chemotherapy

Store below 30°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.